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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Kleefstra Syndrome - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
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<meta name="citation_title" content="Kleefstra Syndrome">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2023/01/26">
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<meta name="citation_author" content="Tjitske Kleefstra">
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<meta name="citation_author" content="Nicole de Leeuw">
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<meta name="citation_keywords" content="9q34.3 Microdeletion Syndrome">
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<meta name="citation_keywords" content="9qSTDS">
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<meta name="citation_keywords" content="9q Subtelomeric Deletion Syndrome">
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<meta name="citation_keywords" content="9q Subtelomeric Deletion Syndrome">
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<meta name="citation_keywords" content="9qSTDS">
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<meta name="citation_keywords" content="9q34.3 Microdeletion Syndrome">
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<meta name="citation_keywords" content="Histone-lysine N-methyltransferase EHMT1">
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<meta name="citation_keywords" content="EHMT1">
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<meta name="citation_keywords" content="Kleefstra Syndrome">
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<meta name="DC.Title" content="Kleefstra Syndrome">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Tjitske Kleefstra">
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<meta name="DC.Contributor" content="Nicole de Leeuw">
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<meta name="description" content="Kleefstra syndrome is characterized by intellectual disability, autistic-like features, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate-to-severe spectrum of intellectual disability although a few individuals have mild delay and total IQ within low-normal range. While most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed; these include heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy / febrile seizures, psychiatric disorders, and extreme apathy or catatonic-like features after puberty.">
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<meta name="og:description" content="Kleefstra syndrome is characterized by intellectual disability, autistic-like features, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate-to-severe spectrum of intellectual disability although a few individuals have mild delay and total IQ within low-normal range. While most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed; these include heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy / febrile seizures, psychiatric disorders, and extreme apathy or catatonic-like features after puberty.">
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class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK47079_"><span class="title" itemprop="name">Kleefstra Syndrome</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: 9q34.3 Microdeletion Syndrome, 9qSTDS, 9q Subtelomeric Deletion Syndrome</div><p class="contribs">Kleefstra T, de Leeuw N.</p><p class="fm-aai"><a href="#_NBK47079_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 23 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="kleefstra.Summary" itemprop="description"><h2 id="_kleefstra_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Kleefstra syndrome is characterized by intellectual disability, autistic-like features, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate-to-severe spectrum of intellectual disability although a few individuals have mild delay and total IQ within low-normal range. While most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed; these include heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy / febrile seizures, psychiatric disorders, and extreme apathy or catatonic-like features after puberty.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of Kleefstra syndrome is established in a proband who has a heterozygous deletion at chromosome 9q34.3 that includes at least part of <i>EHMT1</i> (~50%) or a heterozygous intragenic <i>EHMT1</i> pathogenic variant (~50%).</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Ongoing routine care by a multidisciplinary team specializing in the care of children or adults with intellectual disability. Referral to age-appropriate early-childhood intervention programs, special education programs, or vocational training; speech-language therapy, physical and occupational therapy, and sensory integration therapy; specialized care for those with extreme behavior issues, movement disorders, sleep disorders, and/or epilepsy; standard treatment for vision, hearing, cardiac, renal, urologic, and other medical issues.</p><p><i>Surveillance:</i> Monitoring as needed of cardiac and renal/urologic abnormalities.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Kleefstra syndrome, caused by a deletion at 9q34.3 or pathogenic variants in <i>EHMT1</i>, is inherited in an autosomal dominant manner. Almost all cases reported to date have been <i>de novo</i>; rarely, recurrence in a family has been reported when a parent has a balanced translocation involving the 9q34.3 region or somatic mosaicism for an interstitial 9q34.3 deletion. Except for individuals with somatic mosaicism for a 9q34.3 deletion, no individuals with Kleefstra syndrome have been known to reproduce. Prenatal testing may be offered to unaffected parents of a child with a 9q34.3 deletion or an <i>EHMT1</i> pathogenic variant because of the increased risk of recurrence associated with the possibility of germline mosaicism, somatic mosaicism including the germline, or a balanced chromosome translocation.</p></div></div><div id="kleefstra.Diagnosis"><h2 id="_kleefstra_Diagnosis_">Diagnosis</h2><p>Kleefstra syndrome is characterized by intellectual disability, childhood hypotonia, and distinctive facial features. A complex pattern of other findings can also be observed [<a class="bibr" href="#kleefstra.REF.dawson.2002.488" rid="kleefstra.REF.dawson.2002.488">Dawson et al 2002</a>, <a class="bibr" href="#kleefstra.REF.cormierdaire.2003.300" rid="kleefstra.REF.cormierdaire.2003.300">Cormier-Daire et al 2003</a>, <a class="bibr" href="#kleefstra.REF.stewart.2004.340" rid="kleefstra.REF.stewart.2004.340">Stewart et al 2004</a>, <a class="bibr" href="#kleefstra.REF.kleefstra.2005.299" rid="kleefstra.REF.kleefstra.2005.299">Kleefstra et al 2005</a>, <a class="bibr" href="#kleefstra.REF.yatsenko.2005.328" rid="kleefstra.REF.yatsenko.2005.328">Yatsenko et al 2005</a>, <a class="bibr" href="#kleefstra.REF.kleefstra.2006a.370" rid="kleefstra.REF.kleefstra.2006a.370">Kleefstra et al 2006a</a>, <a class="bibr" href="#kleefstra.REF.kleefstra.2006b.618" rid="kleefstra.REF.kleefstra.2006b.618">Kleefstra et al 2006b</a>, <a class="bibr" href="#kleefstra.REF.stewart.2007.383" rid="kleefstra.REF.stewart.2007.383">Stewart & Kleefstra 2007</a>, <a class="bibr" href="#kleefstra.REF.kleefstra.2009.598" rid="kleefstra.REF.kleefstra.2009.598">Kleefstra et al 2009</a>, <a class="bibr" href="#kleefstra.REF.yatsenko.2009.1924" rid="kleefstra.REF.yatsenko.2009.1924">Yatsenko et al 2009</a>, <a class="bibr" href="#kleefstra.REF.willemsen.2012.202" rid="kleefstra.REF.willemsen.2012.202">Willemsen et al 2012</a>].</p><div id="kleefstra.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Kleefstra syndrome <b>should be suspected</b> in individuals with the following:</p><ul><li class="half_rhythm"><div>Intellectual disability, usually moderate to severe and associated with severe speech delay</div></li><li class="half_rhythm"><div>Distinctive facial features (See <a href="#kleefstra.Clinical_Description">Clinical Description</a>.)</div></li><li class="half_rhythm"><div>Childhood hypotonia</div></li><li class="half_rhythm"><div>Visual issues (hypermetropia)</div></li><li class="half_rhythm"><div>Hearing loss (sensorineural and/or conductive)</div></li><li class="half_rhythm"><div>Motor delay</div></li><li class="half_rhythm"><div>Heart defects</div></li><li class="half_rhythm"><div>Renal/urologic defects</div></li><li class="half_rhythm"><div>Genital defects (males)</div></li><li class="half_rhythm"><div>Severe infections (respiratory)</div></li><li class="half_rhythm"><div>Epilepsy / febrile seizures</div></li><li class="half_rhythm"><div>Autism spectrum disorder</div></li><li class="half_rhythm"><div>Psychiatric disorders (mood and psychotic disorders)</div></li><li class="half_rhythm"><div>Extreme apathy or catatonic(-like) features post puberty</div></li><li class="half_rhythm"><div>Nonspecific brain abnormalities: structural defects (corpus callosum hypoplasia), cortical hypoplasia, or white matter defects</div></li></ul></div><div id="kleefstra.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of Kleefstra syndrome <b>is established</b> in a proband who has one of the following on molecular genetic testing (see <a href="/books/NBK47079/table/kleefstra.T.molecular_genetic_testing_us/?report=objectonly" target="object" rid-ob="figobkleefstraTmoleculargenetictestingus">Table 1</a>):</p><ul><li class="half_rhythm"><div>A heterozygous deletion of 9q34.3 (~50% of affected individuals) [Author, personal experience]. In 28 unrelated individuals with a 9q34.3 deletion, three distinct categories were identified [<a class="bibr" href="#kleefstra.REF.yatsenko.2009.1924" rid="kleefstra.REF.yatsenko.2009.1924">Yatsenko et al 2009</a>]:</div><ul><li class="half_rhythm"><div>50% bona fide <i>de novo</i> terminal deletions</div></li><li class="half_rhythm"><div>25% interstitial deletions</div></li><li class="half_rhythm"><div>25% complex rearrangements or derivative chromosomes</div></li></ul></li><li class="half_rhythm"><div>A heterozygous pathogenic (or likely pathogenic) variant involving <i>EHMT1</i> (~50% of affected individuals)</div></li></ul><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [<a class="bibr" href="#kleefstra.REF.richards.2015.405" rid="kleefstra.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous <i>EHMT1</i> variant of uncertain significance does not establish or rule out the diagnosis.</p><p>When the phenotypic findings suggest the diagnosis of Kleefstra syndrome, molecular genetic testing approaches can include <b>chromosomal microarray analysis (CMA)</b>, <b>single-gene testing</b>, use of a <b>multigene panel</b>, and rarely <b>karyotype</b>.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Chromosomal microarray analysis (CMA)</b> uses SNP and/or oligonucleotide arrays to detect genome-wide large deletions/duplications (including <i>EHMT1</i>) that cannot be detected by typical sequence analysis.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Single-gene testing.</b> Sequence analysis of <i>EHMT1</i> detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.</div><div class="half_rhythm">Approximately 5% of individuals with Kleefstra syndrome have an intragenic deletion detectable by an assay designed to detect single-exon deletions or duplications (e.g., multiplex ligation-dependent probe amplification [MLPA], qPCR, and gene-targeted CMA). Deletions that are not intragenic but too small to be detected by CMA (e.g., containing the last part of <i>C90RF37</i> and the first exon of <i>EHMT1</i>) require such gene-targeted methods designed for this region for detection.</div><div class="half_rhythm">Note: (1) FISH cannot reliably detect deletions <50-100 kb and cannot routinely size the deletion. (2) The 9q34.3 deletion cannot be identified by routine chromosome analysis.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>An intellectual disability multigene panel</b> that includes <i>EHMT1</i> and other genes of interest (see <a href="#kleefstra.Differential_Diagnosis">Differential Diagnosis</a>) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see <a href="/books/NBK47079/table/kleefstra.T.molecular_genetic_testing_us/?report=objectonly" target="object" rid-ob="figobkleefstraTmoleculargenetictestingus">Table 1</a>).</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Karyotype.</b> In rare instances, Kleefstra syndrome can be caused by a balanced chromosome rearrangement that disrupts the expression of <i>EHMT1</i>. If this is suspected, karyotype and FISH analysis for the 9q34.3 region can be considered. However, the typical 9q34.3 deletion cannot be identified by routine chromosome analysis.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Epigenetic signature analysis / methylation array.</b> A distinctive epigenetic signature (disorder-specific genome-wide changes in DNA methylation profiles) in peripheral blood leukocytes has been identified in individuals with Kleefstra syndrome [<a class="bibr" href="#kleefstra.REF.arefeshghi.2020.356" rid="kleefstra.REF.arefeshghi.2020.356">Aref-Eshghi et al 2020</a>, <a class="bibr" href="#kleefstra.REF.goodman.2020.23" rid="kleefstra.REF.goodman.2020.23">Goodman et al 2020</a>, <a class="bibr" href="#kleefstra.REF.levy.2021.100075" rid="kleefstra.REF.levy.2021.100075">Levy et al 2021</a>]. Epigenetic signature analysis of a peripheral blood sample or DNA banked from a blood sample can therefore be considered to clarify the diagnosis in individuals with: (1) <a href="#kleefstra.Suggestive_Findings">suggestive findings</a> of Kleefstra syndrome but in whom no pathogenic variant in <i>EHMT1</i> has been identified via chromosomal microarray or sequence analysis; or (2) <a href="#kleefstra.Suggestive_Findings">suggestive findings</a> of Kleefstra syndrome and a <i>EHMT1</i> variant of uncertain clinical significance identified by molecular genetic testing. For an introduction to epigenetic signature analysis click <a href="/books/n/gene/epigenetics/?report=reader">here</a>.</div><div class="half_rhythm">The epigenetic signature results should not be interpreted in isolation, as sensitivity and specificity are not 100%; these results only provide part of the evidence used in variant interpretation [<a class="bibr" href="#kleefstra.REF.richards.2015.405" rid="kleefstra.REF.richards.2015.405">Richards et al 2015</a>, <a class="bibr" href="#kleefstra.REF.brnich.2019.3" rid="kleefstra.REF.brnich.2019.3">Brnich et al 2019</a>]. Even though no overlap between the Kleefstra syndrome epigenetic signature and those of other genetic disorders has been described to date, it is well known that pathogenic variants in molecularly related genes could have overlapping epigenetic signatures, resulting in misdiagnosis.</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figkleefstraTmoleculargenetictestingus"><a href="/books/NBK47079/table/kleefstra.T.molecular_genetic_testing_us/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobkleefstraTmoleculargenetictestingus"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="kleefstra.T.molecular_genetic_testing_us"><a href="/books/NBK47079/table/kleefstra.T.molecular_genetic_testing_us/?report=objectonly" target="object" rid-ob="figobkleefstraTmoleculargenetictestingus">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Kleefstra Syndrome </p></div></div></div></div><div id="kleefstra.Clinical_Characteristics"><h2 id="_kleefstra_Clinical_Characteristics_">Clinical Characteristics</h2><div id="kleefstra.Clinical_Description"><h3>Clinical Description</h3><p>Kleefstra syndrome has a clinically recognizable phenotype that includes physical, developmental, and behavioral features. Males and females are affected equally [<a class="bibr" href="#kleefstra.REF.stewart.2004.340" rid="kleefstra.REF.stewart.2004.340">Stewart et al 2004</a>, <a class="bibr" href="#kleefstra.REF.yatsenko.2005.328" rid="kleefstra.REF.yatsenko.2005.328">Yatsenko et al 2005</a>, <a class="bibr" href="#kleefstra.REF.kleefstra.2006b.618" rid="kleefstra.REF.kleefstra.2006b.618">Kleefstra et al 2006b</a>, <a class="bibr" href="#kleefstra.REF.stewart.2007.383" rid="kleefstra.REF.stewart.2007.383">Stewart & Kleefstra 2007</a>, <a class="bibr" href="#kleefstra.REF.kleefstra.2009.598" rid="kleefstra.REF.kleefstra.2009.598">Kleefstra et al 2009</a>, <a class="bibr" href="#kleefstra.REF.willemsen.2012.202" rid="kleefstra.REF.willemsen.2012.202">Willemsen et al 2012</a>].</p><p>Birth weight is usually within the normal or above-normal range; weight increases in childhood, leading to obesity (50%) [<a class="bibr" href="#kleefstra.REF.cormierdaire.2003.300" rid="kleefstra.REF.cormierdaire.2003.300">Cormier-Daire et al 2003</a>, <a class="bibr" href="#kleefstra.REF.kleefstra.2009.598" rid="kleefstra.REF.kleefstra.2009.598">Kleefstra et al 2009</a>, <a class="bibr" href="#kleefstra.REF.willemsen.2012.202" rid="kleefstra.REF.willemsen.2012.202">Willemsen et al 2012</a>]. The facial appearance is characterized by brachy(-micro)cephaly, broad forehead, unusual shape of eyebrows (arched or straight with synophrys), mildly upslanted palpebral fissures, midface retrusion, thickened ear helices, short nose with anteverted nares, fleshy everted vermilion of the lower lip and exaggerated Cupid's bow or "tented" appearance of the vermilion of the upper lip, and protruding tongue and relative prognathism (<a class="figpopup" href="/books/NBK47079/figure/kleefstra.F1/?report=objectonly" target="object" rid-figpopup="figkleefstraF1" rid-ob="figobkleefstraF1">Figure 1</a>, <a class="figpopup" href="/books/NBK47079/figure/kleefstra.F2/?report=objectonly" target="object" rid-figpopup="figkleefstraF2" rid-ob="figobkleefstraF2">Figure 2</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figkleefstraF1" co-legend-rid="figlgndkleefstraF1"><a href="/books/NBK47079/figure/kleefstra.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figkleefstraF1" rid-ob="figobkleefstraF1"><img class="small-thumb" src="/books/NBK47079/bin/kleefstra-Image001.gif" src-large="/books/NBK47079/bin/kleefstra-Image001.jpg" alt="Figure 1. . Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midface retrusion, protruding tongue, eversion of the vermilion of the lower lip, and prognathism of chin." /></a><div class="icnblk_cntnt" id="figlgndkleefstraF1"><h4 id="kleefstra.F1"><a href="/books/NBK47079/figure/kleefstra.F1/?report=objectonly" target="object" rid-ob="figobkleefstraF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midface retrusion, protruding tongue, eversion of the vermilion of the lower lip, and prognathism of <a href="/books/NBK47079/figure/kleefstra.F1/?report=objectonly" target="object" rid-ob="figobkleefstraF1">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figkleefstraF2" co-legend-rid="figlgndkleefstraF2"><a href="/books/NBK47079/figure/kleefstra.F2/?report=objectonly" target="object" title="Figure 2. " class="img_link icnblk_img figpopup" rid-figpopup="figkleefstraF2" rid-ob="figobkleefstraF2"><img class="small-thumb" src="/books/NBK47079/bin/kleefstra-Image002.gif" src-large="/books/NBK47079/bin/kleefstra-Image002.jpg" alt="Figure 2. . Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midface retrusion, protruding tongue, eversion of the vermilion of the lower lip, and prognathism of the chin." /></a><div class="icnblk_cntnt" id="figlgndkleefstraF2"><h4 id="kleefstra.F2"><a href="/books/NBK47079/figure/kleefstra.F2/?report=objectonly" target="object" rid-ob="figobkleefstraF2">Figure 2. </a></h4><p class="float-caption no_bottom_margin">Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midface retrusion, protruding tongue, eversion of the vermilion of the lower lip, and prognathism of <a href="/books/NBK47079/figure/kleefstra.F2/?report=objectonly" target="object" rid-ob="figobkleefstraF2">(more...)</a></p></div></div><p>With age, the facial appearance becomes coarser, with persisting midface retrusion and prognathism. An increased frequency of dental anomalies, specifically neonatal teeth and retention of primary dentition, has been observed.</p><p><b>Cognitive development.</b> Individuals with Kleefstra syndrome exhibit a range of cognitive and adaptive functioning [<a class="bibr" href="#kleefstra.REF.vermeulen.2017a.1821" rid="kleefstra.REF.vermeulen.2017a.1821">Vermeulen et al 2017a</a>]. Most affected individuals function in the moderate-to-severe spectrum of intellectual disability, although a few individuals with only mild delay are known. Rarely, individuals with normal total IQ levels who have a diagnosis of an autism spectrum disorder have been described [<a class="bibr" href="#kleefstra.REF.bock.2016.131" rid="kleefstra.REF.bock.2016.131">Bock et al 2016</a>; Author, personal observation]. Most affected individuals have severe expressive speech delay with hardly any speech development, whereas general language development is usually at a higher level; thus, sign language or use of pictograms is of value to many affected individuals.</p><p><b>Behavior.</b> Besides issues with social behavior, the behavioral phenotype includes sleep disturbances, stereotypies, mild self-injurious behaviors, and autism spectrum disorder usually recognized in early childhood. A few reports of adolescents and adults revealed extreme, progressive apathy and catatonic(-like) behavior [<a class="bibr" href="#kleefstra.REF.verhoeven.2010.536" rid="kleefstra.REF.verhoeven.2010.536">Verhoeven et al 2010</a>, <a class="bibr" href="#kleefstra.REF.vermeulen.2017a.1821" rid="kleefstra.REF.vermeulen.2017a.1821">Vermeulen et al 2017a</a>, <a class="bibr" href="#kleefstra.REF.vermeulen.2017b.185" rid="kleefstra.REF.vermeulen.2017b.185">Vermeulen et al 2017b</a>].</p><ul><li class="half_rhythm"><div>Sleep disturbance is characterized by frequent nocturnal and early-morning awakenings as well as excessive daytime wakefulness – in contrast to the sleep disturbance observed in <a href="/books/n/gene/sms/?report=reader">Smith-Magenis syndrome</a>.</div></li><li class="half_rhythm"><div>Sleep disturbance in affected adolescents and young adults may be a precursor to severe regression, as well as the later development of psychoses, for which treatment is recommended.</div></li></ul><p><b>Motor development</b> is impaired by childhood hypotonia, but almost all individuals achieve independent walking after age two to three years.</p><p><b>Hearing and vision impairment</b>. A substantial proportion of individuals have hypermetropia at a young age. Hearing impairment (both conductive and sensorineuronal) may also be present starting at a young age.</p><p><b>Congenital heart defects</b> are observed in a significant number of individuals with Kleefstra syndrome. In 50% a (conotruncal) heart defect is present. Abnormalities that have been reported include ASD/VSD, tetralogy of Fallot, aortic coarctation, bicuspid aortic valve, and pulmonic stenosis. Atrial flutter has been reported in a number of individuals.</p><p><b>Genitourinary anomalies.</b> Renal defects, seen in 10%-30% of affected individuals, comprise vesicoureteral reflux, hydronephrosis, renal cysts, and chronic renal insufficiency. Genital defects such as hypospadias, cryptorchidism, and small penis are reported in 30% of males.</p><p><b>Seizures,</b> reported in 30%, can include tonic-clonic seizures, absence seizures, and complex partial epilepsy.</p><p><b>Other.</b> Several affected individuals have had talipes equinovarus. Other abnormalities that have been observed are epigastric hernia, tracheo-/bronchomalacia with respiratory insufficiency, and gastroesophageal reflux.</p><p><b>Life expectancy.</b> Longitudinal data are insufficient to determine life expectancy; however, it should be noted that death in infancy or childhood can occur from complications such as heart defects and recurrent aspiration and pulmonary infections [<a class="bibr" href="#kleefstra.REF.stewart.2007.383" rid="kleefstra.REF.stewart.2007.383">Stewart & Kleefstra 2007</a>].</p></div><div id="kleefstra.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p><i>EHMT1</i> loss of function accounts for the majority of features in Kleefstra syndrome. Current data indicate that individuals with an intragenic <i>EHMT1</i> pathogenic variant (e.g., a missense, frameshift, or nonsense variant) and those with a small (<1-Mb) 9q34.3 deletion have similar clinical findings. Individuals with larger deletions (≥1 Mb), however, generally have more severe intellectual disability and more medical problems, such as congenital anomalies, feeding issues, and respiratory issues. Pulmonary infections and aspiration difficulties in particular appear to be more severe in individuals with larger 9q34 deletions than in those with smaller deletions or intragenic <i>EHMT1</i> pathogenic variants.</p></div><div id="kleefstra.Nomenclature"><h3>Nomenclature</h3><p>The disorder was first recognized following widespread subtelomeric FISH studies [<a class="bibr" href="#kleefstra.REF.knight.1999.1676" rid="kleefstra.REF.knight.1999.1676">Knight et al 1999</a>, <a class="bibr" href="#kleefstra.REF.dawson.2002.488" rid="kleefstra.REF.dawson.2002.488">Dawson et al 2002</a>]. After the identification of an individual with a similar phenotype and a <i>de novo</i> balanced translocation disrupting <i>EHMT1</i>, it was hypothesized that haploinsufficiency of this gene caused the phenotype present in individuals with a 9q34 deletion [<a class="bibr" href="#kleefstra.REF.kleefstra.2005.299" rid="kleefstra.REF.kleefstra.2005.299">Kleefstra et al 2005</a>]. Subsequent identification of additional individuals with intragenic <i>EHMT1</i> defects led OMIM to assign the name Kleefstra to the syndrome.</p></div><div id="kleefstra.Prevalence"><h3>Prevalence</h3><p>Based on incidence estimates of <i>de novo</i> variants in neurodevelopmental disorders together with data from other rare disorders, Kleefstra syndrome is estimated to affect 1:25,000 to 1:35,000 individuals [<a class="bibr" href="#kleefstra.REF.mcrae.2017.433" rid="kleefstra.REF.mcrae.2017.433">McRae et al 2017</a>; <a class="bibr" href="#kleefstra.REF.l_pezrivera.2020.1099" rid="kleefstra.REF.l_pezrivera.2020.1099">López-Rivera et al 2020</a>; Author, personal observation]. The actual prevalence of Kleefstra syndrome may be higher as many individuals are not diagnosed.</p></div></div><div id="kleefstra.Genetically_Related_Allelic_Di"><h2 id="_kleefstra_Genetically_Related_Allelic_Di_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with deletion in the genes located within the 9q34.3 critical region or with pathogenic variants in <i>EHMT1</i>.</p></div><div id="kleefstra.Differential_Diagnosis"><h2 id="_kleefstra_Differential_Diagnosis_">Differential Diagnosis</h2><p>Kleefstra syndrome should be distinguished from other syndromes that include developmental delay, infantile hypotonia, short stature, distinctive facies, and a behavioral phenotype. The most common of these include those in <a href="/books/NBK47079/table/kleefstra.T.disorders_to_consider_in_the/?report=objectonly" target="object" rid-ob="figobkleefstraTdisorderstoconsiderinthe">Table 2</a>, which can be distinguished using cytogenetic (FISH) and/or molecular analysis.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figkleefstraTdisorderstoconsiderinthe"><a href="/books/NBK47079/table/kleefstra.T.disorders_to_consider_in_the/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobkleefstraTdisorderstoconsiderinthe"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="kleefstra.T.disorders_to_consider_in_the"><a href="/books/NBK47079/table/kleefstra.T.disorders_to_consider_in_the/?report=objectonly" target="object" rid-ob="figobkleefstraTdisorderstoconsiderinthe">Table 2. </a></h4><p class="float-caption no_bottom_margin">Disorders to Consider in the Differential Diagnosis of Kleefstra Syndrome </p></div></div></div><div id="kleefstra.Management"><h2 id="_kleefstra_Management_">Management</h2><div id="kleefstra.Evaluations_Following_Initial"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with Kleefstra syndrome, the evaluations summarized in <a href="/books/NBK47079/table/kleefstra.T.recommended_evaluations_foll/?report=objectonly" target="object" rid-ob="figobkleefstraTrecommendedevaluationsfoll">Table 3</a> (if not performed as part of the evaluation that led to diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figkleefstraTrecommendedevaluationsfoll"><a href="/books/NBK47079/table/kleefstra.T.recommended_evaluations_foll/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobkleefstraTrecommendedevaluationsfoll"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="kleefstra.T.recommended_evaluations_foll"><a href="/books/NBK47079/table/kleefstra.T.recommended_evaluations_foll/?report=objectonly" target="object" rid-ob="figobkleefstraTrecommendedevaluationsfoll">Table 3. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with Kleefstra Syndrome </p></div></div></div><div id="kleefstra.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Treatment is primarily supportive. Ongoing routine pediatric care by a pediatrician or neurologist, psychiatrist, and/or (for adults) specialist in the care of adults with intellectual disability is recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figkleefstraTtreatmentofmanifestations"><a href="/books/NBK47079/table/kleefstra.T.treatment_of_manifestations/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobkleefstraTtreatmentofmanifestations"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="kleefstra.T.treatment_of_manifestations"><a href="/books/NBK47079/table/kleefstra.T.treatment_of_manifestations/?report=objectonly" target="object" rid-ob="figobkleefstraTtreatmentofmanifestations">Table 4. </a></h4><p class="float-caption no_bottom_margin">Treatment of Manifestations in Individuals with Kleefstra Syndrome </p></div></div><div id="kleefstra.Developmental_Delay__Intellect"><h4>Developmental Delay / Intellectual Disability Management Issues</h4><p>The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.</p><p><b>Ages 0-3 years.</b> Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.</p><p>
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<b>Ages 5-21 years</b>
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</p><ul><li class="half_rhythm"><div>In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.</div></li><li class="half_rhythm"><div>Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.</div></li></ul><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.</p><p>Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</p><p>In the US:</p><ul><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div><div id="kleefstra.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p>
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<b>Gross motor dysfunction</b>
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</p><ul><li class="half_rhythm"><div>Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).</div></li><li class="half_rhythm"><div>Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).</div></li><li class="half_rhythm"><div>For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox<sup>®</sup>, anti-parkinsonian medications, or orthopedic procedures.</div></li></ul><p><b>Fine motor dysfunction.</b> Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.</p><p><b>Oral motor dysfunction.</b> Assuming that the individual is safe to eat by mouth, feeding therapy – typically from an occupational or speech therapist – is recommended for affected individuals who have difficulty feeding as a result of poor oral motor control.</p><p><b>Communication issues.</b> Consider evaluation for alternative means of communication (e.g., <a href="https://www.asha.org/NJC/AAC/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">augmentative and alternative communication</a> [AAC]) for individuals who have expressive language difficulties.</p></div><div id="kleefstra.SocialBehavioral_Concerns"><h4>Social/Behavioral Concerns</h4><p>Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.</p><p>Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.</p><p>Specialized neurologic and psychiatric care is advised for individuals with extreme behavior issues and/or movement disorder. Behavioral therapies include special education techniques that may help minimize behavioral outbursts in the school setting by emphasizing individualized instruction, structure, and a set daily routine.</p></div></div><div id="kleefstra.Surveillance"><h3>Surveillance</h3><p>Cardiac and renal/urologic abnormalities should be monitored as needed.</p></div><div id="kleefstra.Evaluation_of_Relatives_at_Ris"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#kleefstra.Related_Genetic_Counseling_Iss">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="kleefstra.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="kleefstra.Genetic_Counseling"><h2 id="_kleefstra_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="kleefstra.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Kleefstra syndrome, caused by a deletion at 9q34.3 or an intragenic <i>EHMT1</i> pathogenic variant, is inherited in an autosomal dominant manner; almost all cases reported to date have been <i>de novo</i>.</p></div><div id="kleefstra.Risk_to_Family_Members"><h3>Risk to Family Members</h3><div id="kleefstra.9q34_3_Deletion"><h4>9q34.3 Deletion</h4><p>9q34.3 deletion is usually <i>de novo</i> but may be inherited as the result of a complex chromosomal rearrangement or mosaicism in a parent.</p><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>To date, no parent-to-child transmission of an unbalanced derivative chromosome involving the 9q34.3 region has been observed.</div></li><li class="half_rhythm"><div>Recurrence in families with a parent having a balanced translocation involving the 9q34.3 region has been described [<a class="bibr" href="#kleefstra.REF.knight.1999.1676" rid="kleefstra.REF.knight.1999.1676">Knight et al 1999</a>, <a class="bibr" href="#kleefstra.REF.dawson.2002.488" rid="kleefstra.REF.dawson.2002.488">Dawson et al 2002</a>].</div></li><li class="half_rhythm"><div>To date, all interstitial 9q34.3 deletions detected are <i>de novo</i>, except for three families in which one of the parents was shown to have a somatic mosaic deletion. In one family, a parent with learning difficulties had two severely affected children; in another family, a parent with learning difficulties had one affected child [<a class="bibr" href="#kleefstra.REF.willemsen.2011.31" rid="kleefstra.REF.willemsen.2011.31">Willemsen et al 2011</a>, <a class="bibr" href="#kleefstra.REF.de_boer.2018.5" rid="kleefstra.REF.de_boer.2018.5">de Boer et al 2018</a>].</div></li><li class="half_rhythm"><div>Recommendations for the evaluation of asymptomatic parents of a proband with a 9q34.3 deletion include routine karyotyping with additional FISH analysis to determine if a balanced chromosome rearrangement involving the 9q34.3 region is present.</div></li></ul><p>
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<b>Sibs of a proband</b>
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</p><ul><li class="half_rhythm"><div>The risk to the sibs of the proband depends on the genetic status of the parents.</div></li><li class="half_rhythm"><div>In the (unlikely) event that a parent has either germline mosaicism for a 9q34.3 deletion, low-level somatic mosaicism that includes the germline, or a balanced structural chromosome rearrangement involving the 9q34.3 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.</div></li></ul><p>
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<b>Offspring of a proband</b>
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</p><ul><li class="half_rhythm"><div>To date, five individuals diagnosed with a mosaic 9q34.3 deletion have been known to reproduce [<a class="bibr" href="#kleefstra.REF.willemsen.2011.31" rid="kleefstra.REF.willemsen.2011.31">Willemsen et al 2011</a>, <a class="bibr" href="#kleefstra.REF.de_boer.2018.5" rid="kleefstra.REF.de_boer.2018.5">de Boer et al 2018</a>].</div></li><li class="half_rhythm"><div>Individuals who have the 9q34.3 deletion would be expected to have a 50% chance of transmitting the deletion to each child.</div></li></ul></div><div id="kleefstra.EHMT1_Pathogenic_Variant"><h4><i>EHMT1</i> Pathogenic Variant</h4><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>In the vast majority of cases, <i>EHMT1</i> pathogenic variants have occurred <i>de novo</i>. All affected individuals represent simplex cases (i.e., a single occurrence in the family).</div></li><li class="half_rhythm"><div>To date, only one parent of an individual with an <i>EHMT1</i> pathogenic variant has also had the pathogenic variant, although it was a mosaic pathogenic variant in an unaffected parent [<a class="bibr" href="#kleefstra.REF.rump.2013.887" rid="kleefstra.REF.rump.2013.887">Rump et al 2013</a>].</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a proband with an apparent <i>de novo</i> pathogenic variant.</div></li><li class="half_rhythm"><div>If the <i>EHMT1</i> pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred <i>de novo</i> in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with germline mosaicism [<a class="bibr" href="#kleefstra.REF.rump.2013.887" rid="kleefstra.REF.rump.2013.887">Rump et al 2013</a>].</div></li></ul><p>
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<b>Sibs of a proband</b>
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</p><ul><li class="half_rhythm"><div>The risk to the sibs of the proband depends on the genetic status of the parents.</div></li><li class="half_rhythm"><div>In the (unlikely) event that a parent has germline mosaicism or low-level somatic mosaicism for an <i>EHMT1</i> pathogenic variant that also includes the germline, the risk to sibs is increased.</div></li></ul><p>
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<b>Offspring of a proband</b>
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</p><ul><li class="half_rhythm"><div>No individual with a non-mosaic <i>EHMT1</i> pathogenic variant has been known to reproduce.</div></li><li class="half_rhythm"><div>Individuals who have a non-mosaic <i>EHMT1</i> pathogenic variant would be expected to have a 50% chance of transmitting the pathogenic variant to each child.</div></li></ul></div></div><div id="kleefstra.Related_Genetic_Counseling_Iss"><h3>Related Genetic Counseling Issues</h3><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who may be at risk of having a child with Kleefstra syndrome.</div></li></ul></div><div id="kleefstra.Prenatal_Testing_and_Preimplan"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Prenatal testing for at-risk pregnancies and preimplantation genetic testing require prior identification of the 9q34.3 deletion or an <i>EHMT1</i> pathogenic variant in the proband and/or of balanced carrier status in a parent. Prenatal testing may be offered to unaffected parents who have had a child with a 9q34.3 deletion or an <i>EHMT1</i> pathogenic variant because of the recurrence risk associated with the possibility of germline mosaicism, somatic mosaicism including the germline, or a balanced chromosome translocation.</p><p><b>Pregnancies not known to be at increased risk for the 9q34.3 deletion.</b> CMA performed in a pregnancy not known to be at increased risk may detect the 9q34.3 deletion [<a class="bibr" href="#kleefstra.REF.guterman.2018.570" rid="kleefstra.REF.guterman.2018.570">Guterman et al 2018</a>].</p></div></div><div id="kleefstra.Resources"><h2 id="_kleefstra_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>Chromosome Disorder Outreach Inc.</b>
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</div><div><b>Phone:</b> 561-395-4252</div><div><b>Email:</b> info@chromodisorder.org</div><div>
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<a href="http://www.chromodisorder.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">chromodisorder.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Unique: Understanding Rare Chromosome and Gene Disorders</b>
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</div><div>United Kingdom</div><div><b>Phone:</b> +44 (0) 1883 723356</div><div><b>Email:</b> info@rarechromo.org</div><div>
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<a href="http://www.rarechromo.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rarechromo.org</a>
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</div></li></ul>
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</div><div id="kleefstra.Molecular_Genetics"><h2 id="_kleefstra_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figkleefstramolgenTA"><a href="/books/NBK47079/table/kleefstra.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobkleefstramolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="kleefstra.molgen.TA"><a href="/books/NBK47079/table/kleefstra.molgen.TA/?report=objectonly" target="object" rid-ob="figobkleefstramolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Kleefstra Syndrome: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figkleefstramolgenTB"><a href="/books/NBK47079/table/kleefstra.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobkleefstramolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="kleefstra.molgen.TB"><a href="/books/NBK47079/table/kleefstra.molgen.TB/?report=objectonly" target="object" rid-ob="figobkleefstramolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Kleefstra Syndrome (View All in OMIM) </p></div></div><p><b>Gene structure.</b> The previously defined <i>EHMT1</i> transcript (<a href="https://www.ncbi.nlm.nih.gov/nuccore/40217807" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_024757.3</a>) contained 26 exons, the translation start site being located in exon 2. The "updated" <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_024757.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_024757.4</a> version varies significantly and contains an extra 5' exon. The novel open reading frame comprises 27 coding exons. The translation start site is located in the "novel" exon 1, 97.6 kb proximal to the "old" ATG start codon. Diagnostic testing so far has been directed towards the 25 coding exons of the <i>EHMT1</i> NM_024757.3 sequence. Since three individuals with Kleefstra syndrome harbor interstitial 9q deletions encompassing only this novel <i>EHMT1</i> sequence in addition to several proximally located genes [Author, personal observation], routine diagnostic testing should be adjusted to the novel transcript. For a detailed summary of gene and protein information, see <a href="/books/NBK47079/?report=reader#kleefstra.molgen.TA">Table A</a>, <b>Gene</b>.</p><p><b>Pathogenic variants.</b>
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<i>EHMT1</i> sequence variants include nonsense, splice site, and missense variants and small deletions and duplications [<a class="bibr" href="#kleefstra.REF.kleefstra.2006a.370" rid="kleefstra.REF.kleefstra.2006a.370">Kleefstra et al 2006a</a>, <a class="bibr" href="#kleefstra.REF.kleefstra.2009.598" rid="kleefstra.REF.kleefstra.2009.598">Kleefstra et al 2009</a>, <a class="bibr" href="#kleefstra.REF.willemsen.2012.202" rid="kleefstra.REF.willemsen.2012.202">Willemsen et al 2012</a>].</p><p><b>Normal gene product.</b> The <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_024757.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_024757.4</a> transcript encodes euchromatin histone-lysine N-methyl transferase 1, a protein of 1,298 amino acid residues involved in histone methylation. DNA is wrapped around histones, and histone tails have an important role in folding of chromatin fibers. Methylation of these histone tails is thought to regulate this folding process, thereby altering the accessibility of DNA to proteins mediating transcription [<a class="bibr" href="#kleefstra.REF.martin.2005.838" rid="kleefstra.REF.martin.2005.838">Martin & Zhang 2005</a>]. The restricted expression of <i>EHMT1</i> in the mouse brain (olfactory bulb, the anterior/ventral ventricular wall, hippocampus, and piriform cortex) supports a role of epigenetic histone modification in normal brain development [<a class="bibr" href="#kleefstra.REF.kleefstra.2005.299" rid="kleefstra.REF.kleefstra.2005.299">Kleefstra et al 2005</a>].</p><p><b>Abnormal gene product.</b> Haploinsufficiency resulting from deletion or inactivation of one <i>EHMT1</i> allele is the cause of Kleefstra syndrome. The majority of pathogenic variants disrupt the open reading frame of <i>EHMT1</i> and are predicted to lead to nonsense-mediated decay. The one pathogenic missense variant described to date is predicted to have an influence on the local conformation of the pre-SET domain of the EHMT1 protein, thereby reflecting a null allele [<a class="bibr" href="#kleefstra.REF.kleefstra.2009.598" rid="kleefstra.REF.kleefstra.2009.598">Kleefstra et al 2009</a>]. Besides <i>EHMT1</i>, other genes associated with intellectual disability (e.g., <i>MECP2</i>, <i>RSK2</i>, and <i>XNP</i>) appear to play a role in chromatin remodeling [<a class="bibr" href="#kleefstra.REF.ausi_.2003.83" rid="kleefstra.REF.ausi_.2003.83">Ausió et al 2003</a>]. Loss of proper regulation of chromatin structure can result in deregulation of gene transcription and inappropriate protein expression. This can in turn contribute to complex genetic disorders including intellectual disability.</p></div><div id="kleefstra.Chapter_Notes"><h2 id="_kleefstra_Chapter_Notes_">Chapter Notes</h2><div id="kleefstra.Author_History"><h3>Author History</h3><p>Nicole de Leeuw, PhD (2019-present)<br />Tjitske Kleefstra, MD, PhD (2010-present)<br />Willy M Nillesen, BSc; Radboud University Medical Center (2010-2019)<br />Helger G Yntema, PhD; Radboud University Medical Center (2010-2019)</p></div><div id="kleefstra.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>26 January 2023 (tk) Revision: <a href="#kleefstra.Prevalence">prevalence</a> updated</div></li><li class="half_rhythm"><div>13 October 2022 (sw) Revision: epigenetic signature analysis (<a href="#kleefstra.Establishing_the_Diagnosis">Establishing the Diagnosis</a>)</div></li><li class="half_rhythm"><div>21 March 2019 (ma) Comprehensive update posted live</div></li><li class="half_rhythm"><div>7 May 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>5 October 2010 (me) Review posted live</div></li><li class="half_rhythm"><div>28 May 2010 (tk) Original submission</div></li></ul></div></div><div id="kleefstra.References"><h2 id="_kleefstra_References_">References</h2><div id="kleefstra.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="kleefstra.REF.arefeshghi.2020.356">Aref-Eshghi E, Kerkhof J, Pedro VP, Groupe DI. France, Barat-Houari M, Ruiz-Pallares N, Andrau JC, Lacombe D, Van-Gils J, Fergelot P, Dubourg C, Cormier-Daire V, Rondeau S, Lecoquierre F, Saugier-Veber P, Nicolas G, Lesca G, Chatron N, Sanlaville D, Vitobello A, Faivre L, Thauvin-Robinet C, Laumonnier F, Raynaud M, Alders M, Mannens M, Henneman P, Hennekam RC, Velasco G, Francastel C, Ulveling D, Ciolfi A, Pizzi S, Tartaglia M, Heide S, Héron D, Mignot C, Keren B, Whalen S, Afenjar A, Bienvenu T, Campeau PM, Rousseau J, Levy MA, Brick L, Kozenko M, Balci TB, Siu VM, Stuart A, Kadour M, Masters J, Takano K, Kleefstra T, de Leeuw N, Field M, Shaw M, Gecz J, Ainsworth PJ, Lin H, Rodenhiser DI, Friez MJ, Tedder M, Lee JA, DuPont BR, Stevenson RE, Skinner SA, Schwartz CE, Genevieve D, Sadikovic B. Evaluation of dna methylation episignatures for diagnosis and phenotype correlations in 42 mendelian neurodevelopmental disorders. <span><span class="ref-journal">Am J Hum Genet. </span>2020;<span class="ref-vol">106</span>:356–70.</span> [<a href="/pmc/articles/PMC7058829/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7058829</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32109418" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32109418</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kleefstra.REF.ausi_.2003.83">Ausió J, Levin DB, de Amorim GV, Bakker S, MacLeod PM. Syndromes of disordered chromatin remodeling. <span><span class="ref-journal">Clin Genet. </span>2003;<span class="ref-vol">64</span>:83–95.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12859401" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12859401</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kleefstra.REF.bock.2016.131">Bock I, Németh K, Pentelényi K, Balicza P, Balázs A, Molnár MJ, Román V, Nagy J, Lévay G, Kobolák J, Dinnyés A. 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Behavioral phenotype in the 9q subtelomeric deletion syndrome: a report about two adult patients. <span><span class="ref-journal">Am J Med Genet B Neuropsychiatr Genet. </span>2010;<span class="ref-vol">153B</span>:536–41.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19642112" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19642112</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kleefstra.REF.vermeulen.2017a.1821">Vermeulen K, de Boer A, Janzing JGE, Koolen DA, Ockeloen CW, Willemsen MH, Verhoef FM, van Deurzen PAM, van Dongen L, van Bokhoven H, Egger JIM, Staal WG, Kleefstra T. Adaptive and maladaptive functioning in Kleefstra syndrome compared to other rare genetic disorders with intellectual disabilities. <span><span class="ref-journal">Am J Med Genet A. </span>2017a;<span class="ref-vol">173</span>:1821–30.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28498556" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28498556</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kleefstra.REF.vermeulen.2017b.185">Vermeulen K, Staal WG, Janzing JG, van Bokhoven H, Egger JIM, Kleefstra T. Sleep disturbance as a precursor of severe regression in Kleefstra syndrome suggests a need for firm and rapid pharmacological treatment. <span><span class="ref-journal">Clin Neuropharmacol. </span>2017b;<span class="ref-vol">40</span>:185–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28622207" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28622207</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kleefstra.REF.willemsen.2011.31">Willemsen MH, Beunders G, Callaghan M, de Leeuw N, Nillesen WM, Yntema HG, van Hagen JM, Nieuwint AW, Morrison N, Keijzers-Vloet ST, Hoischen A, Brunner HG, Tolmie J, Kleefstra T. Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions. <span><span class="ref-journal">Clin Genet. </span>2011;<span class="ref-vol">80</span>:31–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21204793" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21204793</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kleefstra.REF.willemsen.2012.202">Willemsen MH, Vulto-van Silfhout AT, Nillesen WM, Wissink-Lindhout WM, van Bokhoven H, Philip N, Berry-Kravis EM, Kini U, van Ravenswaaij-Arts CM, Delle Chiaie B, Innes AM, Houge G, Kosonen T, Cremer K, Fannemel M, Stray-Pedersen A, Reardon W, Ignatius J, Lachlan K, Mircher C, Helderman van den Enden PT, Mastebroek M, Cohn-Hokke PE, Yntema HG, Drunat S, Kleefstra T. Update on Kleefstra syndrome. <span><span class="ref-journal">Mol Syndromol. </span>2012;<span class="ref-vol">2</span>:202–12.</span> [<a href="/pmc/articles/PMC3366700/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3366700</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22670141" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22670141</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kleefstra.REF.yatsenko.2009.1924">Yatsenko SA, Brundage EK, Roney EK, Cheung SW, Chinault AC, Lupski JR. Molecular mechanisms for subtelomeric rearrangements associated with the 9q34.3 microdeletion syndrome. <span><span class="ref-journal">Hum Mol Genet. </span>2009;<span class="ref-vol">18</span>:1924–36.</span> [<a href="/pmc/articles/PMC2678925/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2678925</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19293338" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19293338</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kleefstra.REF.yatsenko.2005.328">Yatsenko SA, Cheung SW, Scott DA, Nowaczyk MJ, Tarnopolsky M, Naidu S, Bibat G, Patel A, Leroy JG, Scaglia F, et al. Deletion 9q34.3 syndrome: genotype-phenotype correlations and an extended deletion in a patient with features of Opitz C trigonocephaly. <span><span class="ref-journal">J Med Genet. </span>2005;<span class="ref-vol">42</span>:328–35.</span> [<a href="/pmc/articles/PMC1736036/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1736036</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15805160" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15805160</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK47079_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Tjitske Kleefstra</span>, MD, PhD<div class="affiliation small">Department of Human Genetics<br />Radboud University Medical Center<br />Nijmegen, the Netherlands<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ln.cmuduobdar@artsfeelk.ekstijt" class="oemail">ln.cmuduobdar@artsfeelk.ekstijt</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Nicole de Leeuw</span>, PhD<div class="affiliation small">Department of Human Genetics<br />Radboud University Medical Center<br />Nijmegen, the Netherlands<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ln.cmuduobdar@wueeled.elocin" class="oemail">ln.cmuduobdar@wueeled.elocin</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">October 5, 2010</span>; Last Revision: <span itemprop="dateModified">January 26, 2023</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Kleefstra T, de Leeuw N. Kleefstra Syndrome. 2010 Oct 5 [Updated 2023 Jan 26]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/kindler/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/mdel17q21_31/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobkleefstraTmoleculargenetictestingus"><div id="kleefstra.T.molecular_genetic_testing_us" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Kleefstra Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47079/table/kleefstra.T.molecular_genetic_testing_us/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__kleefstra.T.molecular_genetic_testing_us_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_kleefstra.T.molecular_genetic_testing_us_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_kleefstra.T.molecular_genetic_testing_us_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_kleefstra.T.molecular_genetic_testing_us_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_kleefstra.T.molecular_genetic_testing_us_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>EHMT1</i>
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</td><td headers="hd_h_kleefstra.T.molecular_genetic_testing_us_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CMA <sup>3</sup></td><td headers="hd_h_kleefstra.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~50% <sup>4</sup></td></tr><tr><td headers="hd_h_kleefstra.T.molecular_genetic_testing_us_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>5</sup></td><td headers="hd_h_kleefstra.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~50%</td></tr><tr><td headers="hd_h_kleefstra.T.molecular_genetic_testing_us_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>6</sup></td><td headers="hd_h_kleefstra.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 7.</td></tr><tr><td headers="hd_h_kleefstra.T.molecular_genetic_testing_us_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Karyotype</td><td headers="hd_h_kleefstra.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare; see footnote 8.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="kleefstra.TF.1.1"><p class="no_margin">See <a href="/books/NBK47079/?report=reader#kleefstra.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="kleefstra.TF.1.2"><p class="no_margin">See <a href="#kleefstra.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="kleefstra.TF.1.3"><p class="no_margin">A chromosomal microarray (CMA) that includes probe coverage of <i>EHMT1</i> can detect deletions of 9q34.3 (<i>de novo</i> terminal deletions, complex rearrangements or derivative chromosomes, interstitial deletion).</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="kleefstra.TF.1.4"><p class="no_margin">CMA testing is appropriate to define breakpoints of large deletions; however, intragenic deletions in <i>EHMT1</i> may not be detected by this method.</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="kleefstra.TF.1.5"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="kleefstra.TF.1.6"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="kleefstra.TF.1.7"><p class="no_margin">Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. Gene-targeted deletion/duplication analysis of <i>EHMT1</i> may detect an additional ~5% of affected individuals who have had a normal chromosomal microarray, but this is highly dependent on the resolution and probe coverage of the array platform that was used for analysis.</p></div></dd></dl><dl class="bkr_refwrap"><dt>8. </dt><dd><div id="kleefstra.TF.1.8"><p class="no_margin">Routine karyotype will not detect the 9q34.3 deletion. Karyotype may be considered in those with features of Kleefstra syndrome in whom a pathogenic variant (mutation or deletion) of <i>EHMT1</i> has not been identified using other methods (e.g., CMA, sequence analysis). Karyotype can detect balanced chromosomal rearrangements that disrupt <i>EHMT1</i>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobkleefstraTdisorderstoconsiderinthe"><div id="kleefstra.T.disorders_to_consider_in_the" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Disorders to Consider in the Differential Diagnosis of Kleefstra Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47079/table/kleefstra.T.disorders_to_consider_in_the/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__kleefstra.T.disorders_to_consider_in_the_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene / Genetic<br />Mechanism</th><th id="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Additional Overlapping Clinical Features</th></tr></thead><tbody><tr><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Down syndrome</td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Trisomy 21</td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Virtually all <i>de novo</i></td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Similar facial characteristics, incl:
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<ul><li class="half_rhythm"><div>Brachycephaly</div></li><li class="half_rhythm"><div>Protruding tongue</div></li><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>Hypertelorism</div></li><li class="half_rhythm"><div>Midface retrusion</div></li></ul>
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</td></tr><tr><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/sms/?report=reader">Smith-Magenis syndrome</a>
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</td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Deletion or mutation of <i>RAI1</i> on chromosome 17p11.2 <sup>1</sup></td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Virtually all <i>de novo</i></td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Lethargy</div></li><li class="half_rhythm"><div>Sleep disturbance</div></li><li class="half_rhythm"><div>Midface retrusion</div></li></ul>
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</td></tr><tr><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/pitt-hopkins/?report=reader">Pitt-Hopkins syndrome</a>
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</td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Haploinsufficiency of <i>TCF4</i></td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Most <i>de novo</i></td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Speech is significantly delayed & most persons are nonverbal w/receptive language often stronger than expressive language.</div></li><li class="half_rhythm"><div>Seizures</div></li><li class="half_rhythm"><div>Sleep disturbance</div></li></ul>
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</td></tr><tr><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/angelman/?report=reader">Angelman syndrome</a>
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</td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disruption of maternally imprinted <i>UBE3A</i></td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 2.</td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Receptive language better than expressive language skills</div></li><li class="half_rhythm"><div>Sleep disturbances w/multiple awakenings</div></li><li class="half_rhythm"><div>Midface retrusion w/prognathism</div></li><li class="half_rhythm"><div>See footnote 3 for distinguishing clinical features.</div></li></ul>
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</td></tr><tr><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>KMT2C</i>-associated syndrome <sup>4</sup></td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>KMT2C</i>
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</td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Currently under study to determine overlap</div></li><li class="half_rhythm"><div>ASD & ID</div></li></ul>
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</td></tr><tr><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/mbd5-dis/?report=reader"><i>MBD5 </i>haploinsufficiency</a>
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</td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 5.</td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD; typically <i>de novo</i></td><td headers="hd_h_kleefstra.T.disorders_to_consider_in_the_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>ASD & ID</div></li><li class="half_rhythm"><div>Seizures</div></li><li class="half_rhythm"><div>Developmental regression</div></li></ul>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; ASD = autism spectrum disorder; ID = intellectual disability; MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="kleefstra.TF.2.1"><p class="no_margin">Approximately 95% of individuals with Smith-Magenis syndrome have the disorder as a result of an interstitial 17p11.2 deletion, which may have been previously excluded by chromosomal microarray testing.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="kleefstra.TF.2.2"><p class="no_margin">The risk to sibs of a proband depends on the genetic mechanism leading to the loss of UBE3A function.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="kleefstra.TF.2.3"><p class="no_margin">Facial features that differentiate Kleefstra syndrome from Angelman syndrome include synophrys and everted vermilion of the lower lip. Some mildly affected individuals with Kleefstra syndrome have a ≥100-word vocabulary & speak in sentences, which would be very unusual in an individual with Angelman syndrome.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="kleefstra.TF.2.4"><p class="no_margin">
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<a class="bibr" href="#kleefstra.REF.koemans.2017.e1006864" rid="kleefstra.REF.koemans.2017.e1006864">Koemans et al [2017]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="kleefstra.TF.2.5"><p class="no_margin">The diagnosis of <i>MBD5</i> haploinsufficiency is established in a proband with one of the following: deletion of 2q23.1 that encompasses all or part of <i>MBD5</i> (~90% of affected individuals); intragenic deletion involving one or more exons of <i>MBD5</i> (~5%); a heterozygous pathogenic sequence variant in <i>MBD5</i> (~5%); or, rarely, an apparently balanced complex chromosome rearrangement of the 2q23.1 region involving <i>MBD5</i>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobkleefstraTrecommendedevaluationsfoll"><div id="kleefstra.T.recommended_evaluations_foll" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Kleefstra Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47079/table/kleefstra.T.recommended_evaluations_foll/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__kleefstra.T.recommended_evaluations_foll_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Constitutional</b>
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</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Weight, height, & body mass index (in those age >2 yrs)</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to nutritionist in those w/obesity.</td></tr><tr><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Dental</b>
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</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dental eval</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for dental issues, incl retention of primary dentition</td></tr><tr><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Eyes</b>
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</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic eval</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for refractive errors</td></tr><tr><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Ears</b>
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</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologic eval</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for hearing loss</td></tr><tr><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cardiovascular</b>
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</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram & EKG</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for structural heart defects & rhythm disturbance; consider referral to cardiologist.</td></tr><tr><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Respiratory</b>
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</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for history of sleep disturbance.</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to sleep disorders clinic.</td></tr><tr><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Gastrointestinal/</b>
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<br />
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<b>Feeding</b>
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</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for signs & symptoms of gastroesophageal reflux disease.</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Genitourinary</b>
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</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Renal ultrasound</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for structural renal anomalies & hydronephrosis</td></tr><tr><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
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</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to neurologist.</td></tr><tr><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">EEG</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If seizures are suspected</td></tr><tr><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Head MRI</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">If seizures &/or mvmt disorder, extreme apathy / catatonia, &/or regression in psychomotor development is present</td></tr><tr><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Psychiatric/</b>
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<br />
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<b>Behavioral</b>
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</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropsychiatric eval</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Persons age >12 mos: screen for behavior concerns incl sleep disturbances, mood issues, psychotic disorders, anxiety, &/or findings suggestive of ASD.</td></tr><tr><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Miscellaneous/</b>
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<br />
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<b>Other</b>
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</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluate motor, speech-language, general cognitive, & vocational skills.</td></tr><tr><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td><td headers="hd_h_kleefstra.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">ASD = autism spectrum disorder</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobkleefstraTtreatmentofmanifestations"><div id="kleefstra.T.treatment_of_manifestations" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Kleefstra Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47079/table/kleefstra.T.treatment_of_manifestations/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__kleefstra.T.treatment_of_manifestations_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Refractive error</b>
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</td><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment</td><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hearing loss</b>
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</td><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Auditory amplification as appropriate</td><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="/books/n/gene/deafness-overview/?report=reader">Hereditary Hearing Loss and Deafness Overview</a>.</td></tr><tr><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Congenital heart defects</b>
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<br />
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<b>& rhythm disturbance</b>
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</td><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per cardiologist</td><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Sleep disturbance</b>
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</td><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment</td><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No well-controlled treatment trials have been reported.</td></tr><tr><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Gastroesophageal reflux</b>
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<br />
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<b>disease</b>
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</td><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment</td><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to gastroenterologist for those w/severe issues.</td></tr><tr><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Renal anomalies</b>
|
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</td><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment</td><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to urologist &/or nephrologist.</td></tr><tr><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Seizures</b>
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</td><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment w/ASM by experienced neurologist <sup>1</sup></td><td headers="hd_h_kleefstra.T.treatment_of_manifestations_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">ASM = anti-seizure medication</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="kleefstra.TF.4.1"><p class="no_margin">Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see <a href="https://www.epilepsy.com/tools-resources/forms-resources#Epilepsy-Foundation-Toolbox" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Epilepsy Foundation Toolbox</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobkleefstramolgenTA"><div id="kleefstra.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Kleefstra Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47079/table/kleefstra.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__kleefstra.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_kleefstra.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_kleefstra.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_kleefstra.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_kleefstra.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_kleefstra.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_kleefstra.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_kleefstra.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/79813" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>EHMT1</i>
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</a>
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</td><td headers="hd_b_kleefstra.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=79813" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">9q34<wbr style="display:inline-block"></wbr>​.3</a>
|
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</td><td headers="hd_b_kleefstra.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="http://www.uniprot.org/uniprot/Q9H9B1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Histone-lysine N-methyltransferase EHMT1</a>
|
|
</td><td headers="hd_b_kleefstra.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="http://databases.lovd.nl/shared/genes/EHMT1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EHMT1 database</a>
|
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</td><td headers="hd_b_kleefstra.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=EHMT1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EHMT1</a>
|
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</td><td headers="hd_b_kleefstra.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=EHMT1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EHMT1</a>
|
|
</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="kleefstra.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
|
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
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chromosome locus from
|
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
|
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
|
<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobkleefstramolgenTB"><div id="kleefstra.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Kleefstra Syndrome (<a href="/omim/607001,610253" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47079/table/kleefstra.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__kleefstra.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<a href="/omim/607001" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">607001</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EUCHROMATIC HISTONE METHYLTRANSFERASE 1; EHMT1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/610253" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">610253</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">KLEEFSTRA SYNDROME 1; KLEFS1</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobkleefstraF1"><div id="kleefstra.F1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK47079/bin/kleefstra-Image001.jpg" alt="Figure 1. . Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midface retrusion, protruding tongue, eversion of the vermilion of the lower lip, and prognathism of chin." /></div><h3><span class="label">Figure 1. </span></h3><div class="caption"><p>Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midface retrusion, protruding tongue, eversion of the vermilion of the lower lip, and prognathism of chin. Five people (AB), (CD), (EF), (GH), and (IJ) with EHMT1 pathogenic variants are shown</p><p>Reproduced from <a class="bibr" href="#kleefstra.REF.kleefstra.2009.598" rid="kleefstra.REF.kleefstra.2009.598">Kleefstra et al [2009]</a> with permission from BMJ Publishing Group Ltd.</p></div></div></article><article data-type="fig" id="figobkleefstraF2"><div id="kleefstra.F2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK47079/bin/kleefstra-Image002.jpg" alt="Figure 2. . Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midface retrusion, protruding tongue, eversion of the vermilion of the lower lip, and prognathism of the chin." /></div><h3><span class="label">Figure 2. </span></h3><div class="caption"><p>Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midface retrusion, protruding tongue, eversion of the vermilion of the lower lip, and prognathism of the chin. Three different people (rows A, B, and C) with interstitial 9q34.3 microdeletions at different ages show evolution with age.</p><p>Reproduced from <a class="bibr" href="#kleefstra.REF.kleefstra.2009.598" rid="kleefstra.REF.kleefstra.2009.598">Kleefstra et al [2009]</a> with permission from BMJ Publishing Group Ltd.</p></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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