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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="El-Hattab-Alkuraya Syndrome" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2022/09/29" /><meta name="citation_author" content="Mohammed Almannai" /><meta name="citation_author" content="Dana Marafi" /><meta name="citation_author" content="Ayman W El-Hattab" /><meta name="citation_pmid" content="36173873" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK584547/" /><meta name="citation_keywords" content="WDR45B-Related Neurodevelopmental Disorder" /><meta name="citation_keywords" content="WDR45B-Related Neurodevelopmental Disorder" /><meta name="citation_keywords" content="WD repeat domain phosphoinositide-interacting protein 3" /><meta name="citation_keywords" content="WDR45B" /><meta name="citation_keywords" content="El-Hattab-Alkuraya Syndrome" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="El-Hattab-Alkuraya Syndrome" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Mohammed Almannai" /><meta name="DC.Contributor" content="Dana Marafi" /><meta name="DC.Contributor" content="Ayman W El-Hattab" /><meta name="DC.Date" content="2022/09/29" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK584547/" /><meta name="description" content="El-Hattab-Alkuraya syndrome is characterized by microcephaly (often early onset and progressive); severe-to-profound developmental delay; refractory and early-onset seizures; spastic quadriplegia with axial hypotonia; and growth deficiency with poor weight gain and short stature. Characteristic findings on brain imaging include cerebral atrophy that is disproportionately most prominent in the frontal lobes; ex vacuo ventricular dilatation with notable posterior horn predominance; brain stem volume loss with flattening of the belly of the pons; and symmetric under-opercularization. Neurologic involvement is progressive, with significant morbidity and mortality." /><meta name="og:title" content="El-Hattab-Alkuraya Syndrome" /><meta name="og:type" content="book" /><meta name="og:description" content="El-Hattab-Alkuraya syndrome is characterized by microcephaly (often early onset and progressive); severe-to-profound developmental delay; refractory and early-onset seizures; spastic quadriplegia with axial hypotonia; and growth deficiency with poor weight gain and short stature. Characteristic findings on brain imaging include cerebral atrophy that is disproportionately most prominent in the frontal lobes; ex vacuo ventricular dilatation with notable posterior horn predominance; brain stem volume loss with flattening of the belly of the pons; and symmetric under-opercularization. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK584547_"><span class="title" itemprop="name">El-Hattab-Alkuraya Syndrome</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: <i>WDR45B</i>-Related Neurodevelopmental Disorder</div><div class="contrib half_rhythm"><span itemprop="author">Mohammed Almannai</span>, MD, FAAP, FACMG<div class="affiliation small">Genetics and Precision Medicine Department<br />King Abdullah Specialized Children's Hospital<br />King Abdulaziz Medical City<br />Ministry of National Guard Health Affairs<br />Riyadh, Saudi Arabia<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.liamg@18iannamm" class="oemail">moc.liamg@18iannamm</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Dana Marafi</span>, MD, MSc<div class="affiliation small">Department of Pediatrics<br />Faculty of Medicine<br />Kuwait University<br />Jabriya, Kuwait<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="wk.ude.uk@eifaram.anad" class="oemail">wk.ude.uk@eifaram.anad</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Ayman W El-Hattab</span>, MD, FAAP, FACMG<div class="affiliation small">College of Medicine<br />University of Sharjah<br />Sharjah, United Arab Emirates<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.oohay@wabattahle" class="oemail">moc.oohay@wabattahle</a></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">September 29, 2022</span>.</p><p><em>Estimated reading time: 15 minutes</em></p></div><div class="body-content whole_rhythm" itemprop="text"><div id="el-hattab-alkuraya.Summary" itemprop="description"><h2 id="_el-hattab-alkuraya_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>El-Hattab-Alkuraya syndrome is characterized by microcephaly (often early onset and progressive); severe-to-profound developmental delay; refractory and early-onset seizures; spastic quadriplegia with axial hypotonia; and growth deficiency with poor weight gain and short stature. Characteristic findings on brain imaging include cerebral atrophy that is disproportionately most prominent in the frontal lobes; <i>ex vacuo</i> ventricular dilatation with notable posterior horn predominance; brain stem volume loss with flattening of the belly of the pons; and symmetric under-opercularization. Neurologic involvement is progressive, with significant morbidity and mortality.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of El-Hattab-Alkuraya syndrome is established in a proband by identification of biallelic pathogenic variants in <i>WDR45B</i> on molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Standardized treatments for seizures, spasticity, mobility, feeding issues, and ocular manifestations; developmental services and educational interventions for developmental delay and intellectual disability.</p><p><i>Surveillance:</i> Monitor for changes in seizures, tone, movement disorders, nutrition, and safety of oral intake at each visit. Monitor development, educational needs, behavior, vision, and hearing annually or as needed.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>El-Hattab-Alkuraya syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a <i>WDR45B</i> pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the <i>WDR45B</i> pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.</p></div></div><div id="el-hattab-alkuraya.Diagnosis"><h2 id="_el-hattab-alkuraya_Diagnosis_">Diagnosis</h2><div id="el-hattab-alkuraya.Suggestive_Findings"><h3>Suggestive Findings</h3><p>El-Hattab-Alkuraya syndrome <b>should be considered</b> in individuals with the following clinical, imaging, and family history findings.</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Progressive microcephaly</div></li><li class="half_rhythm"><div>Developmental delay</div></li><li class="half_rhythm"><div>Early-onset, refractory seizures</div></li><li class="half_rhythm"><div>Spastic quadriplegia</div></li><li class="half_rhythm"><div>Growth deficiency (poor weight gain, short stature)</div></li></ul><p>
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<b>Imaging findings on brain MRI</b>
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</p><ul><li class="half_rhythm"><div>Cerebral atrophy with disproportionate atrophy of the frontal lobes</div></li><li class="half_rhythm"><div><i>Ex vacuo</i> ventricular dilatation with posterior horn predominance</div></li><li class="half_rhythm"><div>Brain stem volume loss with flattening of the belly of the pons</div></li><li class="half_rhythm"><div>Symmetric under-opercularization</div></li></ul><p><b>Family history</b> is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.</p></div><div id="el-hattab-alkuraya.Establishing_the_Diag"><h3>Establishing the Diagnosis</h3><p>The diagnosis of El-Hattab-Alkuraya syndrome <b>is established</b> in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in <i>WDR45B</i> identified by molecular genetic testing (see <a href="/books/NBK584547/table/el-hattab-alkuraya.T.molecular_genetic_t/?report=objectonly" target="object" rid-ob="figobelhattabalkurayaTmoleculargenetict">Table 1</a>).</p><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="bk_pop" href="#el-hattab-alkuraya.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 biallelic <i>WDR45B</i> variants of uncertain significance (or of one known <i>WDR45B</i> pathogenic variant and one <i>WDR45B</i> variant of uncertain significance) does not establish or rule out a diagnosis.</p><p><b>Molecular genetic testing</b> in a child with developmental delay may begin with exome sequencing, a multigene panel, or chromosomal microarray analysis. Note: Single-gene testing (sequence analysis of <i>WDR45B</i>) is rarely useful and typically NOT recommended.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Comprehensive genomic testing</b> does not require the clinician to determine which gene(s) are likely involved. <b>Exome sequencing</b> is most commonly used, and yields results similar to an intellectual disability (ID) multigene panel, with the additional advantage that exome sequencing includes genes recently identified as causing ID whereas some multigene panels may not. <b>Genome sequencing</b> is also possible.</div><div class="half_rhythm">For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A multigene panel</b> that includes <i>WDR45B</i> and other genes of interest (see <a href="#el-hattab-alkuraya.Differential_Diagnosi">Differential Diagnosis</a>) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul><div id="el-hattab-alkuraya.T.molecular_genetic_t" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in El-Hattab-Alkuraya Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK584547/table/el-hattab-alkuraya.T.molecular_genetic_t/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__el-hattab-alkuraya.T.molecular_genetic_t_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_el-hattab-alkuraya.T.molecular_genetic_t_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_el-hattab-alkuraya.T.molecular_genetic_t_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_el-hattab-alkuraya.T.molecular_genetic_t_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_el-hattab-alkuraya.T.molecular_genetic_t_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>WDR45B</i>
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</td><td headers="hd_h_el-hattab-alkuraya.T.molecular_genetic_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_el-hattab-alkuraya.T.molecular_genetic_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <sup>4</sup></td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.molecular_genetic_t_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></td><td headers="hd_h_el-hattab-alkuraya.T.molecular_genetic_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported <sup>4</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="el-hattab-alkuraya.TF.1.1"><p class="no_margin">See <a href="/books/NBK584547/#el-hattab-alkuraya.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd><dt>2. </dt><dd><div id="el-hattab-alkuraya.TF.1.2"><p class="no_margin">See <a href="#el-hattab-alkuraya.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd><dt>3. </dt><dd><div id="el-hattab-alkuraya.TF.1.3"><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/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="el-hattab-alkuraya.TF.1.4"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bk_pop" href="#el-hattab-alkuraya.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd><dt>5. </dt><dd><div id="el-hattab-alkuraya.TF.1.5"><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></div></div></div></div></div><div id="el-hattab-alkuraya.Clinical_Characterist"><h2 id="_el-hattab-alkuraya_Clinical_Characterist_">Clinical Characteristics</h2><div id="el-hattab-alkuraya.Clinical_Description"><h3>Clinical Description</h3><p>El-Hattab-Alkuraya syndrome is characterized by congenital and progressive microcephaly, developmental delay, seizures, spastic quadriplegia, associated brain imaging findings, and progressive neurologic involvement with significant morbidity and mortality. To date, 22 individuals with biallelic pathogenic variants in <i>WDR45B</i> have been identified [<a class="bk_pop" href="#el-hattab-alkuraya.REF.najmabadi.2011.57">Najmabadi et al 2011</a>, <a class="bk_pop" href="#el-hattab-alkuraya.REF.anazi.2017.615">Anazi et al 2017</a>, <a class="bk_pop" href="#el-hattab-alkuraya.REF.suleiman.2018.360">Suleiman et al 2018</a>, <a class="bk_pop" href="#el-hattab-alkuraya.REF.almannai.2022.530">Almannai et al 2022</a>]. The following description of the phenotypic features associated with this condition is based on these reports.</p><div id="el-hattab-alkuraya.T.elhattabalkuraya_sy" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>El-Hattab-Alkuraya Syndrome: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK584547/table/el-hattab-alkuraya.T.elhattabalkuraya_sy/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__el-hattab-alkuraya.T.elhattabalkuraya_sy_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Persons<br />w/Feature <sup>1, 2</sup></th><th id="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_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_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Microcephaly</td><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">19/22</td><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental delay</td><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">22/22</td><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe to profound</td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Seizures</td><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">16/18</td><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Refractory, early onset</td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Spastic quadriplegia</td><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15/17</td><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Poor weight gain</td><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7/11</td><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Short stature</td><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10/12</td><td headers="hd_h_el-hattab-alkuraya.T.elhattabalkuraya_sy_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="el-hattab-alkuraya.TF.2.1"><p class="no_margin">Average age at the time of evaluation was 6.5 years (range 7 months – 14 years)</p></div></dd><dt>2. </dt><dd><div id="el-hattab-alkuraya.TF.2.2"><p class="no_margin">Denominator reflects the number of persons assessed for the feature.</p></div></dd></dl></div></div></div><p><b>Microcephaly.</b> The majority of affected individuals had progressive microcephaly. Most individuals had congenital microcephaly (in those with a known birth head circumference). Microcephaly was identified prenatally in some individuals [<a class="bk_pop" href="#el-hattab-alkuraya.REF.najmabadi.2011.57">Najmabadi et al 2011</a>, <a class="bk_pop" href="#el-hattab-alkuraya.REF.anazi.2017.615">Anazi et al 2017</a>, <a class="bk_pop" href="#el-hattab-alkuraya.REF.suleiman.2018.360">Suleiman et al 2018</a>, <a class="bk_pop" href="#el-hattab-alkuraya.REF.almannai.2022.530">Almannai et al 2022</a>].</p><p><b>Developmental delay.</b> All individuals had severe-to-profound development delay. Individuals with loss-of-function <i>WDR45B</i> variants were profoundly delayed and unable to ambulate or communicate. Two sibs homozygous for a <i>WDR45B</i> missense variant were severely delayed but showed slow acquisition of some skills, and regression was not evident by ages four and 14 years. The two sibs were able to follow simple commands and speak a few monosyllables. Ambulation was achieved by age 30 months in the older sib, but had not been achieved by age four years in the younger sib.</p><p><b>Seizures.</b> Refractory, early-onset seizures were reported in most individuals. The most common seizure type was generalized tonic-clonic. Other reported seizure types included myoclonic and focal. Seizures were refractory and required at least two anti-seizure medications (ASMs) in most individuals. Responses to ASMs were variable, with no particular ASM being more effective.</p><p><b>Spastic quadriplegia.</b> Most individuals had spastic quadriplegia that was associated with axial hypotonia.</p><p><b>Growth deficiency.</b> Poor weight gain was reported in most individuals. Feeding and swallowing problems were commonly observed. Method of feeding was reported for three individuals, who all required gastric tube feeding. Most affected individuals with loss-of-function variants are expected to require tube feeding given the extent of neurologic involvement. Short stature was reported in ten of 12 affected individuals for whom measurements were available.</p><p><b>Ocular manifestations.</b> Most individuals have poor visual tracking; one individual was diagnosed with cortical blindness. Optic atrophy was reported in two individuals, and two other individuals were reported to have strabismus.</p><p><b>Nonspecific dysmorphic features</b> were reported in most individuals. The most common reported features were thick, highly arched eyebrows, large ears, bitemporal narrowing, and long philtrum.</p><p>Common <b>neuroradiographic findings</b> include:</p><ul><li class="half_rhythm"><div>Cerebral atrophy with disproportionate atrophy of the frontal lobe</div></li><li class="half_rhythm"><div>Giant cisterna magna</div></li><li class="half_rhythm"><div>Corpus callosum thinning</div></li><li class="half_rhythm"><div>Brain stem volume loss with flattening of the belly of the pons</div></li><li class="half_rhythm"><div><i>Ex vacuo</i> ventricular dilatation with posterior horn predominance pattern of the ventriculomegaly</div></li><li class="half_rhythm"><div>Symmetric under-opercularization</div></li><li class="half_rhythm"><div>Dysplastic hippocampi</div></li><li class="half_rhythm"><div>Cerebellar atrophy</div></li><li class="half_rhythm"><div>Cervical spine atrophy</div></li></ul><p><b>Other.</b> One individual had behavioral issues including aggression and self-harming behavior.</p><p><b>Prognosis.</b> Five individuals are deceased at the time of this report. The age of death ranged from two to 15 years; mean age of death was 7.9 years. When reported, the most common cause for death was aspiration pneumonia.</p></div><div id="el-hattab-alkuraya.GenotypePhenotype_Cor"><h3>Genotype-Phenotype Correlations</h3><p>The number of affected individuals is insufficient to establish genotype-phenotype correlations. However, two sibs homozygous for missense variant <a href="/books/NBK584547/table/el-hattab-alkuraya.T.notable_wdr45b_path/?report=objectonly" target="object" rid-ob="figobelhattabalkurayaTnotablewdr45bpath">c.674G>A</a> had milder clinical features; only one sib had seizures, and neither sib had characteristic brain MRI findings or spastic quadriplegia [<a class="bk_pop" href="#el-hattab-alkuraya.REF.almannai.2022.530">Almannai et al 2022</a>].</p></div><div id="el-hattab-alkuraya.Nomenclature"><h3>Nomenclature</h3><p>El-Hattab-Alkuraya syndrome may also be referred to as <i>WDR45B</i>-related neurodevelopmental disorder based on the dyadic naming approach proposed by <a class="bk_pop" href="#el-hattab-alkuraya.REF.biesecker.2021.8">Biesecker et al [2021]</a> to delineate mendelian genetic disorders.</p></div><div id="el-hattab-alkuraya.Prevalence"><h3>Prevalence</h3><p>The exact prevalence is unknown, but El-Hattab-Alkuraya syndrome appears to be rare, with only 22 individuals reported to date. Most affected individuals are of Arab ancestry.</p></div></div><div id="el-hattab-alkuraya.Genetically_Related_A"><h2 id="_el-hattab-alkuraya_Genetically_Related_A_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with germline pathogenic variants in <i>WDR45B</i>.</p></div><div id="el-hattab-alkuraya.Differential_Diagnosi"><h2 id="_el-hattab-alkuraya_Differential_Diagnosi_">Differential Diagnosis</h2><p>Because the phenotypic features associated with El-Hattab-Alkuraya syndrome are not sufficient to diagnose this condition, all disorders with intellectual disability without other distinctive findings should be considered in the differential diagnosis. See <a href="https://www.omim.org/phenotypicSeries/PS156200" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM Autosomal Dominant</a>, <a href="https://omim.org/phenotypicSeries/PS249500" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Autosomal Recessive</a>, <a href="https://omim.org/phenotypicSeries/PS309530" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Nonsyndromic X-Linked</a>, and <a href="https://omim.org/phenotypicSeries/PS309510" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Syndromic X-Linked Intellectual Developmental Disorder Phenotypic Series</a>.</p></div><div id="el-hattab-alkuraya.Management"><h2 id="_el-hattab-alkuraya_Management_">Management</h2><div id="el-hattab-alkuraya.Evaluations_Following"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with El-Hattab-Alkuraya syndrome, the evaluations summarized in <a href="/books/NBK584547/table/el-hattab-alkuraya.T.recommended_evaluat/?report=objectonly" target="object" rid-ob="figobelhattabalkurayaTrecommendedevaluat">Table 3</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="el-hattab-alkuraya.T.recommended_evaluat" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with El-Hattab-Alkuraya Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK584547/table/el-hattab-alkuraya.T.recommended_evaluat/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__el-hattab-alkuraya.T.recommended_evaluat_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_el-hattab-alkuraya.T.recommended_evaluat_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_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To incl brain MRI to evaluate extent of disorder</div></li><li class="half_rhythm"><div>EEG</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Development</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To incl motor, adaptive, cognitive, & speech/language eval</div></li><li class="half_rhythm"><div>Assess needs for speech, OT, PT.</div></li><li class="half_rhythm"><div>Eval for early intervention / special education</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Nutritional eval</div></li><li class="half_rhythm"><div>Swallowing assessment for feeding difficulties</div></li></ul>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Ophthalmologic</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Formal ophthalmologic eval</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>ENT</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing assessment</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Although hearing issues have not been reported, hearing assessment is recommended due to developmental issues.</td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic</b>
|
||
<br />
|
||
<b>counseling</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & their families re nature, MOI, & implications of El-Hattab-Alkuraya syndrome to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family support</b>
|
||
<br />
|
||
<b>& resources</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for:
|
||
<ul><li class="half_rhythm"><div>Community or <a href="#el-hattab-alkuraya.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Social work involvement for parental support;</div></li><li class="half_rhythm"><div>Home nursing referral.</div></li></ul>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_evaluat_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy</p></div></dd><dt>1. </dt><dd><div id="el-hattab-alkuraya.TF.3.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="el-hattab-alkuraya.Treatment_of_Manifest"><h3>Treatment of Manifestations</h3><p><b>Supportive care</b> to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in neurology, nutrition, ophthalmology, clinical genetics/metabolism, developmental pediatrics, speech-language therapy, occupational therapy, physical therapy, and audiology.</p><div id="el-hattab-alkuraya.T.treatment_of_manife" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with El-Hattab-Alkuraya Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK584547/table/el-hattab-alkuraya.T.treatment_of_manife/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__el-hattab-alkuraya.T.treatment_of_manife_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_el-hattab-alkuraya.T.treatment_of_manife_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_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Epilepsy</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standardized treatment w/ASM by experienced neurologist</td><td headers="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Seizures are refractory & often require at least 2 ASMs for seizure control.</td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Developmental delay /</b>
|
||
<br />
|
||
<b>Intellectual disability</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#el-hattab-alkuraya.Developmental_Delay">Developmental Delay / Intellectual Disability Management Issues</a>.</td><td headers="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Spasticity /</b>
|
||
<br />
|
||
<b>Mobility issues</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/physical medicine & rehab to help w/mobility or assistive devices (e.g., wheelchair)</td><td headers="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Poor weight gain</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Feeding therapy</div></li><li class="half_rhythm"><div>Nasogastric tube or gastrostomy tube are frequently needed due to feeding difficulties & poor weight gain.</div></li></ul>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Ocular manifestations</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment per ophthalmologist</td><td headers="hd_h_el-hattab-alkuraya.T.treatment_of_manife_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ASM = anti-seizure medication</p></div></dd></dl></div></div></div><div id="el-hattab-alkuraya.Developmental_Delay"><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 as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.</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 for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.</p><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:</p><ul><li class="half_rhythm"><div>IEP services:</div><ul><li class="half_rhythm"><div>An IEP provides specially designed instruction and related services to children who qualify.</div></li><li class="half_rhythm"><div>IEP services will be reviewed annually to determine whether any changes are needed.</div></li><li class="half_rhythm"><div>Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.</div></li><li class="half_rhythm"><div>Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.</div></li><li class="half_rhythm"><div>PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</div></li><li class="half_rhythm"><div>As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.</div></li></ul></li><li class="half_rhythm"><div>A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.</div></li><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US 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="el-hattab-alkuraya.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p>
|
||
<b>Gross motor dysfunction</b>
|
||
</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 and positioning devices 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, tizanidine, 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> should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.</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. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.</p></div><div id="el-hattab-alkuraya.SocialBehavioral_Conc"><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 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, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.</p><p>Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.</p></div></div><div id="el-hattab-alkuraya.Surveillance"><h3>Surveillance</h3><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in <a href="/books/NBK584547/table/el-hattab-alkuraya.T.recommended_surveil/?report=objectonly" target="object" rid-ob="figobelhattabalkurayaTrecommendedsurveil">Table 5</a> are recommended.</p><div id="el-hattab-alkuraya.T.recommended_surveil" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with El-Hattab-Alkuraya Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK584547/table/el-hattab-alkuraya.T.recommended_surveil/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__el-hattab-alkuraya.T.recommended_surveil_lrgtbl__"><table><thead><tr><th id="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Monitor those w/seizures as clinically indicated.</div></li><li class="half_rhythm"><div>Assess for new manifestations incl seizures, changes in tone, & mvmt disorders.</div></li></ul>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Development</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental progress & educational needs.</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually &/or as needed</td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal/</b>
|
||
<br />
|
||
<b>Nutrition</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Eval of nutritional status & safety of oral intake</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Psychiatric/</b>
|
||
<br />
|
||
<b>Behavioral</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Behavioral assessment for anxiety, attention, & aggressive or self-injurious behavior</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually &/or as needed</td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Eyes</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmology exam</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hearing</b>
|
||
</td><td headers="hd_h_el-hattab-alkuraya.T.recommended_surveil_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiology eval</td></tr></tbody></table></div></div></div><div id="el-hattab-alkuraya.Evaluation_of_Relativ"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#el-hattab-alkuraya.Related_Genetic_Couns">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="el-hattab-alkuraya.Therapies_Under_Inves"><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="el-hattab-alkuraya.Genetic_Counseling"><h2 id="_el-hattab-alkuraya_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="el-hattab-alkuraya.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>El-Hattab-Alkuraya syndrome is inherited in an autosomal recessive manner.</p></div><div id="el-hattab-alkuraya.Risk_to_Family_Member"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a proband</b>
|
||
</p><ul><li class="half_rhythm"><div>The parents of an affected child are presumed to be heterozygous for a <i>WDR45B</i> pathogenic variant.</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a <i>WDR45B</i> pathogenic variant and to allow reliable recurrence risk assessment.</div></li><li class="half_rhythm"><div>If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a <i>de novo</i> event in the proband or as a postzygotic <i>de novo</i> event in a mosaic parent [<a class="bk_pop" href="#el-hattab-alkuraya.REF.j_nsson.2017.519">Jónsson et al 2017</a>]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:</div><ul><li class="half_rhythm"><div>A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;</div></li><li class="half_rhythm"><div>Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.</div></li></ul></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
|
||
<b>Sibs of a proband</b>
|
||
</p><ul><li class="half_rhythm"><div>If both parents are known to be heterozygous for a <i>WDR45B</i> pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p><b>Offspring of a proband.</b> To date, individuals with El-Hattab-Alkuraya syndrome are not known to reproduce.</p><p><b>Other family members.</b> Each sib of the proband's parents is at a 50% risk of being a carrier of a <i>WDR45B</i> pathogenic variant.</p></div><div id="el-hattab-alkuraya.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>WDR45B</i> pathogenic variants in the family.</p></div><div id="el-hattab-alkuraya.Related_Genetic_Couns"><h3>Related Genetic Counseling Issues</h3><p>
|
||
<b>Family planning</b>
|
||
</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 are carriers or are at risk of being carriers.</div></li></ul></div><div id="el-hattab-alkuraya.Prenatal_Testing_and"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>WDR45B</i> pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="el-hattab-alkuraya.Resources"><h2 id="_el-hattab-alkuraya_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>American Association on Intellectual and Developmental Disabilities (AAIDD)</b>
|
||
</div><div><b>Phone:</b> 202-387-1968</div><div>
|
||
<a href="https://www.aaidd.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">aaidd.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>American Epilepsy Society</b>
|
||
</div><div>
|
||
<a href="https://www.aesnet.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">aesnet.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Canadian Epilepsy Alliance</b>
|
||
</div><div>Canada</div><div><b>Phone:</b> 1-866-EPILEPSY (1-866-374-5377)</div><div>
|
||
<a href="https://www.canadianepilepsyalliance.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">canadianepilepsyalliance.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>CDC - Child Development</b>
|
||
</div><div><b>Phone:</b> 800-232-4636</div><div>
|
||
<a href="https://www.cdc.gov/child-development/about/developmental-disability-basics.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developmental Disability Basics</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Epilepsy Canada</b>
|
||
</div><div>Canada</div><div><b>Phone:</b> 877-734-0873</div><div><b>Email:</b> epilepsy@epilepsy.ca</div><div>
|
||
<a href="http://www.epilepsy.ca/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">epilepsy.ca</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Epilepsy Foundation</b>
|
||
</div><div><b>Phone:</b> 800-332-1000; 866-748-8008</div><div>
|
||
<a href="https://www.epilepsy.com/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">epilepsy.com</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>MedlinePlus</b>
|
||
</div><div>
|
||
<a href="http://www.nlm.nih.gov/medlineplus/ency/article/001523.htm" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Intellectual Disability</a>
|
||
</div></li></ul>
|
||
</div><div id="el-hattab-alkuraya.Molecular_Genetics"><h2 id="_el-hattab-alkuraya_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 id="el-hattab-alkuraya.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>El-Hattab-Alkuraya Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK584547/table/el-hattab-alkuraya.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__el-hattab-alkuraya.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_el-hattab-alkuraya.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_el-hattab-alkuraya.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_el-hattab-alkuraya.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_el-hattab-alkuraya.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_el-hattab-alkuraya.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_el-hattab-alkuraya.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/56270" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>WDR45B</i>
|
||
</a>
|
||
</td><td headers="hd_b_el-hattab-alkuraya.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=56270" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">17q25<wbr style="display:inline-block"></wbr>.3</a>
|
||
</td><td headers="hd_b_el-hattab-alkuraya.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q5MNZ6" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">WD repeat domain phosphoinositide-interacting protein 3</a>
|
||
</td><td headers="hd_b_el-hattab-alkuraya.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=WDR45B" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">WDR45B</a>
|
||
</td><td headers="hd_b_el-hattab-alkuraya.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=WDR45B[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">WDR45B</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="el-hattab-alkuraya.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
chromosome locus from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
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/">here</a>.</p></div></dd></dl></div></div></div><div id="el-hattab-alkuraya.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for El-Hattab-Alkuraya Syndrome (<a href="/omim/609226,617977" 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/NBK584547/table/el-hattab-alkuraya.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__el-hattab-alkuraya.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/609226" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">609226</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">WD REPEAT-CONTAINING PROTEIN 45B; WDR45B</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/617977" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">617977</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NEURODEVELOPMENTAL DISORDER WITH SPASTIC QUADRIPLEGIA AND BRAIN ABNORMALITIES WITH OR WITHOUT SEIZURES; NEDSBAS</td></tr></tbody></table></div></div><div id="el-hattab-alkuraya.Molecular_Pathogenesi"><h3>Molecular Pathogenesis</h3><p><i>WDR45B</i> encodes for WD (tryptophan-aspartic acid) repeat-containing protein 45B, a member of the WIPI protein family. This protein family plays an important role in autophagy [<a class="bk_pop" href="#el-hattab-alkuraya.REF.bakula.2017.15637">Bakula et al 2017</a>].</p><p><b>Mechanism of disease causation.</b> Loss of function</p><div id="el-hattab-alkuraya.T.notable_wdr45b_path" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Notable <i>WDR45B</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK584547/table/el-hattab-alkuraya.T.notable_wdr45b_path/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__el-hattab-alkuraya.T.notable_wdr45b_path_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_el-hattab-alkuraya.T.notable_wdr45b_path_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_el-hattab-alkuraya.T.notable_wdr45b_path_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_el-hattab-alkuraya.T.notable_wdr45b_path_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_el-hattab-alkuraya.T.notable_wdr45b_path_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_el-hattab-alkuraya.T.notable_wdr45b_path_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_019613.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_019613<wbr style="display:inline-block"></wbr>.4</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_062559.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_062559<wbr style="display:inline-block"></wbr>.2</a>
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</td><td headers="hd_h_el-hattab-alkuraya.T.notable_wdr45b_path_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.674G>A</td><td headers="hd_h_el-hattab-alkuraya.T.notable_wdr45b_path_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg225Gln</td><td headers="hd_h_el-hattab-alkuraya.T.notable_wdr45b_path_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#el-hattab-alkuraya.GenotypePhenotype_Cor">Genotype-Phenotype Correlations</a>.</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></div></div></div></div></div><div id="el-hattab-alkuraya.Chapter_Notes"><h2 id="_el-hattab-alkuraya_Chapter_Notes_">Chapter Notes</h2><div id="el-hattab-alkuraya.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>29 September 2022 (sw) Review posted live</div></li><li class="half_rhythm"><div>5 August 2022 (ma) Original submission</div></li></ul></div></div><div id="el-hattab-alkuraya.References"><h2 id="_el-hattab-alkuraya_References_">References</h2><div id="el-hattab-alkuraya.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="el-hattab-alkuraya.REF.almannai.2022.530">Almannai M, Marafi D, Abdel-Salam GMH, Zaki MS, Duan R, Calame D, Herman I, Levesque F, Elbendary HM, Hegazy I, Chung WK, Kavus H, Saeidi K, Maroofian R, AlHashim A, Al-Otaibi A, Al Madhi A, Abou Al-Seood HM, Alasmari A, Houlden H, Gleeson JG, Hunter JV, Posey JE, Lupski JR, El-Hattab AW. El-Hattab-Alkuraya syndrome caused by biallelic WDR45B pathogenic variants: further delineation of the phenotype and genotype. <span><span class="ref-journal">Clin Genet. </span>2022;<span class="ref-vol">101</span>:530–40.</span> [<a href="/pmc/articles/PMC9359317/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9359317</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35322404" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35322404</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="el-hattab-alkuraya.REF.anazi.2017.615">Anazi S, Maddirevula S, Faqeih E, Alsedairy H, Alzahrani F, Shamseldin HE, Patel N, Hashem M, Ibrahim N, Abdulwahab F, Ewida N, Alsaif HS, Al Sharif H, Alamoudi W, Kentab A, Bashiri FA, Alnaser M, AlWadei AH, Alfadhel M, Eyaid W, Hashem A, Al Asmari A, Saleh MM, AlSaman A, Alhasan KA, Alsughayir M, Al Shammari M, Mahmoud A, Al-Hassnan ZN, Al-Husain M, Osama Khalil R, Abd El Meguid N, Masri A, Ali R, Ben-Omran T, El Fishway P, Hashish A, Ercan Sencicek A, State M, Alazami AM, Salih MA, Altassan N, Arold ST, Abouelhoda M, Wakil SM, Monies D, Shaheen R, Alkuraya FS. Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. <span><span class="ref-journal">Mol Psychiatry. </span>2017;<span class="ref-vol">22</span>:615–24.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27431290" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27431290</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="el-hattab-alkuraya.REF.bakula.2017.15637">Bakula D, Müller AJ, Zuleger T, Takacs Z, Franz-Wachtel M, Thost AK, Brigger D, Tschan MP, Frickey T, Robenek H, Macek B, Proikas-Cezanne T. WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy. <span><span class="ref-journal">Nat Commun. </span>2017;<span class="ref-vol">8</span>:15637.</span> [<a href="/pmc/articles/PMC5460038/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5460038</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28561066" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28561066</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="el-hattab-alkuraya.REF.biesecker.2021.8">Biesecker LG, Adam MP, Alkuraya FS, Amemiya AR, Bamshad MJ, Beck AE, Bennett JT, Bird LM, Carey JC, Chung B, Clark RD, Cox TC, Curry C, Dinulos MBP, Dobyns WB, Giampietro PF, Girisha KM, Glass IA, Graham JM Jr, Gripp KW, Haldeman-Englert CR, Hall BD, Innes AM, Kalish JM, Keppler-Noreuil KM, Kosaki K, Kozel BA, Mirzaa GM, Mulvihill JJ, Nowaczyk MJM, Pagon RA, Retterer K, Rope AF, Sanchez-Lara PA, Seaver LH, Shieh JT, Slavotinek AM, Sobering AK, Stevens CA, Stevenson DA, Tan TY, Tan WH, Tsai AC, Weaver DD, Williams MS, Zackai E, Zarate YA. A dyadic approach to the delineation of diagnostic entities in clinical genomics. <span><span class="ref-journal">Am J Hum Genet. </span>2021;<span class="ref-vol">108</span>:8–15.</span> [<a href="/pmc/articles/PMC7820621/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7820621</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33417889" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33417889</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="el-hattab-alkuraya.REF.j_nsson.2017.519">Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. <span><span class="ref-journal">Nature. </span>2017;<span class="ref-vol">549</span>:519–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28959963" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28959963</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="el-hattab-alkuraya.REF.najmabadi.2011.57">Najmabadi H, Hu H, Garshasbi M, Zemojtel T, Abedini SS, Chen W, Hosseini M, Behjati F, Haas S, Jamali P, Zecha A, Mohseni M, Püttmann L, Vahid LN, Jensen C, Moheb LA, Bienek M, Larti F, Mueller I, Weissmann R, Darvish H, Wrogemann K, Hadavi V, Lipkowitz B, Esmaeeli-Nieh S, Wieczorek D, Kariminejad R, Firouzabadi SG, Cohen M, Fattahi Z, Rost I, Mojahedi F, Hertzberg C, Dehghan A, Rajab A, Banavandi MJ, Hoffer J, Falah M, Musante L, Kalscheuer V, Ullmann R, Kuss AW, Tzschach A, Kahrizi K, Ropers HH. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. <span><span class="ref-journal">Nature. </span>2011;<span class="ref-vol">478</span>:57–63.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21937992" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21937992</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="el-hattab-alkuraya.REF.richards.2015.405">Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. <span><span class="ref-journal">Genet Med. </span>2015;<span class="ref-vol">17</span>:405–24.</span> [<a href="/pmc/articles/PMC4544753/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4544753</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25741868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25741868</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="el-hattab-alkuraya.REF.stenson.2020.1197">Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. <span><span class="ref-journal">Hum Genet. </span>2020;<span class="ref-vol">139</span>:1197–207.</span> [<a href="/pmc/articles/PMC7497289/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7497289</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32596782" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32596782</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="el-hattab-alkuraya.REF.suleiman.2018.360">Suleiman J, Allingham-Hawkins D, Hashem M, Shamseldin HE, Alkuraya FS, El-Hattab AW. WDR45B-related intellectual disability, spastic quadriplegia, epilepsy, and cerebral hypoplasia: a consistent neurodevelopmental syndrome. <span><span class="ref-journal">Clin Genet. </span>2018;<span class="ref-vol">93</span>:360–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28503735" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28503735</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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