Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Apr;2(3-5):202-212.
doi: 10.1159/000335648. Epub 2012 Jan 24.

Update on Kleefstra Syndrome

M H Willemsen  1 , A T Vulto-van Silfhout, W M Nillesen, W M Wissink-Lindhout, H van Bokhoven, N Philip, E M Berry-Kravis, U Kini, C M A van Ravenswaaij-Arts, B Delle Chiaie, A M M Innes, G Houge, T Kosonen, K Cremer, M Fannemel, A Stray-Pedersen, W Reardon, J Ignatius, K Lachlan, C Mircher, P T J M Helderman van den Enden, M Mastebroek, P E Cohn-Hokke, H G Yntema, S Drunat, T Kleefstra
Affiliations

Update on Kleefstra Syndrome

M H Willemsen et al. Mol Syndromol. 2012 Apr.

Abstract

Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Schematic overview of deleted regions in 9q34.3 in patients 1–8 and 11–16. The relative positions of involved genes and the P070 MPLA probe are indicated (UCSC genome browser build February 2009, Hg 19). Deletions of patients 1–3 were identified by MLPA. Deletions of patients 4–8 and 11–16 were detected by genome-wide array analysis. The deletion of patient 4 was identified by 2.7M array, the deletions of patients 5 and 16 by 250K SNP array, the deletions of patients 6 and 8 by 180K oligoarray, the deletion of patient 7 by 60K oligoarray and the deletions of patients 11 and 12 by 105K oligoarray. In patients 13–15, the Affymetrix 6.0 SNP array platform was used. Deletions of patients 9 and 10 are not depicted, because these were poorly delineated.
Fig. 2
Fig. 2
Schematic diagram of the EHMT1 gene structure (including 27 exons) and the protein domain structure of the EHMT1 protein. The conserved domains include the C3HC4 type zinc-finger (RING finger) (C3HC4) domain, 7 ankyrin repeat (ANK) domains, the Su(var)3–9, Enhancer-of-zetste, trithorax (SET) domain and the PreSET domain (N-terminal to the SET domain).The relative positions of in total 22 mutations are displayed, including the 13 mutations of the present patient cohort (1 recurrent mutation (p.Arg620X) present in 2 patients) and 9 previously reported mutations. The first identified intragenic EHMT1 aberration due to a translocation X;9 is not shown. del = Deletion; SS = splice site mutation.
Fig. 3
Fig. 3
A–V Facial profiles of patients with a 9q34.3 deletion. Patient 1 at age 2 years (A) and 5 years (B), patient 2 at age 9 months (C), 2 years (D) and 6 years (E), patient 4 at age 5 years (F, G), patient 5 at age 11 years (H, I), patient 6 at age 1 year (J) and 2 years (K), patient 7 at age 9 months (L), patient 8 at different childhood ages (M–O), patient 10 at young childhood age (P, Q), patient 11 at age 3 years (R, S) and 5 years (T, U) and patient 12 at age 5 years (V). The highly recognizable facial features comprise hypertelorism, midface hypoplasia, prognathism, prominent eyebrows, cupid bow or tented upper lip and everted lower lip.
Fig. 4
Fig. 4
A–W Facial appearance of patients with an EHMT1 mutation. Patient 17 at age 2 years (A, B), patient 18 at age 1 year (C) and 6 years (D, E), patient 19 at age 3 years (F, G), patient 20 at age 41 years (H, I), patient 21 at age 5 years (J, K), patient 24 at age 2 years (L, M) and 10 years (N), patient 25 at childhood age (O), during teenage (P), and age 32 years (Q, R), patient 26 at age 2 years (S) and age 10 years (T, U), patient 27 at age 11 years (V, W). Facial characteristics are similar to Kleefstra syndrome patients with a 9q34.3 deletion.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ayyash H, Mueller R, Maltby E, Horsfield P, Telford N, Tyler R. A report of a child with a deletion (9)(q34.3): a recognisable phenotype? J Med Genet. 1997;34:610–612. - PMC - PubMed
    1. Cormier-Daire V, Molinari F, Rio M, Raoul O, de Blois MC, et al. Cryptic terminal deletion of chromosome 9q34: a novel cause of syndromic obesity in childhood? J Med Genet. 2003;40:300–303. - PMC - PubMed
    1. Dawson AJ, Putnam S, Schultz J, Riordan D, Prasad C, et al. Cryptic chromosome rearrangements detected by subtelomere assay in patients with mental retardation and dysmorphic features. Clin Genet. 2002;62:488–494. - PubMed
    1. Font-Montgomery E, Weaver DD, Walsh L, Christensen C, Thurston VC. Clinical and cytogenetic manifestations of subtelomeric aberrations: report of six cases. Birth Defects Res A Clin Mol Teratol. 2004;70:408–415. - PubMed
    1. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437:270–274. - PubMed