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Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions.

Authors
  • Willemsen, M H1
  • Beunders, G
  • Callaghan, M
  • de Leeuw, N
  • Nillesen, W M
  • Yntema, H G
  • van Hagen, J M
  • Nieuwint, A W M
  • Morrison, N
  • Keijzers-Vloet, S T M
  • Hoischen, A
  • Brunner, H G
  • Tolmie, J
  • Kleefstra, T
  • 1 Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands Department of Clinical Genetics, VU University Medical Centre, Amsterdam, the Netherlands Department of Medical Genetics, Ferguson Smith Centre, Yorkhill Hospital, Glasgow, UK. , (Netherlands)
Type
Published Article
Journal
Clinical Genetics
Publisher
Wiley (Blackwell Publishing)
Publication Date
Jul 01, 2011
Volume
80
Issue
1
Pages
31–38
Identifiers
DOI: 10.1111/j.1399-0004.2010.01607.x
PMID: 21204793
Source
Medline
License
Unknown

Abstract

The Kleefstra syndrome (Online Mendelian Inheritance in Man 607001) is caused by a submicroscopic 9q34.3 deletion or by intragenic euchromatin histone methyl transferase 1 (EHMT1) mutations. So far only de novo occurrence of mutations has been reported, whereas 9q34.3 deletions can be either de novo or caused by complex chromosomal rearrangements or translocations. Here we give the first descriptions of affected parent-to-child transmission of Kleefstra syndrome caused by small interstitial deletions, approximately 200 kb, involving part of the EHMT1 gene. Additional genome-wide array studies in the parents showed the presence of similar deletions in both mothers who only had mild learning difficulties and minor facial characteristics suggesting either variable clinical expression or somatic mosaicism for these deletions. Further studies showed only one of the maternal deletions resulted in significantly quantitative differences in signal intensity on the array between the mother and her child. But by investigating different tissues with additional fluorescent in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) analyses, we confirmed somatic mosaicism in both mothers. Careful clinical and cytogenetic assessments of parents of an affected proband with an (interstitial) 9q34.3 microdeletion are merited for accurate estimation of recurrence risk.

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