Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions
Article first published online: 10 JAN 2011
© 2011 John Wiley & Sons A/S
Volume 80, Issue 1, pages 31–38, July 2011
How to Cite
Willemsen, M., Beunders, G., Callaghan, M., de Leeuw, N., Nillesen, W., Yntema, H., van Hagen, J., Nieuwint, A., Morrison, N., Keijzers-Vloet, S., Hoischen, A., Brunner, H., Tolmie, J. and Kleefstra, T. (2011), Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions. Clinical Genetics, 80: 31–38. doi: 10.1111/j.1399-0004.2010.01607.x
- Issue published online: 8 JUN 2011
- Article first published online: 10 JAN 2011
- Accepted manuscript online: 6 DEC 2010 08:10AM EST
- Received 11 October 2010, revised and accepted for publication 30 November 2010
- chromosome 9q;
- familial cases;
- Kleefstra syndrome;
Willemsen MH, Beunders G, Callaghan M, de Leeuw N, Nillesen WM, Yntema HG, van Hagen JM, Nieuwint AWM, Morrison N, Keijzers-Vloet STM, Hoischen A, Brunner HG, Tolmie J, Kleefstra T. Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions.
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.