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Case Reports
. 2012 Jun;158A(6):1481-5.
doi: 10.1002/ajmg.a.35381. Epub 2012 May 11.

Germline mosaicism in Cornelia de Lange syndrome

Thomas P Slavin  1 , Noam Lazebnik, Dinah M Clark, Jaime Vengoechea, Leslie Cohen, Maninder Kaur, Laura Konczal, Carol A Crowe, Jane E Corteville, Malgorzata J Nowaczyk, Janice L Byrne, Laird G Jackson, Ian D Krantz
Affiliations
Case Reports

Germline mosaicism in Cornelia de Lange syndrome

Thomas P Slavin et al. Am J Med Genet A. 2012 Jun.

Abstract

Cornelia de Lange syndrome (CdLS) is a genetic disorder associated with delayed growth, intellectual disability, limb reduction defects, and characteristic facial features. Germline mosaicism has been a described mechanism for CdLS when there are several affected offspring of apparently unaffected parents. Presently, the recurrence risk for CdLS has been estimated to be as high as 1.5%; however, this figure may be an underrepresentation. We report on the molecularly defined germline mosaicism cases from a large CdLS database, representing the first large case series on germline mosaicism in CdLS. Of the 12 families, eight have been previously described; however, four have not. No one specific gene mutation, either in the NIPBL or the SMC1A gene, was associated with an increased risk for germline mosaicism. Suspected or confirmed cases of germline mosaicism in our database range from a conservative 3.4% up to 5.4% of our total cohort. In conclusion, the potential reproductive recurrence risk due to germline mosiacism should be addressed in prenatal counseling for all families who have had a previously affected pregnancy or child with CdLS.

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Conflict of interest statement

The authors declare that they have no disclosures or competing financial interests.

Figures

Figure 1
Figure 1
Pedigree of Family X. The mother (carrier symbol) has no physical features of Cornelia de Lange syndrome on exam. Her blood was tested and was not found to have the same 64+1 G>A in exon 2 of NIPBL mutation seen in her children. All miscarriages were spontaneous. The mother has no unaffected children. The miscarried products of conception were not molecularly evaluated for NIPBL mutations.
Figure 2
Figure 2
Family XI chromatograms. The proband’s chromatogram is in the center demonstrating heterozygosity for the p.R496H mutation. The unaffected mother and sibling are depicted on the right with normal sequences (homozygous for the “G”). The unaffected father’s forward and reverse sequence are depicted on the left, in both cases demonstrating a small sub “A” peak beneath the normal “G” peak at this base position, indicating a low level mosaicism for the p.R496H mutation. Arrows indicate the base in which the p.R496H mutation occurs.
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