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Open Access Green as soon as Postprint is submitted to ZB.
Novel mosaic variants in two patients with Cornelia de Lange syndrome.
Eur. J. Med. Genet. 61, 680-684 (2017)
Cornelia de Lange syndrome (CdLS) is a dominantly inherited developmental disorder caused by mutations in genes that encode for either structural (SMC1A, SMC3, RAD21) or regulatory (NIPBL, HDAC8) subunits of the cohesin complex. NIPBL represents the major gene of the syndrome and heterozygous mutations can be identified in more than 65% of patients. Interestingly, large portions of these variants were described as somatic mosaicism and often escape standard molecular diagnostics using lymphocyte DNA.Here we discuss the role of somatic mosaicism in CdLS and describe two additional patients with NIPBL mosaicism detected by targeted gene panel or exome sequencing. In order to verify the next generation sequencing data, Sanger sequencing or pyrosequencing on DNA extracted from different tissues were applied. None of the pathogenic variants was originally detected by Sanger sequencing on blood DNA.Patient 1 displays an unusual combination of clinical features: he is cognitively only mildly affected, but shows severe limb reduction defects. Patient 2 presents with a moderate phenotype. Interestingly, Sanger sequencing analysis on fibroblast DNA of this patient did not detect the disease-causing variant previously observed on the same DNA sample by exome sequencing. Subsequent analyses could confirm the variants by Sanger sequencing on buccal mucosa DNA. Notably, this is the first report of a higher mutational load in buccal mucosa than in fibroblast cells of a CdLS patient.Detection of low-level mosaicism is of utmost importance for an accurate molecular diagnosis and a proper genetic counseling of patients with a clinical diagnosis of CdLS. Next-generation sequencing technologies greatly facilitate the detection of low-level mosaicism, which might otherwise remain undetected by conventional sequencing approaches.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Cornelia De Lange Syndrome ; Nipbl ; Mosaicism; Somatic Mosaicism; Overlapping Phenotypes; Molecular Diagnostics; Hdac8 Mutations; Cohesin Complex; Nipped-b; Nipbl; Spectrum; Features; Deletion
ISSN (print) / ISBN
1769-7212
e-ISSN
1729-7212
Quellenangaben
Volume: 61,
Issue: 11,
Pages: 680-684
Publisher
Elsevier
Publishing Place
Po Box 211, 1000 Ae Amsterdam, Netherlands
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Human Genetics (IHG)