Novel mosaic variants in two patients with Cornelia de Lange syndrome

Jelena Pozojevic (1) , Ilaria Parenti (1) , Luitgard Graul-Neumann (1) , Sara Ruiz Gil (1) , Erwan Watrin (1) , Kerstin S Wendt (2) , Ralf Werner (3) , Tim M Strom (3) , Gabriele Gillessen-Kaesbach (3) , Frank J Kaiser (3)

1 IGDR - Institut de Génétique et Développement de Rennes
2 Erasmus MC - Erasmus University Medical Center [Rotterdam]
3 Universität zu Lübeck = University of Lübeck [Lübeck]

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.

Mots clés: NIPBL; Cornelia de Lange syndrome; Mosaicism

Domaines: Génétique humaine

Jelena Pozojevic, Ilaria Parenti, Luitgard Graul-Neumann, Sara Ruiz Gil, Erwan Watrin, et al.. Novel mosaic variants in two patients with Cornelia de Lange syndrome. European Journal of Medical Genetics, 2018, 61 (11), pp.680-684. ⟨10.1016/j.ejmg.2017.11.004⟩. ⟨hal-01812513⟩