TY - JOUR T1 - Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism JF - Journal of Medical Genetics JO - J Med Genet SP - 659 LP - 668 DO - 10.1136/jmedgenet-2014-102573 VL - 51 IS - 10 AU - Morad Ansari AU - Gemma Poke AU - Quentin Ferry AU - Kathleen Williamson AU - Roland Aldridge AU - Alison M Meynert AU - Hemant Bengani AU - Cheng Yee Chan AU - Hülya Kayserili AU - Şahin Avci AU - Raoul C M Hennekam AU - Anne K Lampe AU - Egbert Redeker AU - Tessa Homfray AU - Alison Ross AU - Marie Falkenberg Smeland AU - Sahar Mansour AU - Michael J Parker AU - Jacqueline A Cook AU - Miranda Splitt AU - Richard B Fisher AU - Alan Fryer AU - Alex C Magee AU - Andrew Wilkie AU - Angela Barnicoat AU - Angela F Brady AU - Nicola S Cooper AU - Catherine Mercer AU - Charu Deshpande AU - Christopher P Bennett AU - Daniela T Pilz AU - Deborah Ruddy AU - Deirdre Cilliers AU - Diana S Johnson AU - Dragana Josifova AU - Elisabeth Rosser AU - Elizabeth M Thompson AU - Emma Wakeling AU - Esther Kinning AU - Fiona Stewart AU - Frances Flinter AU - Katta M Girisha AU - Helen Cox AU - Helen V Firth AU - Helen Kingston AU - Jamie S Wee AU - Jane A Hurst AU - Jill Clayton-Smith AU - John Tolmie AU - Julie Vogt AU - Katrina Tatton–Brown AU - Kate Chandler AU - Katrina Prescott AU - Louise Wilson AU - Mahdiyeh Behnam AU - Meriel McEntagart AU - Rosemarie Davidson AU - Sally-Ann Lynch AU - Sanjay Sisodiya AU - Sarju G Mehta AU - Shane A McKee AU - Shehla Mohammed AU - Simon Holden AU - Soo-Mi Park AU - Susan E Holder AU - Victoria Harrison AU - Vivienne McConnell AU - Wayne K Lam AU - Andrew J Green AU - Dian Donnai AU - Maria Bitner-Glindzicz AU - Deirdre E Donnelly AU - Christoffer Nellåker AU - Martin S Taylor AU - David R FitzPatrick Y1 - 2014/10/01 UR - http://jmg.bmj.com/content/51/10/659.abstract N2 - Background Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. Methods We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. Results Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘NIPBL-like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases. Conclusions Future diagnostic testing in ‘mutation-negative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues. ER -