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J Med Genet. 2014 Oct;51(10):659-68. doi: 10.1136/jmedgenet-2014-102573. Epub 2014 Aug 14.

Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.

Author information

1
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
2
Visual Geometry Group, Department of Engineering Science, University of Oxford, Oxford, UK Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
3
Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
4
Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
5
South East of Scotland Clinical Genetic Service, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK.
6
Medical Genetics Unit, St George's University of London, London, UK.
7
North of Scotland Regional Genetics Service, Clinical Genetics Centre, Aberdeen, UK.
8
Department of Medical Genetics, University Hospital of Northern Norway, Tromsø, Norway.
9
Sheffield Children's Hospital, NHS Foundation Trust, Sheffield, UK.
10
Northern Genetics Service, Newcastle upon Tyne Hospitals, Newcastle upon Tyne, UK.
11
Department of Clinical Genetics, Alder Hay Children's Hospital, Liverpool, UK.
12
Northern Ireland Regional Genetics Service (NIRGS), Belfast City Hospital, Belfast, UK.
13
Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
14
Clinical Genetics Department, Great Ormond Street Hospital, London, UK.
15
North West Thames Regional Genetics Service, Kennedy-Galton Centre, North West London Hospitals NHS Trust, Harrow, UK.
16
West Midlands Regional Clinical Genetics Service, Birmingham Women's Hospital, West Midlands, UK.
17
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
18
Department of Genetics, Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
19
Clinical Genetics, Yorkshire Regional Genetics Service, Leeds, UK.
20
Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
21
Department of Clinical Genetics, The Churchill Hospital Old Road, Oxford, UK.
22
SA Clinical Genetics Service, Women's & Children's Hospital, Adelaide, Australia Department of Paediatrics, University of Adelaide, Adelaide, Australia.
23
West of Scotland Regional Genetics Service, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospital, Glasgow, UK.
24
Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.
25
Department of Medical Genetics, Cambridge University Addenbrooke's Hospital, Cambridge, UK.
26
Faculty of Medical and Human Sciences, Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK.
27
Department of Dermatology, Kingston Hospital NHS Trust, Surrey, UK.
28
Medical Genetics Laboratory of Genome, Isfahan University of Medical Sciences, Isfahan, Iran.
29
National Centre for Medical Genetics, Our Lady's Children's Hospital, Dublin 12, Ireland.
30
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
31
National Centre for Medical Genetics, Our Lady's Children's Hospital, Dublin 12, Ireland School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland.
32
Clinical Genetics Department, Great Ormond Street Hospital, London, UK Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London, UK.
33
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.

Abstract

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.

KEYWORDS:

Clinical genetics; Copy-number; Molecular genetics

PMID:
25125236
PMCID:
PMC4173748
DOI:
10.1136/jmedgenet-2014-102573
[Indexed for MEDLINE]
Free PMC Article

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