Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort

J.A.N. Meester; M. Sukalo; K.C. Schröder; D. Schanze; G. Baynam; G. Borck; N.C. Bramswig; D. Duman; B. Gilbert-Dussardier; M. Holder-Espinasse; P. Itin; D.S. Johnson; S. Joss; H. Koillinen; F. McKenzie; J. Morton; H. Nelle; W. Reardon; C. Roll; M.A. Salih; R. Savarirayan; I. Scurr; M. Splitt; E. Thompson; H. Titheradge; C.P. Travers; L. Van Maldergem; M. Whiteford; D. Wieczorek; G. Vandeweyer; R. Trembath; L. Van Laer; B.L. Loeys; M. Zenker; L. Southgate; W. Wuyts

doi:10.1002/humu.23567

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Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort

Journal article

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Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort

J.A.N. Meester, M. Sukalo, K.C. Schröder, D. Schanze, G. Baynam, G. Borck, N.C. Bramswig, D. Duman, B. Gilbert-Dussardier, M. Holder-Espinasse, …

Human Mutation, Vol.39(9), pp.1246-1261

2018

DOI: https://doi.org/10.1002/humu.23567

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Abstract

Adams–Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next‐generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype–phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.

Details

Title: Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort
Authors/Creators: J.A.N. Meester (Author/Creator) - Antwerp University Hospital
M. Sukalo (Author/Creator) - University Hospital Magdeburg
K.C. Schröder (Author/Creator) - University Hospital Magdeburg
D. Schanze (Author/Creator) - University Hospital Magdeburg
G. Baynam (Author/Creator) - King Edward Memorial Hospital
G. Borck (Author/Creator) - Universität Ulm
N.C. Bramswig (Author/Creator) - University of Duisburg-Essen
D. Duman (Author/Creator) - Ankara University
B. Gilbert-Dussardier (Author/Creator) - Université de Poitiers
M. Holder-Espinasse (Author/Creator) - Guy's and St Thomas' NHS Foundation Trust
P. Itin (Author/Creator) - University Hospital of Basel
D.S. Johnson (Author/Creator) - Sheffield Children's NHS Foundation Trust
S. Joss (Author/Creator)
H. Koillinen (Author/Creator) - Helsinki University Hospital
F. McKenzie (Author/Creator) - King Edward Memorial Hospital
J. Morton (Author/Creator) - Birmingham Women's Hospital
H. Nelle (Author/Creator) - Paracelsus Medizinische Privatuniversität
W. Reardon (Author/Creator) - National Maternity Hospital
C. Roll (Author/Creator) - Witten/Herdecke University
M.A. Salih (Author/Creator) - King Khalid University Hospital
R. Savarirayan (Author/Creator) - Victorian Clinical Genetics Services
I. Scurr (Author/Creator) - University Hospitals Bristol NHS Foundation Trust
M. Splitt (Author/Creator) - Newcastle upon Tyne Hospitals NHS Foundation Trust
E. Thompson (Author/Creator) - The University of Adelaide
H. Titheradge (Author/Creator) - Birmingham Women's Hospital
C.P. Travers (Author/Creator) - University of Alabama at Birmingham
L. Van Maldergem (Author/Creator) - Université de franche-comté
M. Whiteford (Author/Creator)
D. Wieczorek (Author/Creator) - Heinrich Heine University Düsseldorf
G. Vandeweyer (Author/Creator) - Antwerp University Hospital
R. Trembath (Author/Creator) - King's College London
L. Van Laer (Author/Creator) - Antwerp University Hospital
B.L. Loeys (Author/Creator) - Antwerp University Hospital
M. Zenker (Author/Creator) - University Hospital Magdeburg
L. Southgate (Author/Creator) - King's College London
W. Wuyts (Author/Creator) - Antwerp University Hospital
Publication Details: Human Mutation, Vol.39(9), pp.1246-1261
Publisher: John Wiley & Sons Inc.
Identifiers: 991005540881107891
Copyright: © 2018 Wiley Periodicals, Inc.
Murdoch Affiliation: Centre for Comparative Genomics
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.158 Dermatology - General; 1.158.2138 Congenital Skin Disorders
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics