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

Josephina A.N. Meester, Maja Sukalo, Kim C. Schröder, Denny Schanze, Gareth Baynam, Guntram Borck, Nuria C. Bramswig, Duygu Duman, Brigitte Gilbert-Dussardier, Muriel Holder-Espinasse, Peter Itin, Diana S. Johnson, Shelagh Joss, Hannele Koillinen, Fiona McKenzie, Jenny Morton, Heike Nelle, Willie Reardon, Claudia Roll, Mustafa A. SalihRavi Savarirayan, Ingrid Scurr, Miranda Splitt, Elizabeth Thompson, Hannah Titheradge, Colm P. Travers, Lionel Van Maldergem, Margo Whiteford, Dagmar Wieczorek, Geert Vandeweyer, Richard Trembath, Lut Van Laer, Bart L. Loeys, Martin Zenker, Laura Southgate, Wim Wuyts

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1246-1261
Number of pages16
JournalHuman Mutation
Volume39
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018

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