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

Meester JAN1, Sukalo M2, Schröder KC2, Schanze D2, Baynam G3,4,5, Borck G6, Bramswig NC7, Duman D8, Gilbert-Dussardier B9, Holder-Espinasse M10, Itin P11, Johnson DS12, Joss S13, Koillinen H14, McKenzie F15, Morton J16, Nelle H17, Reardon W18, Roll C19, Salih MA20, Savarirayan R21, Scurr I22, Splitt M23, Thompson E24,25, Titheradge H16, Travers CP26, Van Maldergem L27, Whiteford M28, Wieczorek D29, Vandeweyer G1, Trembath R30, Van Laer L1, Loeys BL1, Zenker M2, Southgate L30,31, Wuyts W1.

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 is 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. This article is protected by copyright. All rights reserved.