Elucidating the genetic architecture of Adams–Oliver syndrome in a large European cohort
2018
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
DOCK6and 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 architectureof 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 screeningacross the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype–phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.
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