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

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.

Current opinion in the molecular genetics of Adams-Oliver syndrome

“…Whilst limited conclusions can be drawn from the small number reported to date, all ARHGAP31 mutations are proteintruncating variants located in the terminal exon 12, of which c.2047C>T (p.Gln683*) is recurrent. [9] Mutations of ARHGAP31 are highly correlated with TTLD specifically ( Table 2) and, thus far, no cardiovascular or neurological defects have been described in this cohort. [11] Subsequent discovery of homozygous and compound heterozygous mutations in the dedicator of cytokinesis 6 (DOCK6) gene confirmed the existence of an autosomal recessive form of AOS and cemented the central role of Rho GTPase dysregulation in AOS pathogenesis.…”

“…[2,5,8] Developmental delay and seizures each occur in 8-9% of AOS cases overall, but are significantly more frequent (>45%) in patients with microcephaly and are strongly correlated with intracranial vascular defects. [5,9] Additional developmental defects manifesting in <2% of cases include gastrointestinal, renal or reproductive anomalies and facial dysmorphism. Based on the prevalence of cardiovascular and neurological abnormalities in AOS, the following additional diagnostic criteria should be considered highly suggestive of a diagnosis: a) ACC and/or TTLD in combination with CHD, CMTC or other vascular anomaly; b) ACC and/or TTLD in association with CNS defects; c) cardiovascular or CNS defects and a first-degree relative with features consistent with AOS (Table 1).…”

“…Whilst the vast majority exhibit the hallmark features of AOS, DOCK6 mutation carriers also have a broad range of additional abnormalities and are strongly correlated with CNS and ocular defects ( Table 2). [8,9] Of note, it has been demonstrated that DOCK6 harbours a high than expected frequency of likely deleterious variation in the general population, highlighting the possibility of a more complex disease aetiology for this gene, potentially dependent on genetic background. [13] More recently, a particular focus has developed around the Notch signalling cascade in the aetiology of AOS.…”

“…EOGT was identified as a causal AOS gene through genome-wide autozygosity mapping and has been independently validated in a small number of sporadic cases. [9,15] Of interest, nine probands share a c.1074delA (p.Gly359Aspfs*28) mutation; however, as the majority belong to Bedouin tribes, this likely indicates a founder mutation in the Arab population. [15,16] The major genetic risk factors for autosomal dominant AOS are NOTCH1 and the delta-like canonical Notch ligand 4 (DLL4).…”

“…Consequently, >20% of identified NOTCH1 variants are considered variants of unknown significance (and have therefore not been included here). [9] Given the clustering of AOS mutations within the Notch pathway, DLL4 was screened as a candidate gene due to its essential role in vascular development. Missense or nonsense DLL4 mutations account for ~6% of all reported AOS cases and, by contrast to ARHGAP31, have a stronger correlation with ACC ( Table 2).…”