Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.
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DOI：
10.1002/humu.23567
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发表时间：
2018-09
期刊：
影响因子：
3.9
通讯作者：
Wuyts W
中科院分区：
文献类型：
--
作者：
Meester JAN;Sukalo M;Schröder KC;Schanze D;Baynam G;Borck G;Bramswig NC;Duman D;Gilbert-Dussardier B;Holder-Espinasse M;Itin P;Johnson DS;Joss S;Koillinen H;McKenzie F;Morton J;Nelle H;Reardon W;Roll C;Salih MA;Savarirayan R;Scurr I;Splitt M;Thompson E;Titheradge H;Travers CP;Van Maldergem L;Whiteford M;Wieczorek D;Vandeweyer G;Trembath R;Van Laer L;Loeys BL;Zenker M;Southgate L;Wuyts W
Adams-Oliver综合征（AOS）是一种罕见的发育障碍性疾病，其特征是先天性头皮发育不全（ACC）和横向末端肢体缺损（TTLD）。AOS的常染色体显性形式与ARHGAP 31、DLL 4、NOTCH 1或RBPJ中的突变相关，而DOCK 6和EOGT是常染色体隐性遗传的基础。目前关于大型队列中突变频率和分布的数据有限。因此，本研究的目的是在广泛的队列中全面检查AOS的遗传结构。使用下一代和/或毛细管测序分析对194个AOS/ACC/TTLD先证者/家族进行分子诊断筛查。总共，我们确定了63个（可能的）致病突变，包括56个不同的和22个新的突变，为30%的患者提供了分子诊断。与以前的报告一起，这些发现使报告的疾病变体总数达到63种，在家族性病例中的诊断率为36%。NOTCH 1是主要贡献者，是10% AOS/ACC/TTLD病例的基础，DLL 4（6%）、DOCK 6（6%）、ARHGAP 31（3%）、EOGT（3%）和RBPJ（2%）代表该队列中的其他因果关系。我们确认了AOS/ACC/TTLD谱中遗传筛查的相关性，突出了初步但重要的基因型-表型相关性。该队列提供了进一步基因鉴定的潜力，以解决缺失的遗传性。
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.
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