Normandie Univ, UNIROUEN, INSERM U1245; Rouen University Hospital, Department of Pathology, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.
Institut National de la Santé et de la Recherche Médicale (Inserm), UMR-1195, Université Paris Saclay, Le Kremlin-Bicetre, France.
J Med Genet. 2022 Jun;59(6):559-567. doi: 10.1136/jmedgenet-2020-107595. Epub 2021 Apr 5.
Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.
Several genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.
We achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (, , , , , , , and ). Moreover, we identified pathogenic variants in and expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).
New genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.
先天性多发性关节挛缩症（AMC）的特征是两个或多个身体部位存在先天性关节挛缩。AMC 表现出广泛的表型和遗传异质性。我们的目标是提高 AMC 的遗传诊断率，评估全外显子组测序（WES）相对于靶向外显子组测序（TES）的附加价值，并在 315 个未确诊的 AMC 无关家族中鉴定新基因。
使用了几种基因组方法，包括在多态性或近亲家族中对疾病基因座进行遗传作图、TES 然后是 WES。进行 Sanger 测序以鉴定或验证变体。
我们在 52.7%的 AMC 索引患者中实现了疾病基因鉴定，包括最近鉴定的九个基因（、、、、、、、和）。此外，我们在和中鉴定出了致病性变异，扩展了与这些基因相关的表型。AMC 最常见的原因是骨骼肌肉的原发性受累（40%），其次是大脑（22%）。最常见的遗传方式是常染色体隐性遗传（66.3%的患者）。在非近亲父母（n=60）所生的散发性患者中，在其中 30 名患者（50%）中观察到从头出现的常染色体显性或 X 连锁变异。
最近在 AMC 中鉴定的新基因代表了我们队列中致病基因的 21%。观察到大量的新生变异表明，这种机制在这种发育性疾病中起着重要作用。与 TES 相比，我们的数据表明 WES 的附加价值，因为一些疾病基因的临床谱比最初描述的更大，并且鉴定了新的基因。
