DNAH14 变体与神经发育障碍有关,Human Mutation

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DNAH14 变体与神经发育障碍有关
Human Mutation ( IF 3.3 ) Pub Date : 2022-04-19 , DOI: 10.1002/humu.24386
Juan Li _{1,

2,

3} , Yu Yuan _{1,

2,

3} , Chaorong Liu _{1,

2,

3} , Yuchen Xu _{1,

2,

3} , Neng Xiao ₄ , Hongyu Long _{1,

2,

3} , Zhaohui Luo _{1,

2,

3} , Shujuan Meng _{1,

2,

3} , Hua Wang _{5,

6} , Bo Xiao _{1,

2,

3} , Xiao Mao _{5,

6} , Lili Long _{1,

2,

3,

6}

Affiliation

神经发育障碍 (NDD) 是涉及遗传和环境科学的复杂且多方面的疾病。测序技术的快速发展使得识别新的致病基因成为可能。我们的研究旨在鉴定与NDDs相关的新基因。进行三重全外显子组测序以评估潜在的 NDD 变体。我们确定了三名具有复合杂合DNAH14变体的无关患者。获得并系统回顾了招募患者的详细临床信息和遗传结果。三复合杂合DNAH14变体鉴定如下：c.6100C > T(p.Arg2034Ter) 和 c.5167A > G(p.Arg1723Gly)、c.12640_12641delAA(p.Lys4214Valfs*7) 和 c.4811T > A(p.Leu1604Gln)， andc.7615C > A(p.Pro2539Thr) 和 c.11578G > A(p.Gly3860Ser)，包括一种无义、一种移码和四种错义变体，根据 gnomAD 数据库，这些变体不存在或次要等位基因频率较低。通过使用多种生物信息学工具，假设错义变体具有破坏性或可能破坏性。其中四个变体位于 AAA+ ATPase 结构域，而两个位于 C 末端结构域。大多数受影响的氨基酸在各种物种中高度保守。观察到一系列神经和发育表型，包括癫痫发作、整体发育迟缓、小头畸形和肌张力减退。因此，DNAH14可能导致以前无法识别的 NDD。

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DNAH14 variants are associated with neurodevelopmental disorders

Neurodevelopmental disorders (NDD) are complex and multifaceted diseases involving genetic and environmental sciences. Rapid developments in sequencing techniques have made it possible to identify new disease-causing genes. Our study aimed to identify novel genes associated with NDDs. Trio whole-exome sequencing was performed to evaluate potential NDD variants. We identified three unrelated patients with compound heterozygous DNAH14 variants. The detailed clinical information and genetic results of the recruited patients were obtained and systematically reviewed. Three compound heterozygous DNAH14 variants were identified as follows: c.6100C > T(p.Arg2034Ter) and c.5167A > G(p.Arg1723Gly), c.12640_12641delAA(p.Lys4214Valfs*7) and c.4811T > A(p.Leu1604Gln), andc.7615C > A(p.Pro2539Thr) and c.11578G > A(p.Gly3860Ser), including one nonsense, one frameshift, and four missense variants, which were not existent or with low minor allele frequencies based on the gnomAD database. The missense variants were assumed to be damaging or probably damaging by using multiple bioinformatics tools. Four of these variants were located in the AAA+ ATPase domain, while two were located in the C-terminal domain. Most affected amino acids were highly conserved in various species. A spectrum of neurological and developmental phenotypes was observed, including seizures, global developmental delay, microcephaly, and hypotonia. Thus, our findings indicate that variants of DNAH14 could lead to previously unrecognized NDDs.

更新日期：2022-04-19

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