Wei Weidong, Wang Xiaosha, Zhang Tao, Zhong Yongxing, Zhang Jintang, Yuan Hua, Shi Xiaoliang, He Yao, Pan Haitao, Yang Zhen, Wang Yuejuan
Shaoxing Maternity and Child Health Care Hospital, Shaoxing, Zhejiang, China.
Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, Zhejiang, China.
Front Pediatr. 2025 Jul 31;13:1611387. doi: 10.3389/fped.2025.1611387. eCollection 2025.
The gene, a member of the basic helix-loop-helix (bHLH) family of transcription factors, plays a critical role in limb development. Mutations in have been associated with various limb malformations, including syndactyly and split-hand/foot malformation. This study aimed to identify and characterize novel variants in a fetus with complex limb and renal abnormalities, providing further insights into the genetic basis of developmental disorders.
We performed Exome sequencing (ES) on a fetus with severe limb malformations and renal anomalies, along with the parents. Sanger sequencing was used to validate the identified variants. Evolutionary conservation analysis and structural predictions using AlphaFold were conducted to assess the functional impact of the variants. Protein-protein interaction networks were generated using the STRING database to explore potential functional partners of BHLHA9.
The proband exhibited multicystic dysplasia of the left kidney, an accessory renal artery, bilateral hand anomalies (four fingers with absent thumbs), bilateral foot syndactyly, and a facial scar. ES identified two novel compound heterozygous variants in the gene: c.251C>T (p.Ala84Val) inherited from the father, and c.250_261dup (p.Ala84_Ala87dup) inherited from the mother. The two variants all located within the helix-loop-helix (HLH) domain, a critical region for protein-protein interactions and DNA binding. Evolutionary conservation analysis revealed that the affected residues are highly conserved across species, and structural predictions suggested that the two variants may disrupt the HLH domain's structural integrity. Protein-protein interaction analysis identified several potential functional partners of BHLHA9, including ASCL5, YWHAE, and PAFAH1B1, which are involved in transcriptional regulation, signaling pathways, and neuronal migration, respectively.
This study identifies novel compound heterozygous variants in the gene represents a rare autosomal recessive disorder with severe limb and renal abnormalities. The c.251C>T and c.250_261dup variants, located within the HLH domain, is predicted to impair protein function, potentially disrupting limb development. These findings expand the spectrum of mutations linked to developmental disorders and highlight the importance of the HLH domain in BHLHA9's regulatory role.
该基因是转录因子基本螺旋-环-螺旋（bHLH）家族的成员，在肢体发育中起关键作用。该基因突变与多种肢体畸形有关，包括并指畸形和裂手/裂足畸形。本研究旨在鉴定和表征一名患有复杂肢体和肾脏异常的胎儿中的新型基因变异，为发育障碍的遗传基础提供进一步的见解。
我们对一名患有严重肢体畸形和肾脏异常的胎儿及其父母进行了外显子组测序（ES）。使用桑格测序法验证鉴定出的变异。进行进化保守性分析，并使用AlphaFold进行结构预测，以评估变异的功能影响。使用STRING数据库生成蛋白质-蛋白质相互作用网络，以探索BHLHA9的潜在功能伙伴。
先证者表现出左肾多囊性发育不良、一条副肾动脉、双侧手部异常（四指缺拇指）、双侧足部并指畸形和面部瘢痕。外显子组测序在该基因中鉴定出两个新型复合杂合变异：从父亲遗传的c.251C>T（p.Ala84Val），以及从母亲遗传的c.250_261dup（p.Ala84_Ala87dup）。这两个变异均位于螺旋-环-螺旋（HLH）结构域内，这是蛋白质-蛋白质相互作用和DNA结合的关键区域。进化保守性分析表明，受影响的残基在物种间高度保守，结构预测表明这两个变异可能破坏HLH结构域的结构完整性。蛋白质-蛋白质相互作用分析确定了BHLHA9的几个潜在功能伙伴，包括ASCL5、YWHAE和PAFAH1B1，它们分别参与转录调控、信号通路和神经元迁移。
本研究鉴定出该基因中的新型复合杂合变异，代表一种罕见的常染色体隐性疾病，伴有严重的肢体和肾脏异常。位于HLH结构域内的c.251C>T和c.250_261dup变异预计会损害蛋白质功能，可能破坏肢体发育。这些发现扩展了与发育障碍相关的基因突变谱，并突出了HLH结构域在BHLHA9调节作用中的重要性。
