Whole-exome sequencing identified compound heterozygous variants in DNAH5 in a Chinese pedigree with idiopathic hypogonadotropic hypogonadism

Abstract Purpose: This study was designed to identify the underlying molecular genetic cause of idiopathic hypogonadotropic hypogonadism (IHH) in a nonconsanguineous Chinese family. Methods: All the family members underwent medical history evaluation, physical examination, and laboratory studies. Whole-exome sequencing and RNA sequencing was performed on 2 affected siblings and unaffected parents. All candidate variants were confirmed in all family members by Sanger sequencing and silico function prediction. Results: The proband and his twin brother were diagnosed with IHH, and an autosomal recessive mode of inheritance was identified. Whole-exome sequencing identified the compound heterozygous variants c.9230G>A (p.Arg3077Gln) and c.12883G>A (p.Val4295Met) in DNAH5 in both affected siblings. Sanger sequencing verified that c.9230G>A in DNAH5 was from the unaffected mother and c.12883G>A was from the unaffected father. In addition, we found heterozygous mutations in BBS2 (c.1705delC, p.Gln569fs) and NR5A1 (c.460G>A, p.Ala154Thr) in the siblings, which were from their father.Conclusion: Compound heterozygous variants in DNAH5 were identified in the affected siblings, and were predicted to be pathogenic by silico analysis. This is the first report that suggests variants in DNAH5 are relevant to the pathogenesis of IHH. This study expands the variant spectrum of genes associated with IHH.