Study on genetic etiology of three cases of Kallmann syndrome using whole-exome sequencing / 中华内分泌代谢杂志

ABSTRACT

Objective:Kallmann syndrome(KS) is a complex genetic disease characterized by congenital hypogonadotropic hypogonadism and anosmia. More than 20 genes have been reported to be associated with KS. Herein, we explore potential genetic aberration in 3 KS patients using the whole-exome sequencing. The potentially pathogenic variants filtered were validated by Sanger sequencing.Methods:Genomic DNA was extracted from the peripheral blood of 3 patients with KS and their family members. Sanger sequencing and pedigree verification were performed on the pathogenic variants identified using whole-exome sequencing. The function of the mutation sites were analyzed with bioinformatics software.Results:The proband 1 was a 25 years old male, characterized by lower gonadotropin gonad hypofunction, early grey hair and bilateral sensorineural hearing loss. A heterozygous mutation c. 475C>T(p.R159W) of SOX10 gene was detected in the proband 1. His mother, sister and cousin who had KS phenotype were also found carrying this mutation, showing an autosomal dominant inheritance. The proband 2 was a 15-year-old male with hypogonadotropic hypogonadism and unilateral renal agenesis. The proband was hemizygous for c. 844delC(p.R282Vfs*28) of ANOS1 gene, his mother was heterozygous for the mutation, which was consistent with the X-linked recessive inheritance. The proband 3 was a 21 years old female, characterized by hypogonadotropic hypogonadism and anosmia. A heterozygous missense mutation c. 149G>A(p.R50Q) was detected in FGF17 gene. The mutation p. R50Q was predicted to be pathogenic by the SIFT and PolyPhen2 programs, and has not been reported in HGDM database yet, which considered to be a novel mutation.Conclusion:KS is a clinically and genetically heterogeneous disease. In this study, ANOS1 c. 844delC, SOX10 c. 475C>T and FGF17 c. 149G>A mutations were found in 3 patients with KS by whole exome sequencing, which would expand the genotypic and phenotype spectrum of KS.