Novel interstitial deletion in Xp22.3 in a typical X-linked recessive family with Kallmann syndrome

Kallmann syndrome (KS) is a clinically and genetically heterogeneous condition characterised by hypogonadotropic hypogonadism with anosmia or hyposmia. More than nineteen genes causing KS have been reported to date. KAL1, first identified to causing the X-linked form of KS, accounts for 10%-20% of KS patients. In this study, we designed a panel including 17 known genes causing KS for genetic diagnosis and research and report a typical and rare family of which three generations had been affected by KS. A novel CNV in Xp22.3 was identified through targeted next-sequencing technology and high-resolution microarray. The breakpoint (chrX:8536480 and chrX:8730416) was defined, and the size of deletion is about 0.24Mb. The CNV including KAL1 and FAM9A had a negative effect on the expression of KAL1, resulting in decreased level of KAL1 mRNA in whole blood. In addition, the proband had significant improvement in testicular volumes and secondary sex characters except spermatogenesis after regular treatment, which indicates the CNV may have a negative effect on spermatogenesis. Our study expands the genotypic spectrum of KAL1 mutations associated with KS and provides a practical pipeline for genetic diagnosis or research.