A Novel Noncanonical Splicing Mutation of ANOS1 Gene in Siblings with Kallmann Syndrome Identified by Whole-Exome Sequencing

Kallmann syndrome (KS) is a rare genetic disorder that is characterized by idiopathic hypogonadotropic hypogonadism associated with anosmia. Genetic variants in ANOS1 gene are the most common mutations associated with X-linked recessive form of KS. Canonical +/- 1 or 2 splice site variants in ANOS1 have been described to be responsible for KS. Here, we identified a novel noncanonical splice site variant (c.1062+4T>C) in ANOS1 gene in two siblings with KS by whole-exome sequencing (WES). Sanger sequencing showed this mutation was inherited from their mother, whose brother was a KS patient as well. Through the functional assay in vitro, we found that this mutation resulted in a 50-bp deletion of exon 7, which caused frameshift mutation leading to a premature termination of translation and a truncated anosmin-1 protein. Our results revealed that this noncanonical splice site variant is involved in KS. Thus, it is suggested that we should pay attention to the noncanonical splice site variants when using molecular genetic diagnostics of KS.

Automated summary

Kallmann syndrome (KS) is a rare genetic disorder characterized by idiopathic hypogonadotropic hypogonadism associated with anosmia. A novel noncanonical splice site variant in the ANOS1 gene was identified in two siblings with KS, leading to a premature termination of translation and a truncated anosmin-1 protein. This study highlights the importance of considering noncanonical splice site variants in molecular genetic diagnostics of KS.