A rare ANOS1 variant in siblings with Kallmann syndrome identified by whole exome sequencing. (6th December 2017) - Lopategui, D. M.
Summary: Kallmann syndrome is a rare genetic condition causing congenital hypogonadotropic hypogonadism. It presents with delayed puberty, anosmia, and infertility. Here, we set out to identify a causative DNA variant for Kallmann syndrome in two affected brothers of Hispanic ancestry. The male siblings presented with a clinical diagnosis of Kallmann syndrome (anosmia, delayed puberty, azoospermia, and undetectable luteinizing hormone and follicle stimulating hormone levels). Genetic variations were investigated by whole exome sequencing. Potentially pathogenic variants were filtered and prioritized followed by validation by Sanger sequencing in the two brothers and their mother. A pathogenic variant was identified in the ANOS1 gene on the X chromosome: c.1267C>T; both brothers were hemizygous, and their mother was heterozygous for the variant. The variant is a single nucleotide change that introduces a stop codon in exon 9 (p.R423*), likely producing a truncated variant of the protein. This variant has only been reported twice in the literature, in the setting of finding genetic causes for other conditions. This result supports the clinical value of whole exome sequencing for identification of genetic pathogenic variants. Genetic diagnosis is the essential first step for genetic counseling, preimplantation diagnosis, and research for a potential treatment.