Abstract 150: Whole exome sequencing of siblings identifies a novel variant p.A399fs in ANOS1 gene associated with Kallman syndrome

Background: Kallman Syndrome is an uncommon condition characterised by absent pubertal development and abnormalities of smell, secondary to GnRH deficiency and aplasia or hypoplasia of the olfactory bulb. Kallman Syndrome is the most common cause of isolated hypogonadotropic hypogonadism, but in the majority of cases, genetic diagnosis remains elusive. The arrival of Next-generation Sequencing (NGS) in the clinical landscape has revolutionised genomic research and helped in the expansion of the genetic repertoire of Kallman Syndrome. Objectives: Identification of the genetic mutation in two siblings with Kallman syndrome. Methods: Whole exome analysis was performed to identify the genetic defect. The variants were prioritized using standard open-source computational pipelines. Results: Whole-exome sequencing and computational analysis identified a novel frameshift mutation (c.1195_1196insG) in exon 8 of the ANOS1 (KAL1) gene. The absence of dental agenesis, synkinesis and renal agenesis in one sibling otherwise commonly seen with ANOS1 variants suggest the p.A399fs variant is associated with a milder phenotype. Conclusions: To the best of our knowledge, this is the first report describing Kallman syndrome due to novel frameshift ANOS1 gene mutations. The report also exemplifies the utility of whole-exome sequencing in cases of atypical presentation of rare diseases.