Whole exome sequencing of paediatric patients with Cogan's syndrome to identify monogenic mimics.

Abstract

OBJECTIVES: Cogan's syndrome (CS) is a rare variable vessel vasculitis, describing sensorineural hearing loss (SNHL), inflammatory ocular disease and vestibular dysfunction. We hypothesized that within paediatric-onset (p)CS, a proportion would have monogenic disease, either autoinflammatory and/or associated with SNHL. METHODS: Whole exome sequencing (WES) was performed and analysed using an in-house pipeline incorporating virtual gene panels for inflammation and SNHL; copy number variant analysis (ExomeDepth); and phenotype-driven variant prioritization (Exomiser). Genetic variants were interpreted by a multi-disciplinary team according to American College of Medical Genetics and Genomics guidelines. RESULTS: Ten patients with a clinical diagnosis of pCS were enrolled. Three/10 (30%) had a monogenic contribution to the phenotype based on Class 4/5 variants: de novo NLRP3 p.T915R (n = 1) associated with Cryopyrin-associated periodic syndrome; MYO7A p.K542Qfs*5 (n = 1) causing SNHL; and HBB homozygous p.E7V causing sickle cell disease (associated with hearing loss and uveitis). A further two cases had possible monogenic contribution with the following rare variants of uncertain significance (class 3): ADGRV1 compound heterozygous variants (n = 1) associated with Usher syndrome; and a novel ALPK1 p.H735P (n = 1), associated with Retinal dystrophy Optic nerve oedema Splenomegaly Anhidrosis Headache (ROSAH) syndrome. CONCLUSIONS: In children presenting with features suggesting CS, genetic screening should be considered before conferring this rare diagnostic label since at least 30% had an alternative monogenic contribution to the phenotype rather than true pCS, with implications for treatment and prognosis. We thus advocate for genetic testing using next-generation sequencing for patients presenting with pCS.