Whole exome sequencing reveals monogenic mimics in pediatric Cogan syndrome
The study reports whole exome sequencing of ten pediatric patients initially diagnosed with Cogan syndrome, a rare variable vessel vasculitis. Investigators found that thirty percent carried pathogenic or likely pathogenic variants in genes linked to autoinflammatory disorders, hearing loss, or sickle cell disease, while two additional cases harbored variants of uncertain significance. These results demonstrate that monogenic conditions frequently mimic this rare vasculitis in children. The findings underscore the diagnostic utility of next-generation sequencing panels in pediatric rheumatology and recommend genetic screening prior to assigning a Cogan syndrome diagnosis to guide targeted management and prognosis.
The original study
Whole exome sequencing of paediatric patients with Cogan's syndrome to identify monogenic mimics.
- Authors
- McLellan K, Price-Kuehne F, Burleigh A, Martin N, Hicks S, Hutton L, et al.
- Journal
- Rheumatology (Oxford, England)
- Type
- Journal Article
- PMID
- 42640550
Original abstract
OBJECTIVES: Cogan's syndrome (CS) is a rare variable vessel vasculitis, describing sensorineural hearing loss (SNHL), inflammatory ocular disease, and vestibular dysfunction. We hypothesised 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 prioritisation (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.