SRRM2 and neuroendocrine cell hyperplasia of infancy: connecting neurodevelopment to the lungs

Extract In 2022, we reported 22 patients with heterozygous loss-of function (LoF) variants in SRRM2, whose phenotype included intellectual disability, overweight and characteristic facial features 1. SRRM2 was initially nominated as a candidate gene for neurodevelopmental disorders (NDDs), based on statistical evidence 2. This enabled us to identify the first group of patients, through a genotype-to-phenotype strategy. Using exome sequencing data from ∼700 individuals with NDD but without a molecular diagnosis, we identified two patients with de novo truncating variants in SRRM2. This prompted an international call for collaboration through the GeneMatcher platform 3, leading to the identification of 20 additional patients from 13 different countries, and introduction of SRRM2-related disorder (SRRM2-RD) as a Mendelian disease. As the cohort progressed, we gradually began to see recurring features in patients, and even recognisable traits (e.g. overweight, hypersociability, or some facial features including deep set eyes and broad bulbous nasal tip), pointing to a distinct syndrome rather than a non-specific entity with NDD. However, beyond neurodevelopmental features, organ dysfunction or malformation remained poorly documented, consisting mainly of sporadic observations of urogenital and cardiac malformations in these patients.