<i>SRRM2</i> and neuroendocrine cell hyperplasia of infancy: connecting neurodevelopment to the lungs

<title>Extract</title> In 2022, we reported 22 patients with heterozygous loss-of function (LoF) variants in <italic>SRRM2</italic>, whose phenotype included intellectual disability, overweight and characteristic facial features [1]. <italic>SRRM2</italic> 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 <italic>de novo</italic> truncating variants in <italic>SRRM2</italic>. 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 <italic>SRRM2</italic>-related disorder (<italic>SRRM2</italic>-RD) as a Mendelian disease. As the cohort progressed, we gradually began to see recurring features in patients, and even recognisable traits (<italic>e.g.</italic> 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.