De novo SRRM2 variants in neuroendocrine cell hyperplasia of infancy and persistent tachypnea of infancy

Background Neuroendocrine cell hyperplasia of infancy (NEHI), also called persistent tachypnea of infancy (PTI), is a major cause of childhood interstitial lung disease. This rare lung disease is responsible for respiratory insufficiency in the first years of life. Non-pulmonary symptoms have also been reported, including failure to thrive and developmental delay. The pathophysiology of NEHI/PTI remains unclear. To identify candidate genes of NEHI/PTI, we performed whole genome and whole exome sequencing in a large cohort of deeply phenotyped patients. Methods Trio whole genomes sequencing were performed (n=21) to identify a candidate gene. Following identification of a candidate gene, whole exomes sequencing wereas performed to screen this gene in the remaining NEHI/PTI patients (n=50). Results Four de novo loss-of-function (LoF) variants of SRRM2 were identified in 4 out of 71 NEHI/PTI patients with typical pulmonary presentation. Serine/arginine repetitive matrix protein 2 (SRRM2) is involved in mRNA splicing, and LoF SRRM2 variants have recently been reported in patients with neurodevelopmental delay (NDD). All four NEHI/PTI patients also had mild NDD. The prevalence of SRRM2 LoF variants in our cohort (5.6%;95% CI: 1.6% to 13.8%) is 20 to 100 times higher than in reported patients with NDD without lung disease, therefore the phenotypic spectrum of SRRM2- associated disease should be extended to NEHI/PTI. Conclusion This study identifies SRRM2- related disorder as a monogenic cause of NEHI/PTI. These results suggest that NEHI/PTI patients should be evaluated by a paediatric neurologist and that SRRM2 sequencing should be included in every NEHI/PTI work-up.