The European respiratory journal · 2026
D e novo SRRM2 variants in neuroendocrine cell hyperplasia of infancy and persistent tachypnoea of infancy.
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Louvrier Camille, Soreze Yohan, Mesinele Julie, de Becdelièvre Alix, Desroziers Tifenn, Nau Valérie, Dastot-Le Moal Florence, Levergeois Romain, Legendre Marie, Giurgea Irina, Konyukh Marina, Abou Taam Rola, Becourt Arnaud, Cosson Laure, Gibertini Isabelle, Borie Raphaël, Rodriguez Diana, Troadec Corinne, Coulomb L'Herminé Aurore, Dubus Jean-Christophe, Nathan Nadia
Аннотация
BACKGROUND: Neuroendocrine cell hyperplasia of infancy (NEHI), also called persistent tachypnoea 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 sequencing (WGS) and whole-exome sequencing (WES) in a large cohort of deeply phenotyped patients.
METHODS: Trio WGS was performed (n=21) to identify a candidate gene. Following identification of a candidate gene, WES was 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 four out of 71 NEHI/PTI patients with typical pulmonary presentation. Serine/arginine repetitive matrix protein 2 (SRRM2) is involved in mRNA splicing, and SRRM2 LoF 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 1.6-13.8%) is 20-100 times higher than reported in 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 workup.
METHODS: Trio WGS was performed (n=21) to identify a candidate gene. Following identification of a candidate gene, WES was 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 four out of 71 NEHI/PTI patients with typical pulmonary presentation. Serine/arginine repetitive matrix protein 2 (SRRM2) is involved in mRNA splicing, and SRRM2 LoF 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 1.6-13.8%) is 20-100 times higher than reported in 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 workup.