Further Genetic Unraveling of Persistent Tachypnea of Infancy

BACKGROUND: Childhood interstitial lung diseases (chILDs) are rare, heterogeneous chronic pulmonary disorders that are often underdiagnosed due to their low prevalence and nonspecific clinical presentation. Persistent tachypnea of infancy (PTI), often referred to as neuroendocrine cell hyperplasia of infancy (NEHI), is 1 of the most frequent forms of chILD, although its underlying etiology remains unknown. RESEARCH QUESTION: Can comprehensive genetic testing significantly improve diagnostic yield in patients with PTI/NEHI compared with limited testing of established genes? STUDY DESIGN AND METHODS: We conducted a comparative genetic analysis, using exome sequencing, in a multicenter cohort of patients who had received diagnoses of PTI/NEHI and contrasted their findings with those of patients with chILD who did not meet the diagnostic criteria for PTI/NEHI (referred to as the non-PTI/NEHI group). Diagnostic yield was assessed in both groups, and patients were further stratified into subgroups to evaluate whether clinical characteristics or comorbidities differed between those with and without genetic diagnosis. RESULTS: In 12 patients with PTI/NEHI, broad genetic testing identified potentially pathogenic variants associated with known human conditions. Notably, the same genes were identified across multiple individuals exclusively in the PTI/NEHI subgroup, including SRRM2 (n = 5) and NAA10 (n = 3). Both genes are associated with complex disorders primarily manifesting neurodevelopmental delay, as are the 4 other genes (BRWD3, DEPDC5, NKX2-1, UBE3B) identified in the children with PTI/NEHI. Among 79 patients with PTI/NEHI, those with neurodevelopmental comorbidity had a significantly higher likelihood of receiving a genetic diagnosis (11 of 24; 45.8%) than those without (1 of 55; Fisher exact test, P < .001). INTERPRETATION: Our data further support the view that PTI/NEHI represents a phenotype rather than a disease entity and may occur in the context of various genetic conditions, including, but probably not limited to, neurodevelopmental disorders. Early genetic testing may help reduce diagnostic delays, and exome sequencing is particularly recommended in patients with PTI/NEHI with neurodevelopmental involvement.