Further genetic unravelling of persistent tachypnoea of infancy (PTI/NEHI)

BACKGROUND: Childhood interstitial lung diseases (chILDs) are rare, heterogeneous chronic pulmonary disorders that are often underdiagnosed due to their low prevalence and non-specific clinical presentation. Persistent tachypnea of infancy, often referred to as neuroendocrine cell hyperplasia of infancy (PTI/NEHI), is one of the most frequent forms of chILD, though its underlying etiology remains unknown. RESEARCH QUESTION: Can comprehensive genetic testing significantly improve diagnostic yield in PTI/NEHI patients compared with limited testing of established genes? METHODS: We conducted a comparative genetic analysis using exome sequencing in a multicenter cohort of patients diagnosed with PTI/NEHI and contrasted their findings with those of chILD patients who did not meet the diagnostic criteria for PTI/NEHI (referred to as 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 differ between those with and without genetic diagnosis. RESULTS: In 12 PTI/NEHI patients, 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 four other genes (BRWD3, DEPDC5, NKX2-1, UBE3B) identified in the PTI/NEHI children. Among 79 PTI/NEHI patients, those with neurodevelopmental comorbidity had a significantly higher likelihood of receiving a genetic diagnosis (11/24, 45.8%) than those without (1/55; Fisher's exact test, P<0.001). 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 PTI/NEHI patients with neurodevelopmental involvement.