Lung functions of survivors of CDH remain abnormal throughout the first 3 years of life. The degree of pulmonary function impairment correlated both with markers of the initial degree of pulmonary hypoplasia and the duration of mechanical ventilation. Understanding the relationship between the phenotypic presentation of CDH and the potential for subsequent lung growth could help refine both pre- and postnatal therapies to optimize lung growth in CDH infants.

Pathogenic variants in PHOX2B lead to congenital central hypoventilation syndrome (CCHS), a rare disorder of the nervous system characterized by autonomic dysregulation and hypoventilation typically presenting in the neonatal period, although a milder late-onset (LO) presentation has been reported. More than 90% of cases are caused by polyalanine repeat mutations (PARMs) in the C-terminus of the protein; however non-polyalanine repeat mutations (NPARMs) have been reported. Most NPARMs are located in exon 3 of PHOX2B and result in a more severe clinical presentation including Hirschsprung disease (HSCR) and/or peripheral neuroblastic tumors (PNTs). A previously reported nonsense pathogenic variant in exon 1 of a patient with LO-CCHS and no HSCR or PNTs leads to translational reinitiation at a downstream AUG codon producing an N-terminally truncated protein. Here we report additional individuals with nonsense pathogenic variants in exon 1 of PHOX2B. In vitro analyses were used to determine if these and other reported nonsense variants in PHOX2B exon 1 produced N-terminally truncated proteins. We found that all tested nonsense variants in PHOX2B exon 1 produced a truncated protein of the same size. This truncated protein localized to the nucleus and transactivated a target promoter. These data suggest that nonsense pathogenic variants in the first exon of PHOX2B likely escape nonsense mediated decay (NMD) and produce N-terminally truncated proteins functionally distinct from those produced by the more common PARMs.

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