A respiratory/Hirschsprung phenotype in a three‐generation family associated with a novel pathogenic PHOX2B splice donor mutation

BACKGROUND: Mutations in the PHOX2B gene cause congenital central hypoventilation syndrome (CCHS), a rare autonomic nervous system dysfunction disorder characterized by a decreased ventilatory response to hypercapnia. Affected subjects develop alveolar hypoventilation requiring ventilatory support particularly during the non‐REM phase of sleep. In more severe cases, hypoventilation may extend into wakefulness. CCHS is associated with disorders characterized by the defective migration/differentiation of neural crest derivatives, including aganglionic megacolon or milder gastrointestinal phenotypes, such as constipation. Most cases of CCHS are de novo, caused by heterozygosity for polyalanine repeat expansion mutations (PARMs) in exon 3. About 10% of cases are due to heterozygous non‐PARM missense, nonsense or frameshift mutations. METHODS: We describe a three‐generation Maltese‐Caucasian family with a variable respiratory/Hirschsprung phenotype, characterized by chronic constipation, three siblings with Hirschsprung disease necessitating surgery, chronic hypoxia, and alveolar hypoventilation requiring non‐invasive ventilation. RESULTS: The sequencing of PHOX2B revealed a novel heterozygous c.241+2delT splice variant in exon 1 that segregates with the CCHS/Hirschsprung phenotype in the family. The mutation generates a non‐functional splice site with a deleterious effect on protein structure and is pathogenic according to ACMG P VS1, PM2, and PP1 criteria. CONCLUSION: This report is significant as no PHOX2B splice‐site mutations have been reported. Additionally, it highlights the variability in clinical expression and disease severity of non‐PARM mutations.