Background: Nephronophthisis is a group of genetically heterogeneous autosomal recessive cystic kidney disorders with a wide spectrum of severity and age of onset. We present a clinical and genetic study of a lethal form of nephronophthisis in neonates. Study Design: Clinical and genetic investigations of a case series. Setting & Participants: 12 affected offspring born to consanguineous parents from the Old Order Amish community. Outcomes: In this extended pedigree, the disorder is particularly severe; affected individuals survive only hours or days, with the cause of death invariably respiratory distress. Results: Cystic kidneys were confirmed in 11 infants and suspected in an additional individual who had 2 affected siblings. Although the renal aspect of the phenotype was a consistent feature in all affected individuals, additional pulmonary, cardiac, and urinary tract abnormalities are variable parts of this syndrome. Physical mapping of the causative mutation in this extended Amish pedigree highlighted a 475-kilobase candidate region on chromosome 3 that contains the NPHP3 gene. Sequence analysis of this gene showed a cytosine to thymine substitution in exon 15 (c.2104C→T) that cosegregated with the disease status. This substitution is predicted to lead to premature termination at position 702 of the protein product (p.Arg702X). Limitations: Because of the severe nature of this disease, few affected infants underwent full clinical evaluation. Conclusion: The presence of congenital malformations in the case series confirms the crucial role of NPHP3 in early embryonic development of the kidneys and urinary tract. The study also highlights the subtle variations in phenotypic expression in a cohort of patients with the same mutation in NPHP3.
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