Pseudodominant inheritance of nephronophthisis caused by a homozygous NPHP1 deletion

Abstract

Nephronophthisis (NPHP) is an autosomal recessive kidney disease characterized by tubular basement membrane disruption, interstitial infiltration, and tubular cysts. NPHP leads to end-stage renal failure (ESRD) in the first three decades of life and is the most frequent genetic cause of chronic renal failure in children and young adults. Extrarenal manifestations are known, such as retinitis pigmentosa, brainstem and cerebellar anomalies, liver fibrosis, and ocular motor apraxia type Cogan. We report on a Turkish family with clinical signs of nephronophthisis. The phenotype occurred in two generations and therefore seemed to be inherited in an autosomal dominant pattern. Nevertheless, a deletion analysis of the NPHP1 gene on chromosome 2 was performed and showed a homozygous deletion. Analysis of the family pedigree indicated no obvious consanguinity in the last three generations. However, haplotype analysis demonstrated homozygosity on chromosome 2 indicating a common ancestor to the parents of all affected individuals. NPHP1 deletion analysis should always be considered in patients with apparently dominant nephronophthisis. Furthermore, three out of four patients developed ESRD between 27 and 43 years of age, which may be influenced by yet unknown modifier genes.

Figure 1

Pedigree of the family F852. Solid symbols, affected individuals; circles, females; squares, males.

Figure 2

Screening for a homozygous deletions in the NPHP1 gene in family F852 using a multiplex PCR approach amplifying five different markers. Two control markers (a, e) and three NPHP1 exon markers [d (exon 7, 236 bp), c (exon 5, 339 bp), b (exon 20, 436 bp)] were amplified in a single multiplex PCR. Note that patients III-2, III-3, III-5, and IV-1 lack the bands for the respective NPHP1 exons, indicating a homozygous NPHP1 deletion and confirming the diagnosis NPHP type 1. L, 100-bp ladder DNA size marker (New England Biolabs, Beverly, MA).

Figure 3

Haplotypes on chromosome 2q12.2 to 2q14.2 of family F852. Six microsatellite markers, from cen to q-ter (top to bottom), are shown to the left of the pedigrees. Symbols are as in figure 1.