Background
Nephronophthisis (NPHP), an autosomal recessive hereditary disease, is a major cause of pediatric end-stage renal disease (ESRD) with an estimated incidence of 1:50,000 in Canada and 1:1,000,000 in the United States [
1‐
4]. The clinical characteristics are highly variable and causal mutations in 20 genes (
NPHP1–20) have been identified (
https://omim.org/search/?index=entry&sort=score+desc%2C+prefix_sort+desc&start=1&limit=10&search=%3DNephronophthisis). However, the genotypes of approximately 60% of NPHP patients remain unclassified [
5]. Homozygous deletion mutations in N
PHP1 are the most common genotype causing NPHP1 [
3,
5,
6]. The clinical characteristics of NPHP1 are generally nonspecific and mostly limited to the kidney, which commonly presents with polydipsia, polyuria, secondary enuresis and renal dysfunction. In some cases, the liver, pancreas, visual system and central nervous system (molar tooth sign on brain Magnetic Resonance Imaging) are involved [
7]. A study from Egypt found that among 20 NPHP1 patients (the mean age at diagnosis was 87 months), 95% had typical NPHP symptoms of polydipsia, polyuria and secondary enuresis and 75% of them presented with sign of ESRD [
8].
Almost all the patients with deletion-causing NPHP1 develop ESRD by the age of 19 years [
7,
9,
10]. Adult NPHP1 with late onset ESRD can easily be ignored by nephrologists in clinical practice. Recently, single-nucleotide polymorphism genotype identified 26 patients with homozygous
NPHP1 deletions among 5606 European patients with adult-onset ESRD. Before this genotyping, only three (12%) of the 26 patients were classified as NPHP. One of the 26 had proteinuria, but polyuria and ophthalmological and neurological anomalies were not detected. The others had been misdiagnosed with other nephropathy (46%) or chronic kidney disease of unknown etiology (42%) [
11]. The clinical heterogeneity of NPHP, particularly in adults, highlights the important role of genetic identification. However, diagnosis based on clinical presentation or Sanger sequencing alone appears to be inaccurate and time-consuming. In this study, we report two novel mutations in the
NPHP1 gene detected by whole-exome sequencing that cause adult NPHP1 with late onset ESRD in a Chinese intermarriage family.
Discussion and Conclusions
NPHP is a genetic disorder with highly variable clinical presentations. The majority of children with NPHP develop ESRD between the ages 11 to 13 years [
7]. Genetic identification is the golden standard for accurate diagnosis. Compared with Sanger sequencing, whole-exome sequencing is more time saving, effective and available along with the improved technique and reduced price. In this study, a novel homozygous nonsense mutation, p.E697X,37, and a novel homozygous missense mutation, p.F691 L, were identified in
NPHP1 by whole-exome sequencing in an adult with late onset ESRD. The proband’s parents and fraternal twin harbored were heterozygous for both loci without any clinical abnormality. As we know, interaction between mutations at different loci in a gene may result in different clinical phenotypes. The homozygous nonsense mutation caused a truncation of the protein is likely to be decisive in causing the disease, while the other missense mutation may modify its effect [
12‐
14]. The cumulative effect of the two
NPHP1 mutations might allow us to analyze the genotype-phenotype correlation.
Based on the age of ESRD onset, NPHP1 can be classified into three clinical forms, infantile, juvenile and adolescent. The median age of onset for juvenile ESRD is about 13 years old, and that for the adolescent form is younger than 19 years of age [
5]. The oldest age of onset for renal symptoms in a recent report of 60 NPHP1 patients was 16 years old [
7]. Recently, out of 5606 renal transplant recipients in Europe, 26 patients were re-diagnosed with NPHP1. Previously 88% of these 26 patients were classified as other chronic kidney disease. Among them, the median age of initial renal replacement therapy was 30 years old [
11]. In the current report, the onset age of renal dysfunction was 27, and his sister died of uremia at 23 years of age. To our knowledge, this is the first report of a case of adult NPHP1 with late onset ESRD in a Chinese intermarriage family [
15‐
17]. The clinical heterogeneity of the renal phenotype onset age may be ascribed to the type and position of the mutations and the interaction between them. The homozygous nonsense mutation caused a truncation of 37 amino acids of each DNA strands. The resulting protein of 696 amino acids may function normally; however, the truncated protein would be vulnerable and may eventually function abnormally. The protein would work normally with the heterozygous mutation.
Nephrocystins, encoded by
NPHP genes, are located in primary cilia and are essential for ciliary function. Mutations in
NPHP genes result in ciliopathy and the involvement of different organs leads to different clinical syndromes [
18,
19]. Joubert syndrome is diagnosed based on the presence of a molar tooth sign on cerebral magnetic resonance imaging; Senior–Løken syndrome presents NPHP and retinitis pigmentosa; COACH syndrome is characterized as additional hepatic fibrosis and/or ocular coloboma [
20]. Only two patients displayed extrarenal anomalies among 26 adult patients with NPHP1 [
11]. In a recent report, most of the patients (77%) with NPHP1 presented with isolated renal phenotypes, compared with 34% of patients with other NPHP subtypes. Within the NPHP1 cohort, the majority of patients reached ESRD between 11 to 13 years of age and the progression of chronic kidney disease was much faster [
7]; however, the family in this report presented high heterogeneity. Despite the tremendous advances in deciphering the molecular genetics of NPHP, the genotype-phenotype correlation is still beyond our understanding; even within the same family, mutations in the same locus can not fully explain the varied clinical manifestations. The cumulative effect of mutations and the interaction between them need to be considered. Of course, in addition to genetics, the onset and progression of NPHP are influenced by environmental, behavioral, biological risk factors that interact with the genetic background [
21,
22].
Sixty percent of pediatric NPHP patients can-not be genetically classified [
5,
7] and accurate diagnosis of adult NPHP is much rarer. Therefore, a biobank of large sample size and further in vivo and/or in vitro experiments are imperative. Research into genotype-phenotype correlation with respect to the onset and progression of NPHP, will shed light on the complex pathogenesis of this disease. This will facilitate prevention, benefit early diagnosis and help to tailor intervention to reduce the incidence and minimize progression.
A novel homozygous nonsense mutation, p.E697X,37, and a novel homozygous missense mutation, p.F691 L, in NPHP1 were identified causing adult NPHP1 with late onset ESRD in a Chinese intermarriage family. Although research into genotype-phenotype correlation is needed, intermarriage should be avoided to prevent autosomal recessive hereditary diseases and breaking the chain of genetic disorder.