High mutation rate of NPHP3 in 18 Chinese infantile nephronophthisis patients.

AIM: The present study was designed to explore mutations of NPHP2 and NPHP3 and clinical features in 18 Chinese infantile nephronophthisis (NPHP) patients. METHODS: Patients were subjected to screen for mutations in both NPHP2 and NPHP3, and clinical data were collected. RESULTS: Eighteen patients from 17 families were included in this study. Eight of 17 (47.1%) patients detected were identified to have mutations in NPHP3, but none had a mutation in NPHP2. Of the patients with NPHP3 mutations, four had compound heterozygous mutations, and the other four harboured single heterozygous mutations. Ten of the NPHP3 mutations were novel. Low molecular weight proteinuria was observed in all 16 detected patients. Renal histology were available in seven children, five patients showed infantile type NPHP features, and the other two patients from the same family showed juvenile type NPHP features. Liver involvement was observed in all patients with NPHP3 mutations and congenital heart disease in two patients harbouring NPHP3 mutation of c.2369 T > C (p.L790P). CONCLUSIONS: In this group of infantile NPHP patients, mutations of NPHP3 were prevalent, whereas mutation of NPHP2 was absent. Genotype to phenotype correlations were observed in patients with NPHP3 mutations and all patients with NPHP3 mutations showed renal-hepatic phenotype.

Syndromic ciliopathies: From single gene to multi gene analysis by SNP arrays and next generation sequencing.

Joubert syndrome (JS) and related disorders (JSRD), Meckel syndrome (MKS) and Bardet-Biedl syndrome (BBS) are autosomal recessive ciliopathies with a broad clinical and genetic overlap. In our multiethnic cohort of 88 MKS, 61 JS/JSRD and 66 BBS families we performed genetic analyses and were able to determine mutation frequencies and detection rates for the most frequently mutated MKS genes. On the basis of determined mutation frequencies, a next generation gene panel for JS/JSRD and MKS was established. Furthermore 35 patients from 26 unrelated consanguineous families were investigated by SNP array-based homozygosity mapping and subsequent DNA sequencing of known candidate genes according to runs of homozygosity size in descending order. This led to the identification of the causative homozygous mutation in 62% of unrelated index cases. Based on our data we discuss various strategies for diagnostic mutation detection in the syndromic ciliopathies JS/JSRD, MKS and BBS.

Molecular characterization of Joubert syndrome in Saudi Arabia.

Joubert syndrome (JS) is a ciliopathy that is defined primarily by typical cerebellar structural and ocular motility defects. The genetic heterogeneity of this condition is significant with 16 genes identified to date. We have used a combination of autozygome-guided candidate gene mutation analysis and exome sequencing to identify the causative mutation in a series of 12 families. The autozygome approach identified mutations in RPGRIP1L, AHI1, TMEM237, and CEP290, while exome sequencing revealed families with truncating mutations in TCTN1 and C5ORF42. Our study, the largest comprehensive molecular series on JS, provides independent confirmation of the recently reported TCTN1, TMEM237, and C5ORF42 as bona fide JS disease genes, and expands the allelic heterogeneity of this disease.

Lethal cystic kidney disease in Amish neonates associated with homozygous nonsense mutation of NPHP3.

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.

Prevalence of renal cysts in a Middle-Eastern population: an evaluation of characteristics and risk factors.

OBJECTIVE: To assess the prevalence of renal cysts in a large Middle-Eastern population presenting for a health-screening programme, evaluating cyst characteristics and risk factors for their development. PATIENTS AND METHODS: The reported prevalence of renal cysts detected by ultrasonography (US) in the general population is 5.0-20.8%, and their development has been linked to several factors. The electronic charts of 8551 patients (from eight nations, predominantly Egypt and Yemen) presenting for the 'check-up' programme at the author's institution during 2005 were retrospectively reviewed. The presence and characteristics of renal cysts on abdominal US were noted, as were any associated renal pathologies. Various risk factors were evaluated for renal cyst development, i.e. age, gender, hypertension, diabetes mellitus and serum creatinine levels, and hyperlipidaemia and a history of bilharziasis were also assessed. RESULTS: The prevalence of renal cysts was 4.2%, ranging from 0.6% for patients in their third decade, to a third of those aged >80 years. Cysts were detected in 4.8% of men and 2.8% of women (P < 0.001). The mean serum creatinine level was 1.02 mg/dL in those with cysts and 0.88 mg/dL in those without (P < 0.001). On univariate analysis, hypertension, diabetes and hyperlipidaemia had a significant influence on the occurrence of renal cysts, but not in the multivariate model. Of the 361 patients with renal cysts, 58 (16.1%) had bilateral and 26 (7.2%) had multiple unilateral cysts, with a mean (range) size of 26 (4-104) mm. The vast majority of cysts were classified as Bosniak I simple cysts; seven were Bosniak II and there was one Bosniak IV cyst. Associated renal pathologies included renal stones in 39 patients, hydronephrosis in nine, increased parenchymal echogenicity in 18, small atrophic kidneys in three, haematuria (not associated with other imaging abnormalities) in six, and a renal mass in one patient. CONCLUSIONS: The prevalence of renal cysts detected by US in a health-screened population from the Middle East was 4.2%. Increasing age, male gender and a higher serum creatinine level were significant independent risk factors for cyst development. There was also a relatively high prevalence of associated renal pathologies (increased parenchymal echogenicity and stones).