Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies.

Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.

A molecular genetic analysis of childhood nephrotic syndrome in a cohort of Saudi Arabian families.

Nephrotic syndrome (NS) is a renal disease characterized by heavy proteinuria, hypoalbuminemia, edema and hyperlipidemia. Its presentation within the first 3 months of life or in multiple family members suggests an underlying inherited cause. To determine the frequency of inherited NS, 62 cases (representing 49 families with NS) from Saudi Arabia were screened for mutations in NPHS1, NPHS2, LAMB2, PLCE1, CD2AP, MYO1E, WT1, PTPRO and Nei endonuclease VIII-like 1 (NEIL1). We detected likely causative mutations in 25 out of 49 families studied (51%). We found that the most common genetic cause of NS in our cohort was a homozygous mutation in the NPHS2 gene, found in 11 of the 49 families (22%). Mutations in the NPHS1 and PLCE1 genes allowed a molecular genetic diagnosis in 12% and 8% of families, respectively. We detected novel MYO1E mutations in three families (6%). No mutations were found in WT1, PTPRO or NEIL1. The pathogenicity of novel variants was analyzed by in silico tests and by genetic screening of ethnically matched control populations. This is the first report describing the molecular genetics of NS in the Arabian Peninsula.

Clinical significance of IgM deposition in pediatric minimal change disease.

BACKGROUND: Idiopathic nephrotic syndrome (INS) is a common pediatric disease. Minimal change disease (MCD) is the most common histopathological subtype and usually has good prognosis. However, in less common presentations, INS may have an unusual course that makes renal biopsy a necessity to identify its etiology. Immunoglobulin M (IgM) occasionally deposits in the mesangium and can be seen under immunofluorescence (IF). The role of IgM is controversial in MCD. It is likely associated with less favorable outcomes for MCD. This study aims to investigate the clinical significance of mesangial IgM deposits on the outcome of MCD in a pediatric population. METHODS: In this retrospective cohort study, we obtained native kidney biopsy samples from 192 children who were diagnosed with MCD from 2003 to 2014. The samples were divided into groups according to the histopathological deposition of IgM in biopsies under IF. The group for which biopsies showed IgM was labeled as IgM + IF (n = 77), and the group for which biopsies were without IgM was labeled as IgM-IF (n = 115). We reviewed hypertension, hematuria, and estimated glomerular filtration rate (eGFR) at the time of presentation to our institute; response to steroid therapy (remission, dependence, frequent relapses, and resistance) and response after adjuvant immunosuppressive therapy (complete remission, partial remission, frequent relapses, and no response) when indicated; development of chronic kidney disease (CKD) and end-stage renal disease during the course of the disease (ESRD). RESULTS: Our results showed that mesangial IgM deposition in MCD showed significant statistical association with hypertension at the time of presentation (P = .05). There was statistically significant association between the presence of IgM deposition and the development of steroid dependence (P = .05) and CKD during the course of the disease (P = .05). CONCLUSIONS: Our study showed that IgM deposition in MCD showed statistical association with hypertension by the time the patient presented to our institute, development of steroid dependence, and CKD. IgM may play a role in MCD. However, we recommend a prospective study to verify the role of IgM in MCD outcomes.

A novel mutation in NPHS2 causing nephrotic syndrome in a Saudi Arabian family.

We report a consanguineous family from Saudi Arabia with three affected children presenting with infantile nephrotic syndrome. In order to provide a molecular diagnosis, a genome-wide SNP analysis of the affected patients was performed. We identified a region of homozygosity on chromosome 1, containing the NPHS2 gene. Direct sequencing, by exon PCR, of NPHS2 identified a homozygous nucleotide change 385C > T within exon 3 in the three affected children, leading to a premature stop codon (Q129X). This homozygous truncating mutation in NPHS2 is novel and was associated with a severe clinical phenotype. Additional mutations in related genes NPHS1, PLCE1 and NEPH1 were not identified, excluding tri-allelism within these genes in this family.

Novel mutations underlying nephrogenic diabetes insipidus in Arab families.

PURPOSE: Nephrogenic Diabetes Insipidus (NDI) is genetically heterogeneous and may be inherited in an X-linked or autosomal recessive manner. We aimed to investigate the molecular basis of NDI among Arab families. METHODS: Direct sequencing of coding regions for AQP2 and AVPR2 was used to identify underlying mutations. One large deletion required Southern blot analysis and a PCR-based strategy to identify deletion junctions. RESULTS: We identified two novel missense mutations (AQP2:p.Gly100Arg and p.Gly180Ser) in AQP2 and one novel missense mutation (AVPR2:p.Gly122Asp), one previously reported missense mutation (AVPR2:p.Arg137His) and one novel contiguous deletion (AVPR2:c.25 + 273_ARHGAP4o:2650-420del) affecting AVPR2. We also describe evidence of lyonization associated with the novel deletion. CONCLUSIONS: Two novel mutations were identified in each of AVPR2 and AQP2 underlying CNDI in Arab families. Identification of these mutations will facilitate early diagnosis of CNDI, counseling of families and provide opportunities for early intervention aimed at reducing morbidity. The presence of affected females and consanguinity, as is often observed in Arab communities should not be used to rule out AVPR2 as a candidate when considering diagnostic testing. Careful observation of phenotypic heterogeneity should be used in referring such families for both AQP2 and AVPR2 molecular genetic testing.