Dataset Information

Genetic mutational testing of Chinese children with familial hematuria with biopsy?proven FSGS.

ABSTRACT: Focal segmental glomerulosclerosis (FSGS) is a pathological lesion rather than a disease, with a diverse etiology. FSGS may result from genetic and non?genetic factors. FSGS is considered a podocyte disease due to the fact that in the majority of patients with proven?FSGS, the lesion results from defects in the podocyte structure or function. However, FSGS does not result exclusively from podocyte?associated genes, however also from other genes including collagen IV?associated genes. Patients who carry the collagen type IVA3 chain (COL4A3) or COL4A4 mutations usually exhibit Alport Syndrome (AS), thin basement membrane neuropathy or familial hematuria (FH). Previous studies revealed that long?time persistent microscopic hematuria may lead to FSGS. A case of a family is presented here where affected individuals exhibited FH with FSGS?proven, or chronic kidney disease. Renal biopsies were unhelpful and failed to demonstrate glomerular or basement membrane defects consistent with an inherited glomerulopathy, and therefore a possible underlying genetic cause for a unifying diagnosis was pursued. Genomic DNA of the siblings affected by FH with biopsy?proven FSGS was analyzed, and their father was screened for 18 gene mutations associated with FSGS [nephrin, podocin, CD2 associated protein, phospholipase C ?, actinin ? 4, transient receptor potential cation channel subfamily C member 6, inverted formin, FH2 and WH2 domain containing, Wilms tumor 1, LIM homeobox transcription factor 1 ?, laminin subunit ? 2, laminin subunit ? 3, galactosida ?, integrin subunit ? 4, scavenger receptor class B member 2, coenzyme Q2, decaprenyl diphosphate synthase subunit 2, mitochondrially encoded tRNA leucine 1 (UUA/G; TRNL1) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a like 1] using matrix?assisted laser desorption/ionization time?of?flight mass spectrometry technology. Then whole exome sequencing (WES) was performed in the two probands to ascertain whether there were other known or unknown gene mutations that segregated with the disease. Using mass array technology, a TRNL1 missense homozygous mutation (m. 3290T>C) was identified in the probands diagnosed with FH and manifested as FSGS on biopsy. In addition, a COL4A4 missense mutation c. 4195A>T (p. M1399L) in heterozygous pattern was identified using WES. None of these variants were detected in their father. In the present study, a mutation in TRNL1 (m. 3290T>C) was identified, which was the first reported variant associated with FSGS. The COL4A4 (c. 4195A>T) may co?segregate with FSGS. Screening for COL4A mutations in familial FSGS patients is suggested in the present study. Genetic investigations of families with similar clinical phenotypes should be a priority for nephrologists. The combination of mass array technology and WES may improve the detection rate of genetic mutation with a high level of accuracy.

SUBMITTER: Li Y

PROVIDER: S-EPMC5780091 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Genetic mutational testing of Chinese children with familial hematuria with biopsy‑proven FSGS.

Li Yongzhen Y Wang Ying Y He Qingnan Q Dang Xiqiang X Cao Yan Y Wu Xiaochuan X Mo Shuanghong S He Xiaoxie X Yi Zhuwen Z

Molecular medicine reports 20171110 1

Focal segmental glomerulosclerosis (FSGS) is a pathological lesion rather than a disease, with a diverse etiology. FSGS may result from genetic and non‑genetic factors. FSGS is considered a podocyte disease due to the fact that in the majority of patients with proven‑FSGS, the lesion results from defects in the podocyte structure or function. However, FSGS does not result exclusively from podocyte‑associated genes, however also from other genes including collagen IV‑associated genes. Patients wh ...[more]

PMID: 29138824

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Project description:Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) have been linked to mutations in many of the proteins that are involved in alternative complement pathway activation. Age and etiology confounded, the prevalence of such mutations has been reported to be over 30 to 50% in these diseases. However, the cohorts studied included many children or individuals with a familial history of complement-related disorders and genetic tests were usually limited to exome sequencing of known causative or risk-associated genes. In this study, a retrospective adult cohort of 35 patients with biopsy-proven thrombotic microangiopathy (the largest in Canada) and 10 patients with C3 glomerulopathy was tested through an extended exome panel to identify causative defects in associated or candidate genes including those of the alternative and terminal complement pathways. A variant of unknown significance was also analyzed for pathogenicity through in vitro studies. To our surprise, the prevalence of known causative or risk-associated variants in either of these cohorts was found to be less than ~ 15% overall. However, the panel used and analyses carried out allowed to identify novel variants of potential clinical significance and a number of candidate genes. The prevalence of known genetic defects in adult-onset aHUS and C3G is thus probably much lower than 30 to 50%. Our results also point towards the importance of investigating diseases of the alternative complement pathway through extended exome panels and in vitro analyses. KEY MESSAGES: The alternative complement pathway plays a major role in the pathogenesis of hemolytic uremic syndrome and C3 glomerulopathy. Based on previous studies, both disorders have been commonly linked to variants in the various intermediates that sustain or regulate this pathway. The prevalence of such mutations in the adult-onset and sporadic forms of these diseases is probably much lower than expected based on larger series. The sporadic forms of complementopathies are likely to involve additional genes that are yet to be uncovered.

Project description:BACKGROUND:About 40-50% of patients with familial microscopic hematuria (FMH) caused by thin basement membrane nephropathy (TBMN) inherit heterozygous mutations in collagen IV genes (COL4A3, COL4A4). On long follow-up, the full phenotypic spectrum of these patients varies a lot, ranging from isolated MH or MH plus low-grade proteinuria to chronic renal failure of variable degree, including end-stage renal disease (ESRD). METHODS:Here, we performed Whole Exome Sequencing (WES) in patients of six families, presenting with autosomal dominant FMH, with or without progression to proteinuria and loss of renal function, all previously found negative for severe collagen IV mutations. Hierarchical filtering of the WES data was performed, followed by mutation prediction analysis, Sanger sequencing and genetic segregation analysis. RESULTS:In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-p.Pro1243Leu and COL4A5-p.Asp654Tyr. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts. CONCLUSIONS:A modifier role of LAMA5 on the background of a hypomorphic Alport syndrome causing mutation is a possible explanation of our findings. Digenic inheritance is another scenario, following the concept that mutations at both loci more accurately explain the spectrum of symptoms, but further investigation is needed under this concept. This is the third report linking a LAMA5 variant with human renal disease and expanding the spectrum of genes involved in glomerular pathologies accompanied by familial hematurias. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced Lama5 protein levels and produced kidney cysts.

Project description:IntroductionLong-term data pertaining to childhood-onset lupus nephritis (cLN) remain extremely scarce.MethodsWe conducted a retrospective cohort study of biopsy-proven cLN with onset age <18 years diagnosed from 2001 to 2020 to ascertain the long-term patient and kidney survival rates, and the incidence of advanced chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] <60 ml/min per 1.73 m2).ResultsA total of 92 subjects (78 female; age 13.7 ± 3.3 years; all Chinese) were included, with follow-up duration of 10.3 years (interquartile range, 5.8-15.9). Of these, 83 children (90%) had proliferative lupus nephritis (LN) (Class III/IV ± V). Mycophenolate was used for induction in 36%, whereas 34% received cyclophosphamide (CYC); 55% received mycophenolate as maintenance immunosuppression. The rates of complete remission (CR) and partial remission (PR) at 6 months and 12 months, respectively, were 65% and 20% and 78% and 8%. Two patients died (mortality rate 2.1/1000 patient-years), with a standardized mortality ratio of 22.3. Three patients (3.2%) developed end-stage kidney disease (ESKD), and advanced CKD occurred in 5 patients (5.4%). Survival rates without advanced CKD, ESKD, or death were 96.7%, 94.2%, 92.7%, 83.2% and 83.2% at 1 year, 5 years, 10 years, 15 years, and 20 years, respectively. Multivariate analysis revealed that severe kidney failure necessitating dialysis at presentation (adjusted hazard ratio 37.7, 95% confidence interval [CI] 4.0-355.6, P = 0.002), nonresponse (NR) after 12 months of treatment (adjusted hazard ratio 11.2, 95% CI 2.3-54.9, P = 0.003), and multiple nephritis flares (adjusted hazard ratio 2.6, 95% CI 1.1-6.2, P = 0.03) were predictive of advanced CKD, ESKD, or death. Other adverse outcomes included infections (2.9 episodes/100 patient-years), osteopenia (32%), hypertension (17%), short stature (14%), and avascular necrosis (7%).ConclusionThe long-term outcomes of cLN appeared to have improved in the present era with effective immunosuppression, cautious drug tapering, and assurance of medication adherence. There is still an unacceptably high prevalence of adverse outcomes.

Dataset Information

Genetic mutational testing of Chinese children with familial hematuria with biopsy?proven FSGS.

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Genetic mutational testing of Chinese children with familial hematuria with biopsy‑proven FSGS.

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