Steroid-Resistant Nephrotic Syndrome due to Variants Is Not Associated With Posttransplant Recurrence.

Introduction: Unlike idiopathic nephrotic syndrome (NS), hereditary podocytopathies are not expected to recur after kidney transplantation. However, some reports of posttransplant recurrence of NS in patients carrying variants in the gene have been described, notably with the p.Arg138Gln variant, which is more prevalent in Europe.

VNtyper enables accurate alignment-free genotyping of coding VNTR using short-read sequencing data in autosomal dominant tubulointerstitial kidney disease.

The human genome comprises approximately 3% of tandem repeats with variable length (VNTR), a few of which have been linked to human rare diseases. Autosomal dominant tubulointerstitial kidney disease- (ADTKD-) is caused by specific frameshift variants in the coding VNTR of the gene. Calling variants from VNTR using short-read sequencing (SRS) is challenging due to poor read mappability.

A wave of deep intronic mutations in X-linked Alport syndrome.

X-linked Alport syndrome (XLAS) is an inherited kidney disease caused exclusively by pathogenic variants in the COL4A5 gene. In 10-20% of cases, DNA sequencing of COL4A5 exons or flanking regions cannot identify molecular causes. Here, our objective was to use a transcriptomic approach to identify causative events in a group of 19 patients with XLAS without identified mutation by Alport gene panel sequencing.

Overcoming the challenges associated with identification of deep intronic variants by whole genome sequencing.

Whole-genome sequencing (WGS) now allows identification of multiple variants in non-coding regions. The large number of variants identified by WGS however complicates their interpretation. Through identification of the first deep intronic variant in NPHS2, which encodes podocin, a protein implicated in autosomal recessive steroid resistant nephrotic syndrome (SRNS), we compare herein three different tools including a newly developed targeted NGS-based RNA-sequencing to explore the splicing effect of intronic variations.

Pseudouridylation defect due to and mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis.

RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in , , or cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition.

Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.

BACKGROUNDProteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria.

APOL1 risk genotype in Europe: Data in patients with focal segmental glomerulosclerosis and after renal transplantation.

Apolipoprotein L1 (APOL1) risk variants are strongly associated with sporadic focal segmental glomerulosclerosis in populations with African ancestry. We determined the frequency of G1/G2 variants in patients with steroid-resistant nephrotic syndrome/focal segmental glomerulosclerosis with African or French West Indies origin in France and its relationships with other steroid-resistant nephrotic syndrome genes. In a cohort of 152 patients (139 families), the APOL1 risk variants were genotyped: the two risk allele (high risk) genotype was found in 43.

Correction: A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies.

[This corrects the article DOI: 10.1371/journal.pgen.

Identification of genetic causes for sporadic steroid-resistant nephrotic syndrome in adults.

Monogenic forms of Steroid-Resistant Nephrotic Syndrome (SRNS) have been widely characterized, but genetic screening paradigms preferentially address congenital, infantile onset, and familial cases. Our aim was to characterize the distribution of disease-causing gene mutations in adults with sporadic SRNS or focal segmental glomerulosclerosis (FSGS). We selected adult patients with non-syndromic, biopsy-proven FSGS or SRNS in the absence of known family history.

APOL1 risk genotype in European steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis patients of different African ancestries.

Background: Apolipoprotein L1 (APOL1) risk variants are strongly associated with sporadic focal segmental glomerulosclerosis (FSGS) in populations with African ancestry. We determined the frequency of G1/G2 variants in steroid-resistant nephrotic syndrome (SRNS)/FSGS patients with African or French West Indies ancestry in France and its relationships with other SRNS genes.

Methods: In a cohort of 152 patients (139 families), the APOL1 risk variants were genotyped by direct Sanger sequencing and pathogenic mutations were screened by next-generation sequencing with a panel including 35 SRNS genes.

A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies.

Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects.

Treatment and outcome of congenital nephrotic syndrome.

Background: Recommendations for management of Finnish-type congenital nephrotic syndrome (CNS) followed by many teams include daily albumin infusions, early bilateral nephrectomy, dialysis and transplantation. We aimed to assess the treatment and outcome of patients with CNS in France.

Methods: We conducted a nationwide retrospective study on 55 consecutive children born between 2000 and 2014 treated for non-infectious CNS.

Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome.

Background: Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease.

Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly.

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality.

Low renal but high extrarenal phenotype variability in Schimke immuno-osseous dysplasia.

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date.

ADCK4-Associated Glomerulopathy Causes Adolescence-Onset FSGS.

Hereditary defects of coenzyme Q10 biosynthesis cause steroid-resistant nephrotic syndrome (SRNS) as part of multiorgan involvement but may also contribute to isolated SRNS. Here, we report 26 patients from 12 families with recessive mutations in ADCK4. Mutation detection rate was 1.

Loss-of-function mutations in WDR73 are responsible for microcephaly and steroid-resistant nephrotic syndrome: Galloway-Mowat syndrome.

Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity mapping and whole-exome sequencing, we identified WDR73 as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. WDR73 encodes a WD40-repeat-containing protein of unknown function.

A homozygous missense mutation in the ciliary gene TTC21B causes familial FSGS.

Several genes, mainly involved in podocyte cytoskeleton regulation, have been implicated in familial forms of primary FSGS. We identified a homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS.

APOL1 polymorphisms and development of CKD in an identical twin donor and recipient pair.

We report an occurrence of progressive loss of transplant function and ultimately transplant failure after living related kidney transplantation involving monozygotic twin brothers of Afro-Caribbean origin who were both heterozygous for the G1 and G2 kidney disease risk alleles in the APOL1 gene, which encodes apolipoprotein L-I. A 21-year-old man with end-stage kidney disease of unknown cause received a kidney from his brother, who was confirmed as a monozygotic twin by microsatellite analysis. Thirty months after transplantation, the patient presented with proteinuria and decreased estimated glomerular filtration rate; a biopsy of the transplant showed typical focal segmental glomerulosclerosis lesions.