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Proteinuric renal disease v6.1 STS John Sayer gene: STS was added
gene: STS was added to Proteinuric renal disease. Sources: Expert list
Mode of inheritance for gene: STS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STS were set to 22419362; 17468528
Phenotypes for gene: STS were set to Proteinuria; ichthyosis
Penetrance for gene: STS were set to Complete
Review for gene: STS was set to GREEN
Added comment: Good evidence this is a proteinuric gene. Cases of whole gene deletion of STS in Genomics England with phenotypes.
Sources: Expert list
Proteinuric renal disease v2.16 APOE Eleanor Williams changed review comment from: Associated with Lipoprotein glomerulopathy #611771 in OMIM. No inheritance pattern listed.

Several publications report variants in the APOE gene in association with Lipoprotein glomerulopathy, mostly in individuals of Asian ethnicity but also in those with European ancestry for example (PMID: 18077821 - Rovin et al 2007). PMID: 31092271 - Xie et al 2019 lists many of the published variants (~12 to date, mostly point mutations, but also some deletions)

In several cases clinical asymptomatic carriers (all female?) also carry the same variants as probands e.g.
PMID: 18077821 - Rovin et al 2007
PMID: 10432380 - Matsunaga et al 1999
PMID: 31092271 - Xie et al 2019




; to: Associated with Lipoprotein glomerulopathy #611771 in OMIM. No inheritance pattern listed.

Several publications report variants in the APOE gene in association with Lipoprotein glomerulopathy, mostly in individuals of Asian ethnicity but also in those with European ancestry (for example PMID: 18077821 - Rovin et al 2007). PMID: 31092271 - Xie et al 2019 lists many of the published variants (~12 to date, mostly point mutations, but also some deletions)

In several cases clinical asymptomatic carriers (all female?) also carry the same variants as probands e.g.
PMID: 18077821 - Rovin et al 2007
PMID: 10432380 - Matsunaga et al 1999
PMID: 31092271 - Xie et al 2019
Proteinuric renal disease v2.16 APOE Eleanor Williams changed review comment from: Associated with Lipoprotein glomerulopathy #611771 in OMIM. No inheritance pattern listed.

PMID: 10432380 - Matsunaga et al 1999 - 32-year-old Japanese male patient with Lipoprotein glomerulopathy, whose history included proteinuria. A heterogyzous missense variant was identified termed apo E2 (Arg25Cys) Kyoto. His asymptomatic mother was also heterogyzous for this same variant.

PMID: 9176854 - Oikawa et al 1997 - report 3 patients with LPG from two families all with the same variant apo E Arg145Pro named APOE Sendai. Only the APOE gene was looked at.

PMID: 18077821 - Rovin et al 2007 - report two unrelated American men of European ancestry who presented with edema and proteinuria in the nephrotic range. Both patients had a heterozygous C→T transition resulting in an amino acid change Arg25Cys. Several female family members were heterozygous carriers of Arg25Cys, none had clinical evidence of lipoprotein glomerulopathy.

Review to be continued; to: Associated with Lipoprotein glomerulopathy #611771 in OMIM. No inheritance pattern listed.

Several publications report variants in the APOE gene in association with Lipoprotein glomerulopathy, mostly in individuals of Asian ethnicity but also in those with European ancestry for example (PMID: 18077821 - Rovin et al 2007). PMID: 31092271 - Xie et al 2019 lists many of the published variants (~12 to date, mostly point mutations, but also some deletions)

In several cases clinical asymptomatic carriers (all female?) also carry the same variants as probands e.g.
PMID: 18077821 - Rovin et al 2007
PMID: 10432380 - Matsunaga et al 1999
PMID: 31092271 - Xie et al 2019
Proteinuric renal disease v1.218 PDSS2 Eleanor Williams edited their review of gene: PDSS2: Added comment: The gene is associated with Coenzyme Q10 deficiency, primary, 3 (#614652) in OMIM and COENZYME Q10 DEFICIENCY, PRIMARY, 3 (confirmed) in Gene2Phenotype.

PMID: 29032433 - Iványi et al 2018 - 1 case - male child of healthy, nonconsanguineous Caucasian parents. At 7 months of age he had general edema, muscle hypotonia, mild inspiratory stridor, and global developmental delay. He did not react to auditory stimuli, and they detected no tracking and focusing eye movements. Urinalysis revealed proteinuria. A heterozygous missense mutation in the PDSS2 gene in exon 3 was found (c.485A > G, p.His162Arg) (maternally inherited) along with a heterozygous 2923-bp deletion that affected a part of exon 8 in the PDSS2 gene. The paternal allele is the NM_020381.3:c.1042_1148-2816del, which causes a 107-base long deletion of exon 8. Despite high-dose CoQ10 treatment he died at 8 months of age.

PMID: 25349199 - Sadowski et al 2015 - 2 cases with homozygous missense changes in PDSS2 in patients with Steroid-resistant nephrotic syndrome. They performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with Steroid-resistant nephrotic syndrome (SRNS) and then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. 2 families were molecularly diagnosed with a causative variant in PDSS2 by multiplex PCR (c.1145C>T,p.Ser382Leu and c.1151C>A, p.Ala384Asp).

PMID: 23926186 - Gasser et al 2013 - genotyped 377 patients with primary Focal segmental glomerulosclerosis (FSGS) or collapsing glomerulopathy, together with 900 controls, for 9 single-nucleotide polymorphisms in the PDSS2 gene in a case-control study. The nine selected SNPs were distributed at approximately equal distances across the PDSS2 gene. All the SNPs that were genotyped occurred within noncoding regions of the gene. They demonstrated that homozygous genotypes for variant alleles for the PDSS2 gene were more common in FSGS patients than controls and that a single haplotype containing three of these SNPs was more common in European American, but not African American, FSGS patients, suggesting that PDSS2 may be an FSGS susceptibility gene.

PMID:17186472 - Lopez et al 2006 - 1 family with child who presented with neonatal pneumonia and hypotonia, developed refractory left-sided seizures with secondary generalization, and became progressively floppy. At age 7 mo, severe episodic vomiting prompted duodenal tube feeding, and was diagnosed with nephrotic syndrome due to low serum albumin and massive proteinuria. They found two nonsynonymous nucleotide changes in PDSS2, each inherited from one parent. Functional tests on cultured patient fibroblast indicate that endogenous levels of decaprenyl diphosphate are reduced.

Mouse model:
PMID: 18437205 - Peng et al 2008 - Kidney disease in mice with missense Pdss2(kd/kd) genotype can be attributed to a mitochondrial CoQ biosynthetic defect. Levels of CoQ9 and CoQ10 in kidney homogenates from B6.Pdss2(kd/kd) mutants were significantly lower than those in B6 control mice. Disease manifestations originate specifically in glomerular podocytes, as renal disease is seen in Podocin/cre,Pdss2(loxP/loxP) knockout mice but not in conditional knockouts targeted to renal tubular epithelium, monocytes, or hepatocytes.

Summary:
4 cases of children with nephrotic syndrome and homozygous or compound heterozygous variants in PDSS2. In two cases the variants are reported to segregate with the disease in the family. Additional evidence from a case control study that PDSS2 is a FSGS susceptibility gene and from a mouse Pdss2 knockout model.; Changed publications: PMID: 23926186
Proteinuric renal disease v1.56 FAT1 Eleanor Williams commented on gene: FAT1: Not associated with any phenotype in OMIM.

PMID: 26905694 - Gee et al 2016. 4 families reported with a variant in FAT1. 27 known genes previously linked to SRNS were screened in these individuals, but no explanatory mutations were detected. All affected individuals exhibited a glomerulotubular nephropathy of SRNS, tubular ectasia and microscopic haematuria among other phenotypes.

Family 1 - A4623, a Turkish boy from consanguineous parents with intellectual disability, pulmonary artery stenosis and bilateral blepharoptosis in early childhood, admitted to the hospital at age 15 years because of proteinuria and haematuria. Kidney biopsy showed a glomerulotubular nephropathy. Following WES and filtering of variants from normal reference sequence, 3 rare variants in FAT1, PIDD and DZIP1 remained. The variant in the FAT1 gene, is a homozygous protein truncating mutation (c.3093_3096del, p.P1032Cfs*11). This variant is classified as a VUS in OMIM.

Family 2 One child of Arab origin (A3027) presented with proteinuria and haematuria. A3027 was diagnosed with Ewing sarcoma, and lung and spinal metastasis at the age of 15 years. Following variant filtering by HM and WES, two rare missense variants in FAT1 and EHD1 remained . Mutations in the 27 known SRNS genes were excluded by evaluation of the WES data. The variant (c.857A>F;p.N286S) in FAT1 is reported as a SNP in the dbSNP database, however, its minor allele frequency is 0.0002 and it never occurred in the homozygous state. The FAT1 variant alters an amino-acid residue conserved throughout evolution down to Drosophila melanogaster.

Families 3 and 4 - When performing highly parallel sequencing of all FAT1 exons in 1,500 additional individuals with features of NS and 800 individuals with features of tubulointerstitial nephroapathy, we detected in 2 additional families. . In a female African-American girl (A789) from non-consanguineous parents, another compound-heterozygous mutation was detected (c.3008C>T, p.A1003V and c.9259C>G, p. R3087G). Further information was not available and segregation analysis was not performed since the girl was lost for follow-up. A3507, an African girl from non-consanguineous parents, showed haematuria and proteinuria at the age of 2 years. One of the compound-heterozygous mutation (c.4517G>A, p.R1506H) was detected in her mother, but not the other. DNA from the father was not available.

Functional studies indicate an absence of FAT1 in patient fibroblasts (from family 1) and decreased migration rates compared to controls. Knockdown of FAT1 in differentiated podocytes showed similarly decreased migration rates, which were associated with decreased active RAC1 and CDC42, implicating a defect in RHO GTPase signaling in the pathogenesis.
Proteinuric renal disease v1.23 TP53RK Eleanor Williams commented on gene: TP53RK: TP53RK is associated with Galloway-Mowat syndrome 4 (617730) in OMIM.

Following discussion with some members of the GMS Renal Specialist Test group on 2019-03-22 it was agreed that proteinuria is a relevant feature of Galloway-Mowat syndrome, and TP53RK should be included on the Proteinuric renal disease panel.

PMID: 28805828 - Braun et al 2017 - 4 patients from 3 unrelated families with Galloway-Mowat syndrome-4. Compound heterozygous or homozygous variants (4 different variants) found in the TP53RK gene. Functional data suggests the variants impaired protein functionality.