Proteinuric renal disease

Gene: ARHGDIA

I don't know

Following discussion with some members of the GMS Renal Specialist Test group on 2019-03-22 it was agreed that although it is clearly rare with no variants found in >600 cases in Bristol, it is appropriate for inclusion in the panel.

Created: 26 Mar 2019, 3:23 p.m.

PMID: 23434736 - Gupta et al 2013 - 2 sisters with congenital nephrotic syndrome who were born to consanguineous parents of Pakistani origin. Using whole exome sequencing, they found both girls have a homozygous in-frame deletion in ARHGDIA, c.553_555del(p.Asp185del). The healthy mother was found to be a heterozygous carrier for this deletion. The father's DNA was unavailable for analysis. Functional studies showed that RhoGDIα protein was strongly expressed in the glomerulus of the adult mouse kidney and that normal binding of mutant protein was impaired.

PMID: 23867502 - Gee et al 2013 - performed homozygosity mapping and then whole exome resequencing in a family of Ashkenazi Jewish origin in whom 2 siblings had early-onset SRNS with renal histology of diffuse mesangial sclerosis. They found in both siblings a homozygous missense mutation (c.518G>T;p.G173V) of ARHGDIA. They then examined 65 additional individuals with DMS and 350 individuals with SRNS, we detected a homozygous mutation (c.358C>T;p.R120X) in an infant (Moroccan) with congenital NS. Functional studies showed both mutant protein had abrogated interaction with RHO GTPases and the nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish.

PMID: 30295827 - Schapiro et al 2019 - screen for 11 AS, aHUS and thrombotic thrombocytopenic purpura-causing genes by exon sequencing and 23 SRNS-causing genes by WES or high-throughput exon sequencing in an international cohort of 371 patients from 362 families presenting with both proteinuria and hematuria before age 25 years. This screen included ARHGDIA. 1 consangineious Jewish family with 2 individuals are homozgous for c.518G>T, p.Gly173Val.

Summary - 4 families with 3 different variants reported. The two Jewish families have the same variant. Functional evidence that the protein is expressed in the kidney and that the function of mutant protein is impared.

Created: 21 Mar 2019, 5:11 p.m.

This gene was part of an initial gene list collated by Elizabeth Watson, North Bristol NHS Trust, February 2019 on behalf of the GMS Renal Specialist Test Group. Gene Symbol submitted: ARHGDIA; Suggested initial gene rating: amber; Evidence for inclusion: PMID: 23434736; PMID: 23867502; PMID: 30295827 ; Other comments: One publication (PMID: 23867502); two unrelated patients with NS and hom variants (not in gnomAD). On diagnostic panel; no positive cases detected in >600 nephrotic syndrome referrals

Created: 4 Feb 2019, 10:41 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Nephrotic syndrome, type 8 #615224

Publications

• 23434736
• 23867502
• 30295827

Variants in this GENE are reported as part of current diagnostic practice

Comment on list classification: Causes recessive severe early nephrotic syndrome.

Created: 16 May 2016, 8:16 p.m.

I don't know

Currently on UK diagnostic panel, but no positive cases over 300 tested. Listed in several reviews

Created: 19 Oct 2015, 1:57 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• J Med Genet. 2013 May
• 50(5):330-8

Variants in this GENE are reported as part of current diagnostic practice