Whole-exome sequencing reveals a novel homozygous mutation in the COQ8B gene associated with nephrotic syndrome

Abstract

Nephrotic syndrome arising from monogenic mutations differs substantially from acquired ones in their clinical prognosis, progression, and disease management. Several pathogenic mutations in the COQ8B gene are known to cause nephrotic syndrome. Here, we used the whole-exome sequencing (WES) technology to decipher the genetic cause of nephrotic syndrome (CKD stage-V) in a large affected consanguineous family. Our study exposed a novel missense homozygous mutation NC_000019.9:g.41209497C > T; NM_024876.4:c.748G > A; NP_079152.3:p.(Asp250Asn) in the 9th exon of the COQ8B gene, co-segregated well with the disease phenotype. Our study provides the first insight into this homozygous condition, which has not been previously reported in 1000Genome, ClinVar, ExAC, and genomAD databases. In addition to the pathogenic COQ8B variant, the WES data also revealed some novel and recurrent mutations in the GLA, NUP107, COQ2, COQ6, COQ7 and COQ9 genes. The novel variants observed in this study have been submitted to the ClinVar database and are publicly available online with the accessions: SCV001451361.1, SCV001451725.1 and SCV001451724.1. Based on the patient's clinical history and genomic data with in silico validation, we conclude that pathogenic mutation in the COQ8B gene was causing kidney failure in an autosomal recessive manner. We recommend WES technology for genetic testing in such a consanguineous family to not only prevent the future generation, but early detection can help in disease management and therapeutic interventions.

COQ8B glomerular nephropathy: Outcomes after kidney transplantation and analysis of characteristics in Chinese population

“…Of these cases, 75% (33/44) had their onset before or at the age of 10 years (range 10 days to 25 years). The median age of onset in the Chinese population was earlier than that of non-Chinese patients ( 1 , 13 – 15 , 17 , 19 , 25 – 29 ) ( Figure 4A ). We also found that the age of onset in the Chinese population was younger than that in other Asian populations, but the difference was not significant ( P = 0.051; Figure 4B ).…”

“…Cases without data on follow-up and patient outcomes were excluded ( 1 , 12 – 14 ). A total of 18 cases were included for subsequent analysis ( 15 – 19 ). The median follow-up time was 24 (IQR 17.8–95.0) months, up to 180 months.…”

Collapsing glomerulopathy: unraveling varied pathogeneses

“…It is thought that the resultant deficit in CoQ 10 levels impairs the mitochondrial respiratory chain and causes podocyte injury. Reinforcing the importance of mitochondrial health CoQ 10 biosynthesis in podocyte biology, in humans, mutations in COQ6 and COQ8B have also been associated with steroid-resistant nephrotic syndrome and collapsing glomerulopathy [38,39],…”

“…It is thought that the resultant deficit in CoQ 10 levels impairs the mitochondrial respiratory chain and causes podocyte injury. Reinforcing the importance of mitochondrial health CoQ 10 biosynthesis in podocyte biology, in humans, mutations in COQ6 and COQ8B have also been associated with steroid-resistant nephrotic syndrome and collapsing glomerulopathy [38,39], and in the kd/kd mouse, truncating mutations in the prenyltransferase-like mitochondrial protein (PLMP) result in mitochondrial defects and collapsing glomerulopathy [40]. The bisphosphonate medications, such as pamidronate, are also thought to impair mitochondrial function and have been linked to collapsing glomerulopathy [41].…”

Clinical features and gene variation analysis of COQ8B nephropathy: Report of seven cases

“…Salviati et al found that the genotypephenotype correlation of COQ8B mutation was not clear, and the mutation might affect the interaction between COQ8B and other COQ proteins (12). Singh et al assumed that COQ8B (p.Asp250Asn) undermined the interaction of proteins by targeting COQ5, which is one of the important components in the COQ giant complex, resulting in a progressive deterioration from normal renal function to renal failure (13). The minimum age of such patients was 1 year and 1 month.…”