Genotype-Phenotype Correlations for Pathogenic COL4A3–COL4A5 Variants in X-Linked, Autosomal Recessive, and Autosomal Dominant Alport Syndrome

Abstract

Alport syndrome is inherited as an X-linked (XL), autosomal recessive (AR), or autosomal dominant (AD) disease, where pathogenic COL4A3 – COL4A5 variants affect the basement membrane collagen IV α3α4α5 network. About 50% of pathogenic variants in each gene (major rearrangements and large deletions in 15%, truncating variants in 20%, splicing changes in 15%) are associated with “severe” disease with earlier onset kidney failure, and hearing loss and ocular abnormalities in males with XL inheritance and in males and females with AR disease. Severe variants are also associated with early proteinuria which is itself a risk factor for kidney failure. The other half of pathogenic variants are missense changes which are mainly Gly substitutions. These are generally associated with later onset kidney failure, hearing loss, and less often with major ocular abnormalities. Further determinants of severity for missense variants for XL disease in males, and in AD disease, include Gly versus non-Gly substitutions; increased distance from a non-collagenous interruption or terminus; and Gly substitutions with a more (Arg, Glu, Asp, Val, and Trp) or less disruptive (Ala, Ser, and Cys) residue. Understanding genotype-phenotype correlations in Alport syndrome is important because they help predict the likely age at kidney failure, and the need for early and aggressive management with renin-angiotensin system blockade and other therapies. Genotype-phenotype correlations also help standardize patients with Alport syndrome undergoing trials of clinical treatment. It is unclear whether severe variants predispose more often to kidney cysts or coincidental IgA glomerulonephritis which are recognized increasingly in COL4A3-, COL4A4 - and COL4A5-associated disease.

A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people

“…Overall the median age for the COL4A4 variant was similar to that reported previously. However, both intra- and interfamilial variability in age at kidney failure has already been described ( 5 , 31 , 32 ), and was also seen here, with the age at ESRD varying from 17 to 42 and with normal renal function in another affected individual.…”

“…The published data suggest that missense variants in COL4A3 and COL4A4 genes have a less severe phenotype than loss-of-function, splice site variants, or large deletions. Individuals with two truncating variants have an earlier onset of kidney failure or hearing loss than those with only one truncating variant, who are in turn more likely to develop ESRD than those with no truncating variant ( 5 , 21 , 28 , 29 ). However, this genotype-phenotype correlation is not always seen ( 30 ).…”

“…Individuals with heterozygous COL4A3 or COL4A4 mutations have thin basement membrane nephropathy or autosomal dominant AS (AD AS) with typically normal kidney function, but proteinuria may occur in later life. The COL4A3 and COL4A4 heterozygotes represent carriers of AR AS (3)(4)(5).…”

The multifaceted phenotypic and genotypic spectrum of type-IV-collagen-related nephropathy—A human genetics department experience

“…Importantly, in 12% of individuals with AS as clinical tentative diagnosis and monoallelic disease-causing variants in COL4A3 / COL4A4 , a clear statement on autosomal dominant AS could not be made taking into account the genetic result and clinical data. There is an unresolved conflict concerning autosomal dominant AS and the frontlines seem to run across two standpoints: A “clinician-centered” view stating that clear diagnoses are important for surveillance and early treatment ( 12 , 32 ); and a “geneticist-centered” view that AS is a monogenic disease with complete penetrance and progressive kidney failure (90% on dialysis by age 40 years in X-linked AS; comparable for autosomal recessive AS) ( 11 , 14 ). For us and others on the genetics-side ( 13 ), there are many questions concerning the simple usage of autosomal dominant AS in any case with a monoallelic disease-causing variant in COL4A3 and COL4A4 : In cases with a clear AS phenotype (for example on kidney biopsy, ATS-F787-II-1 above) but only a monoallelic variant in COL4A3 / COL4A4 , could there be another variant on the other allele missed by routine genetic testing (e.g., intronic variant leading to a splicing defect, complex rearrangement missed by short-read-based NGS)?…”

“…In one recent publication by Furlano et al, the authors propose that any case harboring one heterozygous disease-causing variant in COL4A3 or COL4A4 should be designated as autosomal dominant AS independently from the clinical phenotype which ranges from microscopic hematuria to chronic kidney disease ( 12 ). In contrast, Savige et al classify individuals with a heterozygous disease-causing variant in COL4A3 or COL4A4 as having autosomal dominant inherited TBMN or AS depending on the clinical phenotype and a potential positive familial history ( 13 , 14 ). Furthermore, digenic inheritance has also been discussed as a possible cause in individuals with AS ( 15 – 18 ).…”