Genotype–Phenotype Correlation in X-Linked Alport Syndrome

Abstract

Mutations in the COL4A5 gene cause X-linked Alport syndrome (XLAS). Understanding the correlation between clinical manifestations and the underlying mutations adds prognostic value to genetic testing, which is increasingly available. Our aim was to determine the association between genotype and phenotype in 681 affected male participants with XLAS from 175 US families. Hearing loss and ocular changes were present in 67 and 30% of participants, respectively. Average age of participants at onset of ESRD was 37 years for those with missense mutations, 28 years for those with splice-site mutations, and 25 years for those with truncating mutations (P Ͻ 0.0001). We demonstrated a strong relationship between mutation position and age at onset of ESRD, with younger age at onset of ESRD associated with mutations at the 5Ј end of the gene (hazard ratio 0.766 [95% confidence interval 0.694 to 0.846] per 1000 bp toward the 3Ј end; P Ͻ 0.0001). Affected participants with splice mutations or truncating mutations each had two-fold greater odds of developing eye problems than those with missense mutations; development of hearing impairment showed a similar trend. Hearing loss and ocular changes associated with mutations located closer to the 5Ј end of the gene. These strong genotype-phenotype correlations could potentially help in the evaluation and counseling of US families with XLAS.

Prognostic Value of Glomerular Collagen IV Immunofluorescence Studies in Male Patients with X-Linked Alport Syndrome

“…Finally, correlation between the severity of renal involvement and extrarenal symptoms is well established in X-AS (3,4,20,27). Likewise, we also observed that patients with early-onset CKD developed deafness earlier.…”

“…This is due, at least in part, to differences in the severity of COL4A5 mutations, as indicated by the demonstration of genotype-phenotype correlations (albeit less robust than correlations in other renal diseases) (3,4). More specifically, associations between the type of mutation and the clinical evolution were observed after patients were grouped per category of mutation (3,4,20,21).…”

Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome

“…2 This milder phenotype is associated with unique genotypes such as missense or in-frame variants in COL4A5. [3][4][5] We previously reported a male XLAS patient with a missense COL4A5 variant who showed only hematuria without proteinuria at the age of 33. 18 We also reported a male patient with a somatic COL4A5 variant who showed hematuria and mild proteinuria at the age of 8 years.…”

“…2 These two phenotypes are partially related to the genotype; for example, missense variants or in-frame variants of COL4A5 were reported in cases of later-onset ESRD. [3][4][5] We recently reported that 29% of male XLAS patients expressed the α5(IV) chain in the glomerulus and showed milder clinical manifestations. 6 Interestingly, all α5(IV)-positive patients possessed non-truncating variants (n = 13) or somatic mosaic variants (n = 2) of COL4A5.…”

Mild Forms of Alport Syndrome: Hereditary Nephropathy in the Absence of Extra-Renal Features

“…Clinically the natural history of the nephropathy and other extrarenal lesions are quite variable. A number of researchers have attempted to link genotypes in Alport syndrome to phenotypes (Bekheirnia et al, 2010, Gross et al, 2002, Jais et al, 2000. Gross and colleagues have proposed a classification linking phenotype and genotype into three categories (Gross et al, 2002).…”