Natural History and Genotype–Phenotype Correlation in Female X-Linked Alport Syndrome

Abstract

IntroductionX-linked Alport syndrome (XLAS) is a hereditary disease characterized by progressive nephritis, hearing loss, and ocular abnormalities. Affected male patients usually progress to end-stage renal disease in early or middle adulthood, and disease severity is strongly correlated with genotype. However, the clinical course in female patients has rarely been reported.MethodsWe conducted a retrospective analysis of females with genetically proven XLAS (n = 275) and their affected female family members (n = 61) from 179 Japanese families. Patients suspected to have Alport syndrome from pathologic findings or a family history who were referred from anywhere in Japan for genetic diagnosis between 2006–2015 were included in this study. Clinical and laboratory data were collected from medical records at the time of registration for genetic analysis.ResultsProteinuria was detected in 175 genetically proven patients (72.6%), and the median age for developing proteinuria was 7.0 years. Fifty-two of 336 patients developed end-stage renal disease with a median renal survival age of 65.0 years. No obvious genotype–phenotype correlation was observed. Additionally, targeted sequencing for podocyte-related genes in patients with severe phenotypes revealed no obvious variants considered to be modifier genes except for 1 patient with a COL4A3 gene variant.DiscussionThis study revealed that phenotypes in female XLAS patients may be severe, but genotype does not help to predict the disease severity. Clinicians must therefore pay careful attention to the clinical course and appropriate treatment in females with XLAS.

Comparison between conventional and comprehensive sequencing approaches for genetic diagnosis of Alport syndrome

“…In total, 441 families were included in this study. Among them, 25 families with ADAS (Kamiyoshi et al, ), 24 families with ARAS (Oka et al, ), and 215 families with XLAS (Hashimura et al, ) (Yamamura et al, ) (Horinouchi et al, ) have already been reported by our group.…”

“…Alport syndrome (AS) is a hereditary disease caused by mutations in collagen type‐IV alpha chain genes (specifically, COL4A3 / COL4A4 / COL4A5 , OMIM: 12007, 120131, 303630), which is characterized by progressive renal involvement, hearing loss, and ocular abnormalities (Kashtan & Michael, ). Mutations in COL4A5 , encoding the collagen type IV α5 chain, are responsible for X‐linked AS (XLAS), which is usually more severe in men than women (Jais et al, , ; Yamamura et al, ). Mutations in COL4A3 and COL4A4 , encoding the collagen type IV α3 and α4 chains, are responsible for autosomal AS.…”

Reassessing the pathogenicity of c.2858G>T(p.(G953V)) in COL4A5 Gene: report of 19 Chinese families

“…This is different from the natural history of female patients with XLAS. It has been reported that hematuria, usually microscopic, presented in 96% of females with XLAS and proteinuria developed in 72.6-75% [8,25]. Especially a median renal survival age of 65.0 years in females with XLAS was reported [8].…”

“…Eighty-five percent of families have X-linked Alport syndrome (XLAS) with mutations in COL4A5 gene [6,7]. It is well known that male patients with XLAS, who are hemizygous for mutations in COL4A5 gene, are severely affected [8,9]. All of the males have microscopic hematuria and 90% of them progress to end-stage renal disease (ESRD) before age 40 years [9][10][11][12].…”

Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X‐linked Alport syndrome

“…Males with X-linked Alport syndrome (XLAS) are affected more severely than females (Massella et al, 2003;Raju, Cimbaluk, & Korbet, 2013;Savige, Colville, et al, 2016;Savige, Storey et al, 2016). Ninety percent of males with XLAS progress to end-stage renal disease (ESRD) by age 40, but only about 20% of females with XLAS develop renal failure by age 60 (Jais et al, 2000(Jais et al, , 2003Naito, Kawai, Nomura, Sado, & Osawa, 1996;Wang, Ding, Guo, & Yang, 2002;Wang et al, 2012;Yamamura et al, 2017). Fifteen percent of individuals with Alport syndrome are autosomal recessive inherited caused by homozygous or compound heterozygous mutations from both alleles of either COL4A3 or COL4A4 genes (Storey, Savige, Sivakumar, Abbs, & Flinter, 2013;Wang et al, 2014;Zhang et al, 2012).…”