A Systematic Review of Pathogenic COL4A5 Variants and Proteinuria in Women and Girls With X-linked Alport Syndrome

Gibson, Joel T; Gooyer, Mikayla de; Huang, Mary; Savige, Judy

doi:10.1016/j.ekir.2022.08.021

Cited by 11 publications

(9 citation statements)

References 39 publications

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“…However, in a smaller study of 24 female patients with XLAS 34 , patients with non-missense variants showed a higher frequency of early proteinuria and a higher risk of developing CKD. Moreover, a recent systemic review 10 provided more supportive evidence for a correlation between severe genotype and proteinuria, with proteinuria likely leading to kidney failure in female patients. The review found that proteinuria detected before 15 years of age progressed rapidly to kidney failure 10 (Supplementary Table S4 ).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a recent systemic review 10 provided more supportive evidence for a correlation between severe genotype and proteinuria, with proteinuria likely leading to kidney failure in female patients. The review found that proteinuria detected before 15 years of age progressed rapidly to kidney failure 10 (Supplementary Table S4 ). In our study, more than 90% of the female patients developed overt proteinuria during follow-up, but the exact incidence at disease onset and onset date of proteinuria were unavailable.…”

Section: Discussionmentioning

confidence: 99%

“…In female patients with XLAS, no genotype–phenotype correlations have been observed as they generally present favorable outcomes, with approximately 25% of cases progressing to CKD G5 throughout their lifetime, with a median age of 65 years 8 , 9 . However, a recent systematic review article 10 reported a correlation between severe genotypes and proteinuria. Missense variants are the most common (60%) variants in male patients, and the overall phenotype is favorable, but the prognosis is variable, ranging from mild to severe 11 .…”

Section: Introductionmentioning

confidence: 99%

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Genotype–phenotype correlation of X-linked Alport syndrome observed in both genders: a multicenter study in South Korea

Kim

Lim

Song

et al. 2023

Sci Rep

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The genotype–phenotype correlation of the X-linked Alport syndrome (XLAS) has been well elucidated in males, whereas it remains unclear in females. In this multicenter retrospective study, we analyzed the genotype–phenotype correlation in 216 Korean patients (male:female = 130:86) with XLAS between 2000 and 2021. The patients were divided into three groups according to their genotypes: the non-truncating group, the abnormal splicing group, and the truncating group. In male patients, approximately 60% developed kidney failure at the median age of 25.0 years, and kidney survival showed significant differences between the non-truncating and truncating groups (P < 0.001, hazard ratio (HR) 2.8) and splicing and truncating groups (P = 0.002, HR 3.1). Sensorineural hearing loss was detected in 65.1% of male patients, while hearing survival periods showed a highly significant difference between the non-truncating and truncating groups (P < 0.001, HR 5.1). In female patients, approximately 20% developed kidney failure at the median age of 50.2 years. The kidney survival was significantly different between the non-truncating and truncating groups (P = 0.006, HR 5.7). Our findings support the presence of genotype–phenotype correlation not only in male patients but also in female patients with XLAS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genotype–phenotype correlation of X-linked Alport syndrome observed in both genders: a multicenter study in South Korea

Kim

Lim

Song

et al. 2023

Sci Rep

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“…An affected female will transmit the variant to half of her sons and half of her daughters [17]. Macroscopic hematuria in childhood and nephrotic syndrome are predictors of progressive kidney disease [18,19], especially, the presence of proteinuria was the most signi cant risk factor for progression to end-stage renal disease (ESRD) [20]. Among 10 girls with XLAS in our series, all had proteinuria and 6 (60%) had severe clinical manifestations, which may be related to the small number of patients and strict inclusion criteria.…”

Section: Discussionmentioning

confidence: 99%

X-Linked Alport Syndrome in girls: Clinicopathology, Genotype-phenotype analysis and Diagnostic Advantage of a5(IV) chain Staining on Paraffin section

Yang

Shen

Liu

et al. 2023

Preprint

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Background X-linked Alport syndrome (XLAS) has been poorly studied in girls. The aim of this study was to investigate the clinicopathological features of XLAS in girls, and find out whether α5(IV) chain immunofluorescence staining on paraffin sections have a diagnositic advantage than on frozen sections. Methods The clinicopathological features and genotype-phenotype correlation were investigated retrospectively in 10 girls with XLAS. The expression of α5(IV) chain was compared between paraffin and frozen sections. The percentage of mosaic-positive glomeruli on paraffin sections was counted, and the correlation with proteinuria and age were evaluated. The literature on females with XLAS was reviewed. Results Among 10 girls with XLAS, 6 patients (60%) had intermittent attacks macroscopic hematuria with proteinuria or nephrotic-range proteinuria. Genotype–phenotype correlation was conducted and the results showed that the clinical manifestations of 3 girls with nonsense variants were all severe. Paraffin-embedded sections showed betterpreserved tissue architecture and more glomeruli than frozen sections. The detection rate of mosaic positive glomeruli on the paraffin sections was obviously increased from 60–100% when compared with the frozen section. The glomerular percentage of α5(IV) chain segmental deletion on the paraffin sections varied from 10.53–87.50% in different patients, and the percentage was not related with proteinuria and age. Conclusions Severe clinical manifestations can be seen in girls with XLAS, and nonsense mutant genotype may indicate severe clinical phenotypes. For girls with XLAS, α5(IV) chain staining should be done on paraffin sections to increase the detective rate of mosaic-positive glomeruli.

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“…GBM mosaicism underlies the variable and usually milder phenotypes, and such females were once considered “just carriers” of XLAS. However, they are now included in the AS spectrum because many develop classic AS phenotypes, though with a slower rate of kidney function loss; KF is not inevitable [ 24 ▪▪ , 25 ].…”

Section: Group 2: Mild-to-moderate Alport Syndromementioning

confidence: 99%

Alport syndrome and Alport kidney diseases – elucidating the disease spectrum

Puapatanakul,

Miner

2024

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of review With the latest classification, variants in three collagen IV genes, COL4A3, COL4A4, and COL4A5, represent the most prevalent genetic kidney disease in humans, exhibiting diverse, complex, and inconsistent clinical manifestations. This review breaks down the disease spectrum and genotype–phenotype correlations of kidney diseases linked to genetic variants in these genes and distinguishes “classic” Alport syndrome (AS) from the less severe nonsyndromic genetically related nephropathies that we suggest be called “Alport kidney diseases”. Recent findings Several research studies have focused on the genotype–phenotype correlation under the latest classification scheme of AS. The historic diagnoses of “benign familial hematuria” and “thin basement membrane nephropathy” linked to heterozygous variants in COL4A3 or COL4A4 are suggested to be obsolete, but instead classified as autosomal AS by recent expert consensus due to a significant risk of disease progression. Summary The concept of Alport kidney disease extends beyond classic AS. Patients carrying pathogenic variants in any one of the COL4A3/A4/A5 genes can have variable phenotypes ranging from completely normal/clinically unrecognizable, hematuria without or with proteinuria, or progression to chronic kidney disease and kidney failure, depending on sex, genotype, and interplays of other genetic as well as environmental factors.

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A Systematic Review of Pathogenic COL4A5 Variants and Proteinuria in Women and Girls With X-linked Alport Syndrome

Cited by 11 publications

References 39 publications

Genotype–phenotype correlation of X-linked Alport syndrome observed in both genders: a multicenter study in South Korea

Genotype–phenotype correlation of X-linked Alport syndrome observed in both genders: a multicenter study in South Korea

X-Linked Alport Syndrome in girls: Clinicopathology, Genotype-phenotype analysis and Diagnostic Advantage of a5(IV) chain Staining on Paraffin section

Alport syndrome and Alport kidney diseases – elucidating the disease spectrum

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