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

Kim, Ji Hyun; Lim, Seon Hee; Song, Ji Yeon; Cho, Myung Hyun; Hyun, Hyesun; Yang, Eun Mi; Lee, Jung Won; Cho, Min Hyun; Park, Min Ji; Lee, Joo Hoon; Jung, Jiwon; Yoo, Kee Hwan; Jang, Kyung Mi; Pai, Ki Soo; Suh, Jin-Soon; Namgoong, Mee Kyung; Chung, Woo Yeong; Kim, Su Jin; Cho, Eun Young; Kim, Kyung Min; Kim, Nam Hee; Kim, Min-Sun; Paik, Jin Ho; Kang, Hee Gyung; Ahn, Yo Han; Cheong, Hae Il

doi:10.1038/s41598-023-34053-7

Cited by 5 publications

(6 citation statements)

References 34 publications

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“…Prior studies have suggested that nonsense/frameshift variants confer the worst prognosis, followed by splice variants, and then the mildest phenotypes for missense and in-frame deletion variants. 6,20 In our study, we did not observe this genotype-phenotype correlation. None of the 5 females with nonsense/frameshift variants (mean age 63.8 y [SD 27.0], mean eGFR 75.5 ml/min/1.73m 2 [SD 28.3]) had ESKD or even eGFR <30 ml/min/1.73m 2 .…”

Section: Discussioncontrasting

confidence: 89%

“…Thus, glycine missense variants disrupting the collagenous domain as well as protein-truncating variants (PTVs) are likely to be deleterious. Some but not all studies suggest a worse prognosis for PTVs than missense variants [4][5][6][7][8] . One glycine missense variant, p.Gly624Asp, is adjacent to a non-collagenous region and known to have a more mild phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Genotype-first analysis in an unselected health system-based population reveals variable phenotypic severity ofCOL4A5variants

Zellers,

Solanki,

Kelly

et al. 2024

Preprint

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IntroductionOur knowledge of X-linked Alport Syndrome [AS] comes mostly from selected cohorts with more severe disease.MethodsWe examined the phenotypic spectrum of X-linked AS in males and females with a genotype-based approach using data from the Geisinger MyCode DiscovEHR study, an unselected health system-based cohort with exome sequencing and electronic health record data. Patients withCOL4A5variants reported as pathogenic (P) or likely pathogenic (LP) in ClinVar, or protein-truncating variants (PTVs), were each matched with up to 5 controls withoutCOL4A3/4/5variants by sociodemographics, diabetes diagnosis, and year of first outpatient encounter. AS-related phenotypes included dipstick hematuria, bilateral sensorineural hearing loss (BSHL), proteinuria, decreased eGFR, and ESKD.ResultsOut of 170,856 patients, there were 30 hemizygous males (mean age 52.4 [SD 19.8] years) and 56 heterozygous females (mean age 58.5 [SD 19.4]) with aCOL4A5P/LP variant, including 48 with the hypomorphic variant p.Gly624Asp. Overall, penetrance (having any AS phenotypic feature) was highest for non-p.Gly624Asp P/LP variants (males: 89%, females: 86%), intermediate for p.Gly624Asp (males: 77%, females: 69%), compared to controls (males: 32%; females: 50%). The proportion with ESKD was highest for males with P/LP variants (41%), intermediate for males with p.Gly624Asp (15%) and females with P/LP variants (10%), compared to controls (males: 3%, females 2%). Only 33% of males and 11% of females had a known diagnosis of Alport syndrome or thin basement membrane disease. Only 47% of individuals withCOL4A5had completed albuminuria screening, and a minority were taking renin-angiotensin aldosterone system (RAAS) inhibitors.ConclusionIn an unselected cohort, we show increased risks of AS-related phenotypes in men and women compared to matched controls, while showing a wider spectrum of severity than has been described previously and variability by genotype. Future studies are needed to determine whether early genetic diagnosis can improve outcomes in Alport Syndrome.

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Section: Discussioncontrasting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Genotype-first analysis in an unselected health system-based population reveals variable phenotypic severity ofCOL4A5variants

Zellers,

Solanki,

Kelly

et al. 2024

Preprint

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“…The GBM may show thinning with or without lamellation. Finally, recent data indicate that there are genotype–phenotype correlations in females with XLAS [ 28 ▪ , 29 ] that are consistent with findings described above for the patients in Group 1.…”

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

confidence: 87%

“…From the large European cohort of 506 female XLAS patients from 195 families and another cohort of 275 female patients from 179 families in Japan, only 12–15% developed KF before the age of 40 years, and 30–40% before the age of 60 years [ 16 , 27 ]. A more recent study of 86 female patients with XLAS from Korea estimated the median age at KF to be 50.2 (39.0–61.5) years [ 28 ▪ ]. Hearing loss occurred in 5.5–28%, usually developing by middle age.…”

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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“…Notably, the majority of these patients were male (85.7%), and all exhibited varying degrees of hematuria (gross or microscopic). In a recent retrospective study of Korean patients with XLAS, approximately 20% of the male patients also presented with NS accompanied by hematuria at a median onset age of 7.0 years [13].…”

Section: Discussionmentioning

confidence: 99%

A monocenter study on pediatric Alport syndrome featuring nephrotic syndrome as the primary manifestation

Qian

2024

Preprint

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Background: Alport Syndrome (AS) is a genetic kidney disorder characterized by progressive kidney failure. It is often misdiagnosed as other kidney diseases due to its clinical phenotypic heterogeneity and the lack of specific clinical symptoms in early childhood. Methods: This study retrospectively analyzed clinical data of 7 pediatric patients admitted to Xi'an Children's Hospital between 2016 and 2022 due to clinical manifestations of nephrotic syndrome. Results: The 7 patients were from six families, and 4 patients had a family history of kidney disease. The median(IQR) age at presentation was 9.8 (7.8, 10.8) years and median follow-up was 4.4 (2.4–8.0) years.They all had hematuria, nephrotic proteinuria and hypoproteinemia. Kidney biopsy revealed focal segmental glomerulosclerosis (FSGS) on light microscopy. Among the patients, 8 pathogenic gene mutations were detected, 6 patients had mutations in the COL4A5gene. Furthermore, the mutations in 6 patients (85.7%) were severe.Treatment involved administering renin-angiotensin-aldosterone system (RAAS) inhibitors to all the patients starting from their first visit. Up to the present follow-up time, all the 7 patients exhibited varying degrees of reduction in proteinuria, with 1 of them experiencing kidney function decline, and 1 progressing to end-stage kidney disease (ESKD). Conclusion: AS should be considered in patients co-exhibiting nephrotic syndrome and hematuria, especially those with a poor response to steroid therapy or with a family history of hematuria. Additionally, AS should be considered in the genetic diagnosis of patients with kidney pathology consistent with FSGS. The most common pathogenic gene in AS patients with nephrotic syndrome is the COL4A5 gene, and most of them have severe mutations.

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

Cited by 5 publications

References 34 publications

Genotype-first analysis in an unselected health system-based population reveals variable phenotypic severity ofCOL4A5variants

Genotype-first analysis in an unselected health system-based population reveals variable phenotypic severity ofCOL4A5variants

Alport syndrome and Alport kidney diseases – elucidating the disease spectrum

A monocenter study on pediatric Alport syndrome featuring nephrotic syndrome as the primary manifestation

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