Novel variants in COL4A4 and COL4A5 are rare causes of FSGS in two unrelated families

Hines, Stephanie L.; Agarwal, Anjali; Ghandour, Mohamedanwar; Aslam, Nabeel; Mohammad, Ahmed N.; Atwal, Paldeep S.

doi:10.1038/s41439-018-0016-8

Cited by 7 publications

(5 citation statements)

References 22 publications

(24 reference statements)

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“…However, no hearing impairments or symptoms in eyes were found in the proband. Older than 55 years old, the proband’s father only had asymptomatic microscopic hematuria and proteinuria, which was consistent with other reports[ 13 ].…”

Section: Discussionsupporting

confidence: 92%

Alport syndrome combined with lupus nephritis in a Chinese family: A case report

Liu¹,

Li²,

Peng³

2021

WJCC

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BACKGROUND Alport syndrome (ATS) is a rare hereditary disease caused by mutations in genes such as COL4A3, COL4A4, and COL4A5 . ATS involves a spectrum of phenotypes ranging from isolated hematuria that is nonprogressive to progressive renal disease with extrarenal abnormalities. Although ATS can be combined with other diseases or syndromes, ATS combined with lupus nephritis has not been reported before. CASE SUMMARY A Chinese family with ATS was recruited for the current study. Clinical characteristics (including findings from renal biopsy) of ATS patients were collected from medical records, and potential causative genes were explored by whole-exome sequencing. A heterozygous substitution in intron 22 of COL4A3 (NM_000091 c.2657-1G>A) was found in the patients, which was further confirmed by quantitative polymerase chain reaction. CONCLUSION Heterozygous substitution of a COL4A3 gene splice site was identified by whole-exome sequencing, revealing the molecular pathogenic basis of this disorder. In general, identification of pathogenic genes can help to fully understand the molecular mechanism of disease and facilitate precise treatment.

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Section: Discussionsupporting

confidence: 92%

Alport syndrome combined with lupus nephritis in a Chinese family: A case report

Liu¹,

Li²,

Peng³

2021

WJCC

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“…Thus, the formation of α3/4/5 chains and the abnormality of the basement membrane in our patient were the outcomes of the simultaneous action of these two mutations but could not be attributed solely to the missense mutation or the deletion; it was a complex heterozygous mutation, and the associated symptom was more severe than that with the simple missense mutation or with the single-base deletion mutation. Previous studies have focused on the relationship between FSGS and AS and on that between IgA nephropathy and AS (Gast et al, 2016;Hines et al, 2018;Kamiyoshi et al, 2016;Lin et al, 2014;Malone et al, 2014;Xie et al, 2015), suggesting that AS has variable clinical phenotypes, AS patients who have proteinuria or AS patients who have proteinuria and whose renal biopsy results are consistent with changes in FSGS or in IgA nephropathy are sometimes misdiagnosed with a primary nephropathy such as FSGS. In recent years, several…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have focused on the relationship between FSGS and AS and on that between IgA nephropathy and AS (Gast et al, ; Hines et al, ; Kamiyoshi et al, ; Lin et al, ; Malone et al, ; Xie et al, ), suggesting that AS has variable clinical phenotypes, AS patients who have proteinuria or AS patients who have proteinuria and whose renal biopsy results are consistent with changes in FSGS or in IgA nephropathy are sometimes misdiagnosed with a primary nephropathy such as FSGS. In recent years, several researches and cases reported that AS patients with COL4A5 mutations who have coinherited with COL4A3/COL4A4, MYO1E and LAMA5 mutations could exacerbated phenotypes (Lennon et al, ; Voskarides et al, ).…”

Section: Discussionmentioning

confidence: 99%

Genotype‐phenotype correlation and prognostic impact in Chinese patients with Alport Syndrome

Shang

Peng

Wang

et al. 2019

Molec Gen & Gen Med

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Background Alport Syndrome (AS) is a progressive hereditary glomerular disease. It is often accompanied by sensorineural hearing loss and ocular abnormalities and can sometimes develop into end stage renal disease (ESRD), which is caused by mutations in the genes encoding the collagen type IV family of proteins. Methods This study analyzed the association between the clinical data of seven AS families and genes and the disease progression of different mutation types, including COL4A3 (OMIM 120070)， COL4A4 (OMIM 120131), and COL4A5 (OMIM303630). Results A total of six new pathogenic mutation sites, one complex heterozygous mutation at COL4A3, and a combined mutation of COL4A5 and INF2 (OMIM 610982) were identified in this study. It was revealed that the clinical manifestations of X‐linked AS caused by mutations in the COL4A5 gene were more severe in males than in females. In addition, the difference in patient phenotype can be attributed to the location of gene mutations affecting the protein domain or functional domain. Our data suggested that the gene deletion and nonsense mutations had a high risk for progression to ESRD. Conclusion Our results revealed the spectrum of type IV collagen genes, which contribute to the enrichment of database resources and has important implications in the diagnosis, prognosis, and guiding treatment of AS.

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“…Both had histology consistent with TBMN. Though this gene has typically been associated with recessive Alport syndrome, multiple reports (Marcocci et al 2009;Hines et al 2018;Longo et al 2002) have demonstrated that patients with heterozygous COL4A4 or COL4A3 variants can develop significant renal disease and can benefit from early initiation of renin-angiotensinaldosterone system blockade (Stock et al 2017).…”

Section: Discussionmentioning

confidence: 99%

Diagnostic utility of genetic testing in patients undergoing renal biopsy

Benson

Murray

Doyle

et al. 2020

Cold Spring Harb Mol Case Stud

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High-throughput DNA testing is becoming established as a standard diagnostic test in the renal clinic. Previously published studies on cohorts of patients with unexplained chronic kidney disease of a suspected genetic aetiology have suggested a diagnostic yield for genomic sequencing of up to 18%. Here we determine the yield of targeted gene panel in a clinically unscreened cohort of patients referred for percutaneous native renal biopsy. Patients who underwent renal biopsy for investigation of chronic kidney disease were sequenced using a genomic sequencing panel covering 227 genes in which variation is known to be associated with monogenic chronic kidney disease (CKD). Candidate disease-causing variants were assessed for pathogenicity using guidelines from the American College for Medical Genetics and Genomics. Fifty CKD patients were recruited and sequenced. A molecular diagnosis was obtained for two patients (4%). A molecular diagnosis is possible using genomic testing in ∼4% of clinically unscreened patients undergoing renal biopsy. Genetic screening may be useful for diagnosis in a subset of CKD patients but is most valuable when applied to patients with suspected heritable forms of kidney disease.

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Novel variants in COL4A4 and COL4A5 are rare causes of FSGS in two unrelated families

Cited by 7 publications

References 22 publications

Alport syndrome combined with lupus nephritis in a Chinese family: A case report

Alport syndrome combined with lupus nephritis in a Chinese family: A case report

Genotype‐phenotype correlation and prognostic impact in Chinese patients with Alport Syndrome

Diagnostic utility of genetic testing in patients undergoing renal biopsy

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