Heterozygous Pathogenic COL4A3 and COL4A4 Variants (Autosomal Dominant Alport Syndrome) Are Common, and Not Typically Associated With End-Stage Kidney Failure, Hearing Loss, or Ocular Abnormalities

Savige, Judy

doi:10.1016/j.ekir.2022.06.001

Cited by 26 publications

(22 citation statements)

References 50 publications

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“…In the past 20 years there have been an increasing number of reports of AD kidney failure associated with heterozygous pathogenic variants of COL4A3 or COL4A4 17,31,32,33,34 . These pathogenic variants were initially reported as a cause of autosomal dominant benign familial haematuria in 1996 35 .…”

Section: Discussionmentioning

confidence: 99%

Autosomal dominant tubulointerstitial kidney disease cosegregating with COL4A4:p.G545A in Turkish Cypriot families with kidney failure

Özdemir

Oygar

Behlül

et al. 2023

Preprint

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Chronic kidney disease (CKD) is a global health priority with over 850 million people affected. The starting point for improving outcome must be to diagnose the primary renal disease and in low and middle income countries ‘unknown aetiology’ accounts for the majority of diagnoses. In Cyprus, familial kidney disease is very common. Using next-generation sequencing, we found that a common polymorphism (COL4A4:p.G545A), hitherto considered to be benign or hypomorphic, was present in 5 of 53 Turkish Cypriot families with kidney disease and a glomerular phenotype (at least one person with haematuria and/or proteinuria). Therefore, we tested 49 further families with kidney disease using a restriction fragment length polymorphism assay. From this total of 102 families, we showed that this variant was present in 12 of 85 families (14%) with some evidence of glomerular disease and none of 17 with chronic kidney disease lacking these features. Co-segregation analyses indicated that the variant co-segregated with disease more than would be expected by chance. These families have an autosomal dominantly inherited susceptibility to kidney disease associated with variable and intermittent microscopic haematuria, proteinuria < 1 g/day until the eGFR falls below 30 ml/min. End-stage kidney disease occurred in 17% of those affected at a median of 66 years. The presentation is more characteristic of a tubulointerstitial kidney disease and represents a tubular phenotype of Alport spectrum nephropathy.

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Section: Discussionmentioning

confidence: 99%

Autosomal dominant tubulointerstitial kidney disease cosegregating with COL4A4:p.G545A in Turkish Cypriot families with kidney failure

Özdemir

Oygar

Behlül

et al. 2023

Preprint

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“…Similarly, patients with thin basement membrane lesion alone and any variant in COL4A3, 4, or 5 genes may also be at risk for disease progression. Thus, the terms "thin basement membrane nephropathy" and "benign familial hematuria" are best avoided [9][10][11][12]. For an initial pathology report, the term "thin basement membrane lesion" or a descriptive diagnosis of "diffusely or segmentally thin glomerular basement membranes" should be used.…”

Section: Discussionmentioning

confidence: 99%

Sporadic Case of Heterozygous X-Linked Alport Syndrome

Zuckerman¹,

Srivastava²

2023

Glomerular Dis

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Alport syndrome is a genetically and phenotypically heterogeneous disorder that can be transmitted in an X-linked, autosomal recessive, or autosomal dominant fashion and can affect glomerular, cochlear, and ocular basement membranes. The disorder results from mutations in the collagen IV genes COL4A5 (X chromosome), COL4A3, and COL4A4. Alport patients are at lifetime risk for kidney failure, sensorineural deafness, and ocular abnormalities. Males with Alport syndrome typically present with severe phenotype with progression to end-stage kidney disease and/or sensorineural deafness and eye changes. Females generally having less severe presentation and diagnosis of X-linked Alport syndrome are generally not considered. Here, we report a case of a 3-year-old girl with gross hematuria, proteinuria, and chronic kidney disease who was found to have features of Alport syndrome on kidney biopsy and a sporadic heterozygous pathogenic COL4A5 deletion on molecular testing. This case report emphasizes the importance of kidney biopsy and molecular testing in the work up of pediatric patients with hematuria, proteinuria, and/or chronic kidney disease. It is also a poignant illustration that females with heterozygous X-linked COL4A5 mutations are often affected patients. It further illustrates the phenomenon of sporadic occurrence of genetic kidney disease in the absence of family history of kidney disease.

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“…Many papers report that X-linked Alport syndrome accounts for 80% of cases, but newer studies are challenging this statistic. 28 , 33 , 48 Autosomal recessive Alport syndrome and autosomal dominant Alport syndrome are caused by pathogenic variants in COL4A3 and/or COL4A4 , respectively. 33 , 48 Although autosomal forms were previously felt to account for a minority of cases, this is now changing in light of these more recent studies.…”

Section: Geneticsmentioning

confidence: 99%

“… 28 , 33 , 48 Autosomal recessive Alport syndrome and autosomal dominant Alport syndrome are caused by pathogenic variants in COL4A3 and/or COL4A4 , respectively. 33 , 48 Although autosomal forms were previously felt to account for a minority of cases, this is now changing in light of these more recent studies. Autosomal recessive Alport syndrome results from homozygous or compound heterozygous rare variants in COL4A3 or COL4A4 , whereas autosomal dominant Alport syndrome results from heterozygous rare variants in these genes.…”

Section: Geneticsmentioning

confidence: 99%