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Digenic Alport Syndrome

Savige, Judy; Renieri, Alessandra; Ars, Elisabet; Daga, Sergio; Pinto, Anna Maria; Rothe, Hansjorg; Gale, Daniel P; ... Gibson, Joel T; + view all (2022) Digenic Alport Syndrome. Clinical Journal of the American Society of Nephrology , 17 (6) , Article CJN.03120322. 10.2215/CJN.03120322. Green open access

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Abstract

Digenic Alport syndrome refers to the inheritance of pathogenic variants in COL4A5 plus COL4A3 or COL4A4 or in COL4A3 plus COL4A4 Where digenic Alport syndrome includes a pathogenic COL4A5 variant, the consequences depend on the sex of the affected individual, COL4A5 variant "severity," and the nature of the COL4A3 or COL4A4 change. A man with a pathogenic COL4A5 variant has all his collagen IV α3α4α5-heterotrimers affected, and an additional COL4A3 or COL4A4 variant may not worsen disease. A woman with a pathogenic COL4A5 variant has on average 50% of her heterotrimers affected, which is increased to 75% with a further COL4A3 or COL4A4 variant and associated with a higher risk of proteinuria. In digenic Alport syndrome with pathogenic COL4A3 and COL4A4 variants, 75% of the heterotrimers are affected. The COL4A3 and COL4A4 genes occur head-to-head on chromosome 2, and inheritance is autosomal dominant when both variants affect the same chromosome (in cis) or recessive when they affect different chromosomes (in trans). This form of digenic disease results in increased proteinuria and a median age of kidney failure intermediate between autosomal dominant and autosomal recessive Alport syndrome. Previous guidelines have suggested that all pathogenic or likely pathogenic digenic variants should be identified and reported. Affected family members should be identified, treated, and discouraged from kidney donation. Inheritance within a family is easier to predict if the two variants are considered independently and if COL4A3 and COL4A4 variants are known to be inherited on the same or different chromosomes.

Type: Article
Title: Digenic Alport Syndrome
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.2215/CJN.03120322
Publisher version: https://doi.org/10.2215/CJN.03120322
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: Alport syndrome, COL4A3, COL4A4, COL4A5 genes, collagen, digenic Alport syndrome, genetic renal disease, kidney failure, proteinuria
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10150600
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