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Pseudodominant Alport syndrome caused by pathogenic homozygous and compound heterozygous COL4A3 splicing variants

Lookup NU author(s): Professor John SayerORCiD, Dr Eric OlingerORCiD


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© 2021 John Wiley & Sons Ltd/University College LondonAlport syndrome is a genetic disorder affecting the basement membranes of the kidney, ear and eye, and represents a leading cause of monogenic kidney disease. Alport syndrome is genetically heterogeneous with three key genes involved (COL4A3-5) and several transmission patterns, including monogenic X-linked, autosomal recessive/dominant and digenic. We report a consanguineous family where 13 individuals presented variable features of Alport syndrome including kidney failure on two generations and male-to-male transmission, suggesting autosomal dominant inheritance. COL4A3-5 gene panel analysis surprisingly reveals two distinct, confirmed splice-altering variants in COL4A3 (NM_000091.4: c.1150+5G>A and c.4028-3C>T) present in homozygous or compound heterozygous state in individuals with kidney failure. This adds a further mode of transmission for Alport syndrome where, in a consanguineous family, the independent segregation of two variants at the same locus may create a pseudodominant transmission pattern. These findings highlight the importance of a molecular diagnosis in Alport syndrome for genetic risk counselling, given the variable modes of inheritance, but also the pitfalls of assuming identity by descent in consanguineous families.

Publication metadata

Author(s): Mohamed M, Tellez J, Bergmann C, Gale DP, Sayer JA, Olinger E

Publication type: Article

Publication status: Published

Journal: Annals of Human Genetics

Year: 2022

Volume: 86

Issue: 3

Pages: 145-152

Print publication date: 01/05/2022

Online publication date: 09/12/2021

Acceptance date: 18/11/2021

ISSN (print): 0003-4800

ISSN (electronic): 1469-1809

Publisher: John Wiley and Sons Inc


DOI: 10.1111/ahg.12454


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