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

Pseudodominant Alport syndrome caused by pathogenic homozygous and compound heterozygous COL4A3... Alport 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Human Genetics Wiley

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

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References (25)

Publisher
Wiley
Copyright
© 2022 John Wiley & Sons Ltd/University College London
ISSN
0003-4800
eISSN
1469-1809
DOI
10.1111/ahg.12454
Publisher site
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Abstract

Alport 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.

Journal

Annals of Human Genetics – Wiley

Published: May 1, 2022

Keywords: Alport syndrome; COL4A3; chronic kidney disease; genetic counselling; massively parallel sequencing; haematuria

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