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

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 Xlinked, 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.

Estimation of the Age of the Kashubian-Specific Pathogenic NPHS2 Variant Responsible for Hereditary Steroid-Resistant Nephrotic Syndrome Points to Its Recent Local Origin

“…They both were compound heterozygotes of c.1032delT and c.686G>A, but c.686G>A in the son was inherited from the nonaffected mother. The same can be expected in other populations and other disorders, e.g., Alport disease [45].…”

The impact of consanguinity on human health and disease with an emphasis on rare diseases

“…A consanguineous family of 13 individuals with variable features of Alport syndrome (including hematuria, proteinuria, and kidney failure) appeared to have a male-to-male transmission of disease pattern suggesting autosomal dominant inheritance. Genetic analysis however showed a mixture of homozygous and compound heterozygous alleles producing this pseudo-dominant transmission pattern [30]. This case is a good example of how assuming identity by descent in consanguineous families can be misleading.…”

Impact of consanguinity on spontaneous pregnancy loss and descendants’ health in north Morocco

“…Nevertheless, the negative effects of consanguinity seem to be more important. Indeed, it reduces inter and intra-population genetic variability, which increases the abnormalities caused by the appearance of deleterious genes in these groups (Mohamed et al, 2022;Solignac, Periquet, Anxolabehere, & Petit, 1995). As a result, such marriages have a significant implication in recessive diseases and can increase polygenic or multifactorial diseases, sterility, spontaneous pregnancy loss (SPL), stillbirths, child deaths, infant mortality, as well as congenital malformations (Romdhane et al, 2019;Temaj, Nuhii, & Sayer, 2022;Lal et al, 2016;Alharbi et al, 2020;Emery, 1976;Motulsky and Vogel, 1982;Zlotogora, 1991).…”