Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece

Abstract

Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant pathogenic variants in the X-linked COL4A5 (NM_000495.5) gene or recessive variants in the COL4A3/COL4A4 (NM_000091.4/NM_000092.4) genes. The disease manifests in early childhood with persistent microhematuria and can progress to proteinuria and kidney failure in adolescence or early adulthood if left untreated. On biopsy, pathognomonic features include alternate thinning, thickening and lamellation of the glomerular basement membrane (GBM), in the presence of podocyte foot process effacement. Although previous studies indicate a prevalence of AS of about 1/50,000, a recent publication reported a predicted rate of pathogenic COL4A5 variants of 1/2320. We herewith present 98 patients (40 M/58 F) from 26 Greek families. We are selectively presenting the families segregating the X-linked form of AS with pathogenic variants in the COL4A5 gene. We found 21 different pathogenic variants, 12 novel: eight glycine and one proline substitutions in the collagenous domain, one cysteine substitution in the NC1 domain, two premature termination of translation codons, three splicing variants, one 5-bp insertion/frameshift variant, one indel-frameshift variant and four gross deletions. Notably, patients in six families we describe here and three families we reported previously, carried the COL4A5-p.G624D substitution, a founder defect encountered all over Europe which is hypomorphic with mostly milder symptomatology. Importantly, on several occasions, the correct genetic diagnosis reclassified patients as patients with AS, leading to termination of previous immunosuppressive/cyclosporine A therapy and a switch to angiotensin converting enzyme inhibitors (ACEi). With the understanding that all 98 patients span a wide range of ages from infancy to late adulthood, 15 patients (11 M/4 F) reached kidney failure and 11 (10 M/1 F) received a transplant. The prospects of avoiding lengthy diagnostic investigations and erroneous medications, and the advantage of delaying kidney failure with very early administration of renin-angiotensin-aldosterone system (RAAS) blockade, highlights the importance of timely documentation of AS by genetic diagnosis.

ADrosophilamodel to screen Alport syndromeCOL4A5variants for their functional pathogenicity

“…Key components of its scaffolding are Collagen IV α3α4α5 trimers (Naylor et al, 2021). Alport syndrome is caused by mutations in the genes that encode these Collagen type IV alpha proteins ( COL4A3 , COL4A4 , and COL4A5 ) (Artuso et al, 2012; Barker et al, 1990; Cameron-Christie et al, 2019; Fallerini et al, 2014; Hadjipanagi et al, 2022; Heiskari et al, 1996; Hudson, 2004; Longo et al, 2006; Pokidysheva et al, 2021; Zhang et al, 2019). The mutations inhibit trimeric protein complex formation which prevents a pivotal developmental switch from Collagen type IV α1 and α2 isoforms in fetal kidney to the α3, α4, and α5 isoforms in mature podocytes (Harvey et al, 1998; Kalluri et al, 1997; Miner and Sanes, 1994).…”

Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice

“…Similar observations regarding clinical heterogeneity have been made in patients who inherit pathogenic variants in the COL4A5 gene, responsible for the X-linked form of AS. This is documented through genotype–phenotype correlations and include hypomorphic variants such as the COL4A5 :p.Gly624Asp, which is most frequently, but not always, accompanied by a milder clinical picture [ 16 , 17 ]. The term “hypomorphic” was coined by the 1946 Nobel Prize winner Hermann J. Muller (1890–1967).…”