Abstract
INTRODUCTION: Alport syndrome (AS) is a rare genetic disorder characterized by abnormalities in the kidneys, ears, and eyes. Its clinical presentation typically manifests in childhood or adolescence and varies widely among affected individuals, ranging from isolated hematuria to end-stage renal disease. The genetic causes of AS primarily involve mutations in the genes encoding type IV collagen COL4A3, COL4A4, and COL4A5, which play essential roles in maintaining the structural integrity of the glomerular basement membrane in the kidney, the cochlea, and the retina. They can be transmitted in autosomal dominant, autosomal recessive, and X-linked recessive. CASE PRESENTATION: Here we report a Moroccan consanguineous family with an 18-year-old girl who presented with advanced renal failure and microscopic hematuria. Her audiometry revealed hearing impairment. Urinalysis performed in all the asymptomatic family members showed microscopic hematuria in the mother and younger sister, while computed tomography excluded a urologic cause. Using next-generation sequencing analysis, we identified in the proband a nonsense homozygous variant in the COL4A3 gene (c.4114C>T, p.Gln1372Ter) that was never reported in the literature, and which is considered pathogenic according to the ACMG classification. Segregation analysis in the family showed that the parents were heterozygous like the elder brother, whereas the younger sister was mutated homozygous, and the other brother was homozygous normal. CONCLUSION: We report a novel nonsense pathogenic variant in COL4A3 that expends the allelic spectrum in AS. Clinical exploration and genetic testing of all the family members revealed intrafamilial clinical variability, suggesting a pseudo-dominant inheritance and a reduced penetrance.