Pathogenic synonymous variation of the COL4A3 gene causing Alport syndrome comorbid with IgA deposition in a toddler:...

Alport syndrome (AS) is a hereditary kidney disorder caused by pathogenic variations in COL4 genes and is clinically characterized by hematuria, proteinuria, and progressive renal impairment. IgA nephropathy (IgAN) is a clinicopathological syndrome characterized by the deposition of IgA or IgA-dominant in the glomerular mesangial areas.

This article reports a case of a 2-year-and-3-month-old female toddler who presented with hematuria and proteinuria. Renal biopsy revealed IgA deposition, and a few segments displayed atypical tearing and layering changes in the dense layer. Family screening revealed that the father and grandmother of the patient had been diagnosed with thin basement membrane disease. Genetic testing revealed compound heterozygous variations c.4793T > G (p.Leu1598Arg) and c.765G > A (p.Thr255Thr) in the COL4A3 gene. Both hematuria and proteinuria improved significantly with treatment involving steroids, mycophenolate mofetil, tacrolimus, and angiotensin-converting enzyme inhibitors (ACEIs), but both recurred and slowly increased under ACEIs monotherapy. The toddler was ultimately diagnosed with AS comorbid with IgAN, and the variant c.765G > A (p.Thr255Thr) from the father is suspected to be pathogenic based on familial segregation and predictive evidence.

Younger children with AS exhibit milder clinical manifestations or are asymptomatic. Biallelic pathogenic variations and IgA deposition may accelerate AS disease progression. Synonymous variations can also be pathogenic.