Digenic Alport Syndrome

Abstract

Digenic Alport syndrome refers to the inheritance of pathogenic variants in COL4A5 plus COL4A3 or COL4A4 or in COL4A3 plus COL4A4. Where digenic Alport syndrome includes a pathogenic COL4A5 variant, the consequences depend on the sex of the affected individual, COL4A5 variant “severity,” and the nature of the COL4A3 or COL4A4 change. A man with a pathogenic COL4A5 variant has all his collagen IV α3α4α5-heterotrimers affected, and an additional COL4A3 or COL4A4 variant may not worsen disease. A woman with a pathogenic COL4A5 variant has on average 50% of her heterotrimers affected, which is increased to 75% with a further COL4A3 or COL4A4 variant and associated with a higher risk of proteinuria. In digenic Alport syndrome with pathogenic COL4A3 and COL4A4 variants, 75% of the heterotrimers are affected. The COL4A3 and COL4A4 genes occur head-to-head on chromosome 2, and inheritance is autosomal dominant when both variants affect the same chromosome (in cis) or recessive when they affect different chromosomes (in trans). This form of digenic disease results in increased proteinuria and a median age of kidney failure intermediate between autosomal dominant and autosomal recessive Alport syndrome. Previous guidelines have suggested that all pathogenic or likely pathogenic digenic variants should be identified and reported. Affected family members should be identified, treated, and discouraged from kidney donation. Inheritance within a family is easier to predict if the two variants are considered independently and if COL4A3 and COL4A4 variants are known to be inherited on the same or different chromosomes.

Combined Alport syndrome, Klinefelter syndrome and Fanconi syndrome in a Chinese boy

“…Because there were two COL4A5 variants in one X chromosome in this family, the clinical phenotype of each victim was more severe than other families, the female patient developed ESRD at the age of 40, while the boy himself developed ESRD at the age of 11. In addition to the two COL4A5 variants in one X chromosome, the other X Chromosome also carried the two same COL4A5 variants, which contributed to a more severe renal phenotype in our boy, similar to the AS and FS case reported by Nishida et al 13 with homozygote COL4A5 variants or other digenic AS 20 . We suggest that the reason why AS patients combined with KS have a more severe renal phenotype might be homozygote or variants itself rather than X chromosome inactivation.…”

“…In addition to the two COL4A5 variants in one X chromosome, the other X Chromosome also carried the two same COL4A5 variants, which contributed to a more severe renal phenotype in our boy, similar to the AS and FS case reported by Nishida et al 13 with homozygote COL4A5 variants or other digenic AS. 20 We suggest that the reason why AS patients combined with KS have a more severe renal phenotype might be homozygote or variants itself rather than X chromosome inactivation. However, there are only four case reports of AS with KS in children, and among them two cases did not reach ESRD at the time when reported, see Table 2, the renal phenotypes need further observation with more samples in AS with KS.…”

Alport Syndrome: Clinical Spectrum and Therapeutic Advances

“…Alport syndrome can also follow digenic inheritance, which is the presence of 2 pathogenic variants in different type IV collagen genes. 49 There have been several reports of digenic inheritance in Alport syndrome, which is another factor that likely contributes to variability in clinical presentation. 49 , 50 , 51 …”

“… 49 There have been several reports of digenic inheritance in Alport syndrome, which is another factor that likely contributes to variability in clinical presentation. 49 , 50 , 51 …”

Current and Future Therapeutical Options in Alport Syndrome

“…The diagnosis of thin membrane nephropathy was recommended to be abandoned [ 6 ]. Patients with pathogenic variants in more than one COL4 gene (digenic or trigenic inheritance), e.g., patients with digenic COL4A4 and COL4A3 mutations on different chromosomes (trans position) or on the same chromosome (cis position), demonstrate a clinical course similar to ARAS (trans position) or as ADAS (cis position) [ 7 ]. More studies evaluating the prognosis of patients’ digenic or trigenic mutations are necessary.…”