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.

Keywords: Alport syndrome; COL4A3; COL4A4; COL4A5 genes; collagen; digenic Alport syndrome; genetic renal disease; kidney failure; proteinuria.

Figure 1.

Digenic COL4A5 plus COL4A3 or COL4A4 variants in males are not associated with greater disease severity and earlier-onset kidney failure (P=0.75). (A) Effect of digenic COL4A5 plus COL4A3/COL4A4 variants on heterotrimer formation in men (16). (B) Kidney survival in men with a COL4A5 variant (from LOVD) compared with a COL4A5 plus a COL4A3 or COL4A4 variant. The data and references for the digenic variants are summarized in Table 1, and full data are provided in Supplemental Table 1. The COL4A5 variant (solid line) and the COL4A5 plus a COL4A3 or COL4A4 variant (dashed line) are shown. LOVD, Leiden Open Variation Database.

Figure 2.

Digenic COL4A5 plus COL4A3 or COL4A4 variants in females are associated with a trend to earlier onset of proteinuria (P=0.09). (A) Effect of digenic COL4A5 plus COL4A3/COL4A4 variants on heterotrimer formation in women (16). (B) Proteinuria in women with a COL4A5 variant (37) compared with a COL4A5 plus a COL4A3 or COL4A4 variant (Table 2). The data and references for the digenic variants are summarized in Table 2, and full data are provided in Supplemental Table 2. The COL4A5 variant (solid line) and the COL4A5 plus a COL4A3 or COL4A4 variant (dashed line) are shown.

Figure 3.

Digenic COL4A3 plus COL4A4 variants are associated with disease severity intermediate between autosomal dominant and autosomal recessive Alport syndrome (P=0.01, P<0.001, respectively). (A) Effect of digenic COL4A3 plus COL4A4 variants on heterotrimer formation (16). (B) Kidney survival in digenic Alport syndrome where pathogenic variants affect COL4A3 and COL4A4 compared with autosomal recessive (43) or autosomal dominant (9) Alport syndrome. The data and references for the digenic variants are summarized in Table 3, and full data are provided in Supplemental Table 3. Heterozygous variants (solid line), digenic variants (dotted line), and autosomal recessive variants (dashed line) are shown.