Alport Syndrome Genetics

Alport Syndrome is caused by defects in the chains of type IV collagen of the basement membranes. Type IV collagen is actually a family of six proteins, or chains, that are known as alpha-1 through alpha-6. Mutations that affect the alpha-3, alpha-4, and alpha–5 chains cause Alport Syndrome. The 3 genetic forms of Alport Syndrome are:

  • XLAS (X-linked Alport Syndrome) – The most common form that accounts for 80% to 85% of the cases and results from mutations of the alpha-5 chain type IV collagen (gene COL4A5)
  • ARAS (autosomal recessive Alport Syndrome) – This form accounts for 10% to 15% of the cases and is caused by mutations in the alpha-3 or alpha-4 chains (genes COL4A3 or COL4A4)
  • ADAS (autosomal dominant Alport Syndrome) – Rare form that accounts for about 5% of the cases and is caused by mutations in the alpha-3 or alpha-4 chains (genes COL4A3 or COL4A4).

Mode of Inheritance

XLAS – When the mother is the carrier of the mutation her chance of transmitting it to her children is 50% with each pregnancy as she has two X chromosomes, one affected and one normal. Male offspring who inherit the mutation will have the disease as they have only one X chromosome and a Y chromosome. Female offspring have two X chromosomes, so the normal X chromosome buffers the effect of the mutated X chromosome. Therefore, daughters who inherit the mutation will be carriers like their mothers. Sons who inherit the mutation will pass the disease on to all of their daughters and to none of their sons, because they will give their mutated X-chromosome to their daughters and their normal Y chromosome to their sons. In about 10% of children with XLAS, the COL4A5 mutation arises spontaneously in the child, and neither parent carries a mutation.

ARAS – Autosomal recessive disorders result when both copies of a gene are defective. Typically, each parent of a child with a recessive condition passes a mutant gene to the affected child. The genes COL4A3 and COL4A4 are located on chromosome 2. Each of us has two copies of this chromosome, and two copies of both the COL4A3 and COL4A4 genes. The parents only have one mutation in one of the chromosomes and so they can be asymptomatic (have no symptoms) or have some hematuria (blood in the urine). However, they will not have progression of the disease. When each parent carries a mutation in COL4A3 or COL4A4, there is a 25% probability with every pregnancy that the child will have ARAS.

ADAS – Each child of an affected parent has a 50% chance of inheriting the mutation.

Prenatal testing is available for XLAS and ARAS and may be available for ADAS by laboratories offering custom prenatal testing. See Genetic Labs for more information on testing.