Researchers have found six new mutations underlying Alport syndrome (AS) in seven Chinese families, as well as drawing possible correlations between the type of mutations involved and disease progression, a study reports.
They also found differences between males and females in regards to disease severity and the risk of kidney failure.
The study, “Genotype‐phenotype correlation and prognostic impact in Chinese patients with Alport Syndrome,” was published in the journal Molecular Genetics & Genomics Medicine.
Alport syndrome is a genetic condition that primarily causes kidney disease, hearing loss, and eye abnormalities. It is caused by mutations in the genes that direct the making of collagen type IV — the COL4A3, COL4A4, and COL4A5 genes.
Type 4 collagen is essential for the kidneys to work normally, specifically to filter out water and waste products from the blood. This explains why people with AS experience progressive loss of kidney function.
The disease may also be caused by mutations in the COL4A3 or COL4A4 genes, which are located on non-sex chromosomes. In about 15% of cases, the affected child inherits two faulty copies of either gene (one from the mother and one from the father), developing autosomal recessive Alport syndrome (ARAS).
In rarer cases, fewer than 5%, the condition is inherited in an autosomal dominant pattern (ADAS), where a single copy of a faulty COL4A3 or COL4A4 gene is sufficient to cause the disease.
The onset and severity of Alport symptoms vary among patients, as does the rate at which their disease worsens, a variability usually attributed to the specific gene that is mutated and the type of mutation involved.
Understanding the relationship between genotype — the genetic makeup of an individual — and phenotype — the set of observable traits — can be useful to predict the course of genetic diseases such as Alport, helping doctors reach a diagnosis and decide on treatments.
Researchers at the Chinese PLA Institute of Nephrology examined the relationship between disease traits, progression, and clinical prognosis and the genetic mutations underlying disease in seven Chinese families with Alport syndrome.
Next-generation sequencing was used to identify the mutations carried by eight family members. Six new mutations were identified — one comprising distinct mutations at COL4A3 (complex heterozygous), and a combined mutation of COL4A5 and INF2.
Mutations at IFN2 have been implicated in a type of kidney injury with a fast progression rate termed focal segmental glomerulosclerosis (FSGS). This suggested this mutation was adding to kidney injury already caused by COL4A5 mutations.
Researchers highlighted two other findings revealed by the data. The clinical manifestations of X‐linked AS, due to mutations in the COL4A5 gene, seemed more commonly severe in males than in females.
In addition, the different phenotypes among patients could be attributed to where the mutations were found within each gene. Segmental gene deletions — mutations that eliminate part of the collagen IV protein — and nonsense mutations — which lead to a premature interruption in the protein — appeared to be associated with a higher risk of progression into end-stage renal disease (ESRD) or kidney failure.
However, these findings need to be confirmed in further studies with larger sample sizes, the researchers caution.
“Due to its genetic heterogeneity and phenotypic diversity, AS is easily misdiagnosed as a primary nephropathy such as FSGS, and gene sequencing analysis provides the necessary methods for diagnosis and treatment,” they wrote.
“Summarizing the characteristics of AS gene mutations and the phenotypic and genotypic heterogeneity allows for the provision of database resources for the diagnosis, treatment and prognosis of AS.” they added.