Autosomal Dominant Alport Syndrome

Area of Science:

• Nephrology
• Genetics
• Internal Medicine

Background:

• Autosomal dominant Alport syndrome (ADAS) is the most common monogenic kidney disease, affecting approximately 1% of the population.
• It arises from heterozygous pathogenic variants in COL4A3 or COL4A4, presenting with persistent glomerular hematuria and a thinned glomerular basement membrane.
• Unlike X-linked Alport syndrome, ADAS typically lacks hearing loss and ocular abnormalities, though clinical features can vary significantly, even within families.

Purpose of the Study:

• To elucidate the genetic basis and clinical spectrum of autosomal dominant Alport syndrome.
• To differentiate ADAS from other forms of Alport syndrome and related kidney diseases.
• To establish guidelines for monitoring and treatment of patients with ADAS.

Main Methods:

• Review of clinical data and genetic testing results from patients with suspected Alport syndrome.
• Analysis of genotype-phenotype correlations, particularly regarding COL4A3/COL4A4 variant types and clinical manifestations.
• Comparison of ADAS with X-linked Alport syndrome and digenic inheritance patterns.

Main Results:

• Heterozygous pathogenic variants in COL4A3 or COL4A4 cause ADAS, with incomplete penetrance observed in about one-third of carriers.
• Missense variants, especially Glycine substitutions, are more frequently associated with proteinuria than truncating variants.
• Clinical presentation varies, with incomplete penetrance and inconsistent links between missense variants and kidney failure progression.

Conclusions:

• Genetic testing is essential for diagnosing ADAS and distinguishing it from X-linked Alport syndrome and digenic disease.
• Patients with ADAS require regular monitoring for albuminuria and prompt treatment with ACE inhibitors and potentially SGLT2 inhibitors.
• Genetic testing is recommended for all first-degree relatives of individuals diagnosed with ADAS.