New COL4A4 Mutation Discovered in Young Boy With Alport Syndrome, Case Report Shows

Researchers have discovered a new mutation in the COL4A4 gene that leads to the development of Alport syndrome, according to a recent case report.

The case report, titled “Autosomal recessive Alport syndrome caused by a novel COL4A4 splice site mutation: a case report,” was published in the Croatian Medical Journal.

Alport syndrome (AS) is a genetic disorder characterized by defects in type 4 collagen, a protein involved in the formation of structures in the kidney called the glomeruli. The glomeruli are tiny clusters of looping blood vessels responsible for filtering blood and producing urine. Due to the collagen defects, people with AS often present with proteinuria, or protein in the kidneys, and hematuria, which is blood in the urine.

Mutations in either the COL4A5, COL4A3, or COL4A4 genes, which each provide instructions for making a component of type 4 collagen, are the underlying cause of Alport syndrome.

In this report, researchers present the case of a patient in Croatia with early onset AS caused by a novel mutation, c.193-2A>C, in the COL4A4 gene.

A 10-month-old male infant was referred to the department of pediatrics at Children’s Hospital Zagreb in 2016 due to a delay in psychomotor development — which includes movement and coordination — and megalencephaly, a condition in which an infant or child has an abnormally large, heavy, and usually malfunctioning brain.

Researchers conducted an extensive genetic, metabolic, and neurologic workup and described his condition as familial benign megalencephaly, an inherited disease in which the brain is abnormally large.

The patient continued to display motor, sensory, speech, and developmental delays. He was unresponsiveness to the calling of his name at age 1, lacked the ability to form sentences, and had a short attention span. The child only started walking at 22 months.

At 14 months, the child was found to have macrohematuria, or blood visible in urine, and proteinuria.

This led physicians to perform a kidney biopsy. By looking at the biopsy under a light microscope, they found that 70% of glomeruli had normal appearance and 30% had immature/partly immature appearance. There also was one out of 69 globally sclerosed or scarred glomeruli.

This glomeruli profile, which is above the expected for the patient’s age, is usual in people with AS.

Another technique, called electron microscopy, showed areas of thinning and thickening glomeruli, which is a classic representation of AS.

The patient was therefore diagnosed with AS. The physicians suggested that both he and his and parents undergo genetic testing.

The COL4A3, COL4A4, and COL4A5 genes of both the patient and the parents were sequenced.

The researchers conducted bioinformatics analysis and discovered a new pathogenic or disease-causing mutation — identified as c.193-2A>C — in the COL4A4 gene. This mutation is located in a splice site, which means that the RNA — which provides instructions to make the protein — is not edited correctly.

This mutation has not been previously reported in either The Human Gene Mutation Database, Leiden Open (source) Variation Database, or Ensembl genome database.

Both parents were found to be heterozygous — meaning they each had a single copy of the mutated gene — for c.193-2A>C, while the patient was homozygous, in which both copies of the gene are mutated. Thus, the son was found to have autosomal recessive AS or ARAS.

With regard to how the patient will do in the long-term, the researchers said it is hard to predict his clinical course. However, other studies have shown that people with COL4A4 mutations develop end-stage renal failure at an average age of 25 years.

At this point, the patient — now age 2 — has proteinuria and hematuria, but has normal kidney function.

“We presented a case of ARAS caused by a novel c.193-2A>C COL4A4 splice site mutation. Although renal [kidney] biopsy provides information about the degree of renal parenchyma damage, genetic testing is a more sensitive and specific method that also gives insight into potential disease severity and clinical course, and provides a basis for genetic counseling,” the researchers said.