The women also inherited a mutation in this gene that was previously known, which also contributed to her disease.
The report underlines the importance of using a new genetic screening technology, called targeted next generation sequencing, to reveal new disease-causing mutations and obtain a fast and accurate diagnosis of AS, as happened for this patient.
The study, “Identification of a Novel COL4A4 Variant in Compound-Heterozygous State in a Patient With Alport Syndrome and Histological Findings Similar to Focal Segmental Glomerulosclerosis (FSGS),” was published in the journal Frontiers in Genetics.
Type 4 collagen is essential for the kidneys to work normally, specifically to filter out water and waste products from the blood. That is why people with AS experience progressive loss of kidney function.
Physiologically, the most important part of the kidney filtering system is the glomerular basement membrane (GBM), a specialized matrix primarily composed of type IV collagen.
So, variants in any of the genes that code for type 4 collagen lead to problems in GBM and kidney function.
Autosomal recessive Alport syndrome (ARAS) is one of three types of AS, which depend on the affected genes and their mode of inheritance.
Everyone has two copies of each of these genes, one inherited from the mother and one from the father.
ARAS develops if two copies of these genes are faulty. If a person has only one mutated copy, he or she is considered a carrier.
In this case report, researchers found a woman with AS who had inherited two mutated copies — a novel COL4A4 variant and a previously described mutation in the same gene — one inherited from her mother and the other from her father, respectively.
The women, a 24-year old Chinese, was admitted with proteinuria (abnormal levels of protein in the urine) at the Union Hospital, Huazhong University of Science and Technology in China.
As proteinuria is a typical sign of kidney damage, the patient underwent a kidney biopsy. The exams revealed kidney lesions like those seen in focal segmental glomerulosclerosis (FSGS) — a disease in which scar tissue develops on the kidney’s network of blood vessels that filter waste from the blood, called glomeruli.
The patient also had blurred vision and eye swelling, the latter resolving gradually with no need for treatment.
As her symptoms and exam results were consistent with a diagnosis of AS, doctors went on to confirm the diagnosis by genetic screening.
They used a recent technology called targeted next generation sequencing which, contrary to the traditional DNA sequencing method called Sanger sequencing, enables clinicians to rapidly and simultaneously determine the sequence of a set of target genes. In this case, the three possible causative genes of AS were sequenced — COL4A3, COL4A4 and COL4A5.
Targeted sequencing revealed a new mutation at the COL4A4 gene (c.4760_4761insC) consisting of the insertion of the nucleotide C. Of note, a nucleotide is one of the four chemical bases, or building blocks, that make up DNA: adenine (A), guanine (G), cytosine (C), and thymine (T).
This insertion leads to a “frameshift” — a displacement in the reading frame of the gene that makes the cellular machinery responsible for building proteins to mistakenly produce a shorter COL4A4 protein.
The patient also carried a previously reported variant of COL4A4 (c.1323_1340delTGGCTTGCCTGGAGCACC) — a deletion of a stretch of the gene — predicted to cause disease.
In patients with Alport syndrome, genetic testing is usually performed by Sanger sequencing of COL4A3, COL4A4 and COL4A5.
However, because these three genes represent a large chunk of DNA, performing Sanger sequencing “is very laborious, time consuming and not a cost-effective approach for identifying the candidate variants,” researchers emphasized.
This study highlights the significance of targeted next-generation sequencing as an easier, faster and cost-effective alternative for the genetic screening and clinical diagnosis of AS patients.