Patients with X-linked Alport syndrome who have mutations in their COL4A3 or COL4A4 genes — characteristic of autosomal recessive forms of the disease — are rare but may experience more severe disease, with a higher risk of excess protein in their urine, a recent study suggests.
The study, “Effect of heterozygous pathogenic COL4A3 or COL4A4variants on patients with X‐linked Alport syndrome,” was published in the journal Molecular Genetics & Genomic Medicine.
Between 80% and 85% of Alport syndrome cases result from genetic mutations in the COL4A5 gene, which is located on the X chromosome. Thus, this form of AS is inherited in an X-linked pattern and called X-linked Alport syndrome (XLAS).
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, a child inherits two faulty copies of either gene (one from the mother and one from the father) and develops the disease. This is known as autosomal recessive Alport syndrome (ARAS).
In fewer than 5% of all cases, Alport syndrome 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.
Recent studies report coexisting mutations in either two of the three genes — COL4A3, COL4A4 or COL4A5 — in patients with AS.
However, the clinical outcomes are unclear for XLAS patients (with COL4A5 mutations) who also carry heterozygous variants (one copy is mutated) at either COL4A3 or COL4A4. This type of information is useful to improve clinical assessment and genetic counseling for AS.
“It is important to know whether it would make the XLAS disease worse,” the researchers wrote.
To understand better which type of disease symptoms are associated with this complex AS genetic background, the researchers first investigated its frequency.
They used targeted next‐generation sequencing (NGS) to genetically screen 417 patients referred to the Peking University First Hospital, in China, who were diagnosed with or suspected of having AS.
A few patients were found to have XLAS and heterozygous mutations in COL4A3 or COL4A4 genes — six unrelated children of three boys and three girls.
Three of them carried a pathogenic (disease-causing) gene variant at COL4A5 and COL4A3, and two others at COL4A5 and COL4A4.
One 3.6-year-old girl carried harmful variants at all three genes: two pathogenic variants of COL4A4 and COL4A3 had been transmitted by each parent whereas the COL4A5 variant appeared spontaneously in the child.
This was the first reported case of a patient with three pathogenic variants in all Alport syndrome genes. It is unknown whether her disease would be more severe than females with XLAS or autosomal recessive AS alone. Longer follow-up studies and examining more cases of this kind would be important to find out, the authors added.
Another three males with XLAS only — carrying a single pathogenic variant in COL4A5 — were also identified and included in the study.
The clinical signs and symptoms were then compared between the two groups of males — those with XLAS and COL4A3 or COL4A4 mutations versus those with XLAS only.
Age of onset of symptoms, and hearing loss rate were not significantly different between the two groups. Both groups also had initial symptoms of blood in their urine (hematuria) and excess protein in their urine (proteinuria), and a family history of kidney disease.
However, proteinuria seemed to be severest in boys with XLAS combined with COL4A3 or COL4A4 mutations.
The study suggests that very few Alport cases, less than 1%, stem from a combination of XLAS with heterozygous pathogenic COL4A3 or COL4A4 variants.
“Our data revealed an additional heterozygous pathogenic COL4A3 or COL4A4 variant would make XLAS males suffering from more severe proteinuria. It suggested that another genetic hit from COL4A3 or COL4A4 might make the XLAS disease worse,” the researchers wrote.
A clinical diagnosis of XLAS is clear but the genetic background of patients may vary, which could affect the risk of inheritance in families, they said.
Because of that, the team stressed that “it is necessary to test all the three genes COL4A3‐5 by NGS in patients suspected for Alport syndrome, not only meaningful for diagnosis, but also for the genetic counseling.”