Researchers uncover seven new genetic variants in Gaucher disease
Genetic study in Egypt highlights mutation patterns tied to disease severity
Seven previously unreported mutations linked to type 1 Gaucher disease were identified in a study analyzing the genetic code of dozens of people with the condition in Egypt.
“All patients carrying these novel variants exhibited reduced enzyme levels and clinical symptoms characteristic of type 1 [Gaucher disease], without neurological signs during disease progression,” the researchers wrote, noting that “none of these variants have been previously reported.”
The study, “Acid [beta]-glucosidase (GBA1) gene mutational spectrum and clinical phenotypes in patients with gaucher disease: seven novel mutations in a multicenter retrospective cohort study from upper Egypt,” was published in Molecular and Cellular Pediatrics.Â
Understanding Gaucher disease and its genetic causes
Gaucher disease is a genetic disorder caused by mutations in the GBA1 gene. This gene provides instructions for making an enzyme that breaks down specific fatty molecules. In Gaucher disease, the enzyme is either missing or not working properly, causing these fatty molecules to build up in cells and lead to symptoms such as enlarged organs and blood disorders.
Gaucher disease type 1 is characterized by the absence of neurological symptoms, whereas types 2 and 3 are marked by severe and milder neurological problems, respectively.
All forms of the disease are inherited in an autosomal recessive manner, meaning Gaucher develops only when both copies of the GBA1 gene, one from each biological parent, carry a disease-causing mutation.
More than 700 distinct GBA1 mutations linked to Gaucher disease have been identified. Some mutations are associated with specific disease patterns — for example, the mutation p.Leu483Pro is typically found in people with Gaucher types 2 or 3 and is linked to neurological symptoms, while p.Asn409Ser is most often seen in type 1 disease.
But the connections between specific mutations and clinical manifestations are not fully understood, and there are still Gaucher-causing GBA1Â mutations that have not yet been documented in the scientific literature.
Genetic analysis of 68 patients reveals mutation patterns in Egypt
In this study, researchers analyzed the genetic data of 68 people with Gaucher disease from a region of Egypt with high rates of consanguinity — a term that refers to close biological relatives having children together. About 51.5% of the group had type 3 Gaucher and 44.1% had type 1. Only three children had type 2 disease, and all three died before age 2.
“This study was designed to identify variants in Egyptian [Gaucher disease] patients living in an area of high consanguinity and correlate their [specific mutations] with clinical characteristics,” the scientists wrote.
Although Gaucher disease affects people of all sexes equally, most patients in this study were male. This is “consistent with previous Egyptian studies that reflect cultural behavior in Upper Egypt, where males receive greater medical care and attention,” the researchers wrote.
Because each patient carried two copies of the GBA1Â gene, the researchers analyzed 136 total alleles (copies of the gene). The most common mutation, making up 50.7% of all alleles, was the previously reported p.Leu483Pro.
The researchers noted the high prevalence of p.Leu483Pro has also been reported in studies from Turkey, Iran, and East Asia. As in those studies, this mutation was mainly seen in people with neurological disease, including all of the type 2 patients and 80% of those with type 3.
Common and emerging GBA1 variants show different links to disease types
The second most common mutation was p.Asn409Ser, which made up 7.35% of alleles. This mutation is most common in regions such as Europe, America, Brazil, and Venezuela, but its lower frequency in Egypt matches other studies showing it is less common in Eastern populations.
The researchers also found 17 additional mutations, seven of which had never been reported before. These seven mutations — p.Met88Thr, p.Asp444Gly, p.Ser470Phe, p.Leu303Val, p.Gly525Asp, p.Ala127Gly, and c.453+2T>C — were all found in people with type 1 Gaucher disease.
“Identifying these variants expands the understanding of the global GBA1 variant landscape, provides insights into the disease’s molecular basis, establishes genotype–phenotype correlations, supports genetic counseling, and performs customized molecular analyses for families at risk,” the scientists concluded.
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