Extending gene tests to Gaucher families enables early detection
Excluding relatives not in immediate family is 'significant missed opportunity'
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Extending genetic testing beyond the person initially diagnosed with Gaucher disease can uncover additional affected relatives who might otherwise go undetected, according to a new study.
When researchers tested family members of Gaucher patients, some relatives, including siblings, children, grandparents, aunts, and uncles, were either genetic carriers or undiagnosed cases of Gaucher.
“The exclusion of non-direct relatives from genetic screening represents a significant missed opportunity for timely diagnosis, effective clinical management, and family planning,” the researchers wrote.
The study, “Family studies in Gaucher Disease: a key resource for early diagnosis and personalized treatment strategies,” was published in the Orphanet Journal of Rare Diseases.
In Gaucher, mutations in the GBA1 gene interfere with the production or function of the enzyme glucocerebrosidase (GCase), which is needed to break down a fatty substance called glucocerebroside (Gb1). When not enough functional GCase is present, Gb1 accumulates to toxic levels in certain cells, driving Gaucher disease symptoms. Because Gaucher is inherited in a recessive manner, a person must inherit two mutated GBA1 copies — one from each biological parent — to develop the disease. This means that parents are either healthy carriers or have the condition, and that other family members may also be affected.
Families’ experiences show value of expanded testing
Extending genetic testing beyond the person diagnosed with Gaucher disease has the potential to identify other family members with the disease or at risk of developing symptoms. This would allow for early intervention and reduce the risk of serious complications for those affected.
“However, despite the numerous benefits of family genetic mapping, this investigation is sometimes underestimated in clinical practice,” the researchers wrote.
To help establish the value of family studies, a team of researchers in Italy conducted biochemical and genetic analyses across four families affected by Gaucher.
In one family, a 48-year-old woman was diagnosed with Gaucher after routine blood tests showed low numbers of red blood cells (anemia) and white blood cells. Genetic testing confirmed Gaucher disease, and screening later identified the same disease-causing mutations in her 45-year-old sister, who had experienced occasional abdominal pain. Both women began enzyme replacement therapy (ERT).
The woman’s parents were both healthy carriers, as were her teenage twin daughters, each of whom inherited a different GBA1 mutation.
In the second family, testing began with a 13-year-old boy who had an enlarged liver and spleen, anemia, low platelet counts, and acid reflux. Family screening later revealed that his father and older brother also had Gaucher disease, although the brother had no symptoms at the time of diagnosis. The boy, his father, and his brother all began ERT.
Additional testing identified the boy’s grandmother and two aunts on the father’s side as carriers.
In the third family, a 24-year-old man was diagnosed with Gaucher disease after showing liver and spleen enlargement and low platelet counts. His sister, who had mild symptoms, was later found to carry the same disease-causing mutations. Both started ERT.
The fourth family particularly illustrated the value of broader family testing, according to the team. In that case, the investigation began not with a diagnosed patient, but with a paternal uncle found to carry a single GBA1 mutation.
Further testing identified Gaucher disease in the man’s brother and in the brother’s two young children — an asymptomatic 2-year-old son and an eight-month-old daughter, who had low platelet levels. The father and both of his children are currently receiving ERT.
The researchers said the infant’s diagnosis may otherwise have been delayed because her only symptom was low platelet counts, a nonspecific finding that does not automatically suggest Gaucher disease.
“We propose the systematic incorporation of family studies into the [Gaucher disease] diagnostic pathway,” the researchers wrote. “This approach must not be regarded as an optional addition to clinical management; rather, it should be considered an integral part of the overall strategy.”
