Family Genetic Screening of 331 People Detects 165 New Fabry Cases

Russian researchers find the diagnostic method more effective than other options

Somi Igbene, PhD avatar

by Somi Igbene, PhD |

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The illustration shows a syringe and test tubes, all apparently with blood in them.

Genetic screening for 331 family members of Russian Fabry disease patients led to the detection of 165 undiagnosed cases, a study reports.

Family genetic screening was also found more effective than other screening programs for identifying Fabry cases.

“Family genetic testing was significantly more effective (49.8%) than screening programs in newborns or patients with end-stage renal [kidney] disease, unexplained left ventricular hypertrophy [thickening of the heart wall], or stroke, which are costly and often have a diagnostic yield below 1%. … Genetic testing of all at-risk family members (including males and females) should be encouraged,” the researchers wrote.

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The study, “The Benefits of Family Screening in Rare Diseases: Genetic Testing Reveals 165 New Cases of Fabry Disease among At-Risk Family Members of 83 Index Patients,” was published in Genes.

Fabry disease is a rare genetic disease caused by mutations in the GLA gene, which encodes the alpha-galactosidase A (Gal A) enzyme that breaks down fatty molecules, mainly globotriaosylceramide (Gb3 or Gl-3). Abnormal Gal A proteins lead to a toxic buildup of Gb3 in several organs, especially the heart, kidneys, and nervous system, causing irreversible damage.

Treatment with long-term enzyme replacement therapy and small-molecule pharmacological chaperones can effectively reduce symptoms and slow organ damage if started early. However, Fabry disease is often diagnosed late because symptoms can be nonspecific and clinicians may not be sufficiently aware of the disease.

Programs that screen patients with end-stage renal disease undergoing dialysis or kidney transplantation or those with unexplained left ventricular hypertrophy are expensive and usually only identify up to 0.9% of cases. Russian researchers investigated the possibility and effectiveness of genetically testing families of patients diagnosed with Fabry to increase detection rates and aid early treatment.

The study and its results

They analyzed data from 83 patients (72 males and 11 females) with Fabry disease registered at a Russian reference center for lysosomal diseases. Although most patients showed signs of the disease in early childhood or adolescence, they were not diagnosed until after a median of 21 years, when they had developed advanced disease affecting their kidneys, heart, or brain. All patients provided information about their families, allowing the researchers to identify and genetically screen other family members.

The researchers identified 659 potentially affected family members and tested 331. Fabry disease was diagnosed in 165 family members, 30 of whom were younger than 18. A total of 107 were experiencing symptoms, and after diagnosis, 42 began enzyme replacement therapy.

Unlike other studies where cost is a barrier to family genetic testing, the researchers note that cost is not an issue in Russia because all tests are provided free for patients and medical facilities. However, they confirm that Fabry disease knowledge among physicians is low, which leads to most cases being missed despite patients showing symptoms from childhood.

“It is noteworthy that almost 20% of patients newly diagnosed with Fabry disease in this study were under the age of 18,” the researchers wrote, adding that “[s]trategies for increasing awareness of Fabry disease among pediatricians are particularly important.”

“Genetic testing using cascade genotyping in families of index patients identified through symptom presentation or through a screening program can greatly increase the number of patients diagnosed with Fabry disease and can thus facilitate diagnosis and treatment before irreversible organ damage is present,” they concluded.