Carrier Screening for Gaucher Disease: Lessons for Low-Penetrance, Treatable Diseases

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Carrier screening has been a means of preventing severe, untreatable genetic disorders by identifying couples at risk and providing reproductive options for affected pregnancies. Screening for certain less severe genetic diseases is also possible, although the implications of such screening are unknown. Gaucher disease (GD) is an autosomal recessive enzyme deficiency/storage disease with a carrier frequency of 6% in Ashkenazi Jews. There are 3 forms of GD. The phenotype of Type I GD is highly variable, but ranges from being relatively asymptomatic to having visceral problems related to the accumulation of glucosylceramide in major organs; Types 2 and 3, which are rare, include progressive neurological deterioration. The majority-96%-of GD mutation carriers can be identified by screening for 4 common gene mutations, and the type of GD associated with each mutation can be predicted to a certain extent. The N370S, RecTL, or R496H mutations are associated with mild disease whereas 84 insG, L444P, IVS2DS + 1G-A, and V394L are associated with severe disease; compound heterozygotes have moderate disease. Carrier screening has been offered in Israel since 1995, and was offered at 10 of 12 Israeli genetic centers in the years 1995-2003. The researchers examined outcomes of nationwide (Israeli) GD screening. The carrier frequency in this survey was 5.7%. Eighty-three carrier couples were identified among 28,893 individuals screened. Seventy of 82 couples (85%) were determined to be at risk of having asymptomatic or mildly affected offspring, whereas 12 (15%) were at risk of having a moderately affected child. Sixty-five couples consented to being interviewed, and had a total of 90 pregnancies. Prenatal diagnosis was carried out in 68 of these pregnancies (76%), and 16 fetuses were detected with GD (24% of pregnancies). Pregnancy was terminated in 2 of 13 cases where the fetus was predicted to be mildly affected at most (15%), and in 2 of 3 cases where the fetus was predicted to have moderate disease (67%). The rate of termination was significantly lower in couples having medical counseling by a GD expert in addition to genetic counseling (1 of 13, or 8% vs. 3 of 3, or 100%). Carrier screening for GD did not appear to significantly reduce the birth prevalence of infants with GD in this population because most couples did not terminate affected pregnancies. The stated goals of the screening program were not met, indicating the need to re-assess carrier screening programs for low penetrance genetic diseases.