Experience with carrier screening and prenatal diagnosis for 16 Ashkenazi Jewish genetic diseases

TLDR

Prenatal carrier screening has proven effective in the Ashkenazi Jewish population, prompting panel expansion as new founder mutations are identified, yet many carrier frequencies remain unreported in large cohorts. The study aimed to determine carrier frequencies of over 100 mutations across 16 recessive disorders in the New York metropolitan Ashkenazi Jewish population. This was achieved by screening 100 % Ashkenazi‑descended individuals for these mutations and reporting prenatal testing results for 574 cases. Screening revealed that about one in 3.3 carriers had a mutation for one disease and one in 24 for two, with frequencies ranging from 1 in 15.2 to 1 in 168, 15 % higher than all screenees, and that over 95 % opted for full Ashkenazi disease screening; rare homozygotes with previously unrecognized clinical manifestations were identified, and prenatal testing confirmed general acceptance and comprehensive results for the expanded panel.

Abstract

The success of prenatal carrier screening as a disease prevention strategy in the Ashkenazi Jewish (AJ) population has driven the expansion of screening panels as disease-causing founder mutations have been identified. However, the carrier frequencies of many of these mutations have not been reported in large AJ cohorts. We determined the carrier frequencies of over 100 mutations for 16 recessive disorders in the New York metropolitan area AJ population. Among the 100% AJ-descended individuals, screening for 16 disorders resulted in ∼1 in 3.3 being a carrier for one disease and ∼1 in 24 for two diseases. The carrier frequencies ranged from 0.066 (1 in 15.2; Gaucher disease) to 0.006 (1 in 168; nemaline myopathy), which averaged ∼15% higher than those for all screenees. Importantly, over 95% of screenees chose to be screened for all possible AJ diseases, including disorders with lower carrier frequencies and/or detectability. Carrier screening also identified rare individuals homozygous for disease-causing mutations who had previously unrecognized clinical manifestations. Additionally, prenatal testing results and experience for all 16 disorders (n = 574) are reported. Together, these data indicate the general acceptance, carrier frequencies, and prenatal testing results for an expanded panel of 16 diseases in the AJ population.