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Cystic Fibrosis Carrier Testing in anEthnically Diverse US Population
E.M. Rohlfs, Z. Zhou, R.A. Heim, N. Nagan,L.S. Rosenblum, K. Flynn, T. Scholl, V.R.Akmaev, D.A. Sirko-Osadsa, B.A. Allitto, andE.A. Sugarman
Cystic fibrosis (CF) is a pan-ethnic autosomal recessive disease.– Symptoms include obstructive lung disease, exocrine pancreatic
insufficiency, diabetes, liver disease and male infertility.
Age of onset and clinical expression of CF is variable and only partially dependent on CFTR genotype.– Clinical expression is modified by other genes and
Study population– 364,890 individuals referred for carrier testing.– Over 1400 different ethnicities, combinations of ethnicities or
countries of origin.
Mutation panel of 98 mutations selected based on:– The reported frequency in the literature,– The association with CF disease,– The predicted effect on the CFTR protein.
Table 2. Ethnicity-specific data for individuals w ith no history of CF referred for carrier screening.
Proportion Observed Corrected Calculated of tested carrier carrier from
Ethnic group Individuals, n individuals, % frequency frequency incidencea P
African American 40 071 11.0 1 in 84 1 in 61b; 1 in 63c 1 in 61 0.88; 0.57
Ashkenazi Jewish 15 244 4.2 1 in 29 1 in 27c; 1 in 28d 1 in 24 0.12; 0.052
Asian 19 344 5.3 1 in 242 1 in 176c 1 in 94 0.11
Caucasian 158 658 43.5 1 in 28 1 in 25e 1 in 25 0.63
Hispanic 60 930 16.7 1 in 59 1 in 45b; 1 in 49c 1 in 58 0.11; 0.3
Jewish 1887 0.5 1 in 32
M iddle Eastern 1726 0.5 1 in 91
Native American 491 0.1 1 in 70
South Asian 2365 0.7 1 in 118
Other ethnicity 1663 0.5 1 in 111
> 1 Ethnicity 8514 2.3 1 in 34
Part African American 1238 0.3 1 in 56
Part Caucasian 7510 2.1 1 in 32
Part Hispanic 2380 0.7 1 in 51
Not provided 53 997 14.8 1 in 37
All individuals 364 890 100 1 in 38 l. (11 ). (7 ) (Cystic Fibrosis Foundation data). et al. (15 ). t al. (10 ) (Cystic Fibrosis Foundation data).
a Palomaki et al. (7 ). b Carrier frequency corrected with detection rate reported by Sugarman et a c Carrier frequency corrected with detection rate reported by Palomaki et al. d Carrier frequency corrected with the detection rate reported by Abeliovich e Carrier frequency corrected with the detection rate reported by Palomaki e
The primary ethnic groups in the US share many mutations in common but there is a significant difference in the mutation distribution.– Some mutations appear to be limited to certain ethnic groups.
• Ex: p.S1255X accounted for >1% of mutations in African Americans.
Ethnic limited mutations may make a substantial contribution to the mutation spectrum in a single group but not to the overall population.
– The increased frequency of certain alleles in different ethnic populations is an important consideration in the design of a screening program or diagnostic test.
– CF screening has been widely implemented across the US.
– To assess the utility of expanded panels, the application, composition and populations to be studies should be taken into account.