Differences in SMN1 allele frequencies among ethnic groups within North America

Abstract

Background:Spinal muscular atrophy (SMA) is the most common inherited lethal disease of children. Various genetic deletions involving the bi-allelic loss of SMN1 exon 7 are reported to account for 94% of affected individuals. Published literature places the carrier frequency for SMN1 mutations between 1 in 25 and 1 in 50 in the general population. Although SMA is considered to be a pan-ethnic disease, carrier frequencies for many ethnicities, including most ethnic groups in North America, are unknown.Objectives and methods:To provide an accurate assessment of SMN1 mutation carrier frequencies in African American, Ashkenazi Jewish, Asian, Caucasian, and Hispanic populations, more than 1000 specimens in each ethnic group were tested using a clinically validated, quantitative real-time polymerase chain reaction (PCR) assay that measures exon 7 copy number.Results:The observed one-copy genotype frequency was 1 in 37 (2.7%) in Caucasian, 1 in 46 (2.2%) in Ashkenazi Jew, 1 in 56 (1.8%) in Asian, 1 in 91 (1.1%) in African American, and 1 in 125 (0.8%) in Hispanic specimens. Additionally, an unusually high frequency of alleles with multiple copies of SMN1 was identified in the African American group (27% compared to 3.3–8.1%). This latter finding has clinical implications for providing accurate adjusted genetic risk assessments to the African American population.Conclusions:Differences in the frequency of SMA carriers were significant among several ethnic groups. This study provides an accurate assessment of allele frequencies and estimates of adjusted genetic risk that were previously unavailable to clinicians and patients considering testing.

Parental attitudes toward newborn screening for Duchenne/Becker muscular dystrophy and spinal muscular atrophy

“…It is estimated that the pan ethnic carrier frequency for SMA is between 1:25 and 1:66 (Hendrickson, 2009;Prior, 2010). All the subtypes of proximal SMA are caused by mutations in the survival motor neuron-1 (SMN1) gene (Lefebvre, 1995;Bürglen, 1996).…”

Determination of SMN1 and SMN2 Copy Numbers in a Korean Population using Multiplex Ligation-dependent Probe Amplification

“…DHPLC has been successfully used in screening for SMA carriers; however, when performed by inexperienced technicians, this technique yields inconsistent results. The multiplex ligation-dependent probe amplification (MLPA) assay is efficient in the detection of copy number changes in various genes [3]. Reports indicate that the MLPA assay is better and more efficient than the 2-step DHPLC.…”

A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites

“…They also noted that counseling of tested individuals is complicated by the fact that 3-5% of individuals have the '2+0' genotype and will be incorrectly identified as noncarriers. 1,2,38 Although the costs and benefits of offering SMA carrier screening to the general population are actively debated, 2,39 the case for offering screening to the Hutterite population is more straightforward for several reasons. First, the high carrier frequency (at least one in eight) would, by itself, justify population screening.…”

“…In US Whites, B1 in 35 are SMA carriers. 1,2 SMA is caused by the homozygous loss of survival motor neuron 1 (SMN1) gene function due to a deletion or possibly to a gene conversion event in B95% of cases; 3 the remaining 5% of patients have intragenic mutations that inactivate the gene. [4][5][6] Affected individuals exhibit progressive muscle weakness and paralysis as a result of degeneration and loss of motor neurons in the spinal cord.…”

“…12 In addition, the high homology between SMN1 and SMN2 complicates interpretation of carrier testing results. Carrier and disease status for SMA is typically determined by direct quantification of SMN1 exon 7 dosage, but this method will not identify carriers of intragenic mutations and carriers with the '2+0' genotype, 1,12 in which one chromosome has two copies of SMN1 in cis and the other has zero copies.…”