Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72 400 specimens

Abstract

Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ∼1 in 10 000 live births and is second to cystic fibrosis as a common, life-shortening autosomal recessive disorder. The American College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to facilitate informed reproductive options, although other organizations have cited the need for additional large-scale studies before widespread implementation. We report our data from carrier testing (n=72 453) and prenatal diagnosis (n=121) for this condition. Our analysis of large-scale population carrier screening data (n=68 471) demonstrates the technical feasibility of high throughput testing and provides mutation carrier and allele frequencies at a level of accuracy afforded by large data sets. In our United States pan-ethnic population, the calculated a priori carrier frequency of SMA is 1/54 with a detection rate of 91.2%, and the pan-ethnic disease incidence is calculated to be 1/11 000. Carrier frequency and detection rates provided for six major ethnic groups in the United States range from 1/47 and 94.8% in the Caucasian population to 1/72 and 70.5% in the African American population, respectively. This collective experience can be utilized to facilitate accurate pre- and post-test counseling in the settings of carrier screening and prenatal diagnosis for SMA.

Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study

“…Spinal muscular atrophy (SMA) is the leading genetic cause of death in infants, exhibits a wide range of clinical severity and has an incidence of one in 11,000 live births 1, 2. SMA is caused by homozygous deletion or mutation in the SMN1 ( survival motor neuron 1 ) gene and retention of the nearly identical gene, SMN2 ( survival motor neuron 2 ), which results in reduced expression of full‐length SMN protein 3, 4.…”

Splicing inhibition of U2AF 65 leads to alternative exon skipping

“…Proximal spinal muscular atrophy (SMA) is an autosomal recessive genetic disease (17) and a leading cause of infant mortality. The motor neurons in the anterior horn of spinal cord are severely damaged in patients with type 1 SMA, usually leading to death before age 2 y as a result of a lack of respiratory support (18,19).…”

Current Practice and Attitudes of Australian Obstetricians Toward Population-Based Carrier Screening for Inherited Conditions

“…Screening programs began formally in the 1970s with screening for Tay-Sachs disease carrier status in the Ashkenazi Jewish community (Kaback, 1997). Subsequent programs have targeted cystic fibrosis (CF) in the United States and parts of Italy (Castellani et al, 2009;Hale et al, 2008), thalassaemia in Mediterranean at-risk populations (Cao et al, 1984(Cao et al, , 1997Modell & Mouzouras, 1982), fragile X syndrome in Israel (Berkenstadt et al, 2007), and most recently, spinal muscular atrophy (SMA) in the United States and Taiwan (Su et al, 2011;Sugarman et al, 2012). Several of these programs have reported reductions in the incidence of affected infants born with the conditions tested.…”