Genetic testing and risk assessment for spinal muscular atrophy (SMA)

Abstract

Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases, affecting approximately 1 in 10,000 live births, and with a carrier frequency of approximately 1 in 50. Because of gene deletion or conversion, SMN1 exon 7 is homozygously absent in approximately 94% of patients with clinically typical SMA. Approximately 30 small intragenic SMN1 mutations have also been described. These mutations are present in many of the approximately 6% of SMA patients who do not lack both copies of SMN1, whereas SMA of other patients without a homozygous absence of SMN1 is unrelated to SMN1. A commonly used polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) assay can be used to detect a homozygous absence of SMN1 exon 7. SMN gene dosage analyses, which can determine the copy numbers of SMN1 and SMN2 (an SMN1 homolog and a modifier for SMA), have been developed for SMA carrier testing and to confirm that SMN1 is heterozygously absent in symptomatic individuals who do not lack both copies of SMN1. In conjunction with SMN gene dosage analysis, linkage analysis remains an important component of SMA genetic testing in certain circumstances. Genetic risk assessment is an essential and integral component of SMA genetic testing and impacts genetic counseling both before and after genetic testing is performed. Comprehensive SMA genetic testing, comprising PCR-RFLP assay, SMN gene dosage analysis, and linkage analysis, combined with appropriate genetic risk assessment and genetic counseling, offers the most complete evaluation of SMA patients and their families at this time. New technologies, such as haploid analysis techniques, may be widely available in the future.

Molecular characterization of SMN copy number derived from carrier screening and from core families with SMA in a Chinese population

“…Individuals with the rare '2+0' genotype have two copies of SMN1 in cis on one chromosome and no SMN1 gene on the other chromosome, which results in a compound SMA heterozygous deletion with a carrier frequency that ranges from 1.7 to 3.3% in different ethnic populations. 1,3,13 In the family study, we detected two cases of the '2+0' genotype among the 44 parents of the SMA patients; these parents had an SMN1/SMN2 ratio of 2:1 (Table 3 and 4). This finding suggests that the '2+0' genotype is a considerable SMA determinant and should be tested during carrier screening and clinical molecular diagnosis in the Chinese population.…”

“…1,[2][3][4] SMA is caused by the degeneration of anterior horn cells of the spinal cord, which leads to symmetric proximal muscle weakness and atrophy. 5 On the basis of the age at onset and the clinical course, SMA is classically subdivided into three types: type I is an infantile acute form, and shows the greatest severity; type II is an infantile chronic form with intermediate severity; and type III is a childhood and adolescent form and shows the mildest severity.…”

Inverse correlation between SMN1 and SMN2 copy numbers: evidence for gene conversion from SMN2 to SMN1

“…4,10 We meta-analyzed published data, 3,4,8,10,13,14 and updated deduced SMN1 allele frequencies 5 as follows: 'zero-copy allele' (chromosome 5 lacking SMN1 exon 7), 9.83 Â 10 À3 ; 'one-copy allele', 9.57 Â 10 À1 ; 'two-copy allele' (chromosome 5 with two copies of SMN1 exon 7), 3.27 Â 10 À2 ; and '1 D allele' (chromosome 5 with a small intragenic mutation in SMN1), 1.80 Â 10 À4 . One hypothesis to explain the presence of two copies of SMN1 on one chromosome 5 is unequal crossing over between homologous chromosomes during meiosis.…”

“…2 Approximately 94% of clinically typical SMA patients lack both copies of SMN1 exon 7, 3 and most carriers have only one copy of SMN1 exon 7, as determined by SMN gene dosage analysis. 4,5 In addition to large deletions that include the entire SMN1 gene, loss of SMN1 exon 7 can occur by gene conversion from SMN1 to SMN2. 6 SMA type III patients have, on average, more SMN2 copies than SMA type II or type I patients, [7][8][9] and hence more copies of SMN2 derived by conversion from SMN1.…”

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

“…Copy number variation in SMN2 ranges from 0-3 in the general population, with 10-15% of unaffected individuals having no copies (Ogino, 2002;Gerard, 2000;Prior, 2010). People with SMA must have at least 1 copy of SMN2, but there is still variability.…”