Table 1.

Molecular Genetic Testing Used in Spinal Muscular Atrophy

Type of TestingGene 1Proportion of SMA Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 2 Identifiable by Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
Diagnostic, carrier, prenatal SMN1 ~100%2%-5% 595%-98% 6, 7
Prognostic SMN2 NANASee footnote 8.
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR and multiplex ligation-dependent probe amplification (MLPA) to detect single-exon deletions or duplications. Note that SMN1 and SMN2 are nearly identical; therefore, gene-targeted microarray cannot be used to determine SMN1 and SMN2 copy number.

5.

Detects the 2%-5% of individuals who are compound heterozygous for an intragenic pathogenic variant and an SMN1 deletion of at least exon 7 [Parsons et al 1998, Wirth 2000]

6.
7.

False negatives may occur because about 5%-8% of the population have two copies of SMN1 on a single chromosome and a deletion on the other chromosome, known as a [2+0] configuration. Individuals of sub-Saharan African descent have a higher proportion of the [2+0] configuration [Verhaart et al 2017] (see Carrier Detection, Interpretation of the results of carrier testing).

8.

Gene-targeted deletion/duplication analysis of SMN2 can be performed to provide additional phenotype information if the diagnosis of SMA is confirmed on molecular genetic testing. The number of copies of SMN2 may range from zero to five. Quantitative PCR and MLPA methods are often designed to detect both SMN1 and SMN2 copy number [Anhuf et al 2003, Arkblad et al 2006, Scarciolla et al 2006] (see Genotype-Phenotype Correlations).

From: Spinal Muscular Atrophy

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