Spinal Muscular Atrophy (SMA) Copy Number Analysis

Background information for Spinal Muscular Atrophy (SMA) Copy Number Analysis
Characteristics: Spinal muscular atrophy (SMA) is the most common lethal genetic disease in children, and is characterized by progressive muscle weakness due to degeneration of the lower motor neurons. Onset ranges from before birth to adulthood and severity is highly variable. Individuals with SMA have no functioning copies of the SMN1 gene. Most (95 percent) have homozygous loss of SMN1 due to deletion or gene conversion, while a minority (5 percent) have a deletion of SMN1 on one chromosome and a SMN1 sequence variant on the other. The SMN2 gene, adjacent and highly homologous to SMN1, produces lower levels of survival motor neuron protein compared to SMN1. Disease severity has been shown to be modified by SMN2 gene copy number in some cases, though phenotype cannot be predicted with certainty. An SMN1 variant, c.*3+80T>G (rs143838139), that is part of a haplotype associated with SMN1 duplication in silent carriers (2 copies of SMN1 on one chromosome and no copies on the other), particularly in Ashkenazi Jews, increases the likelihood that 2 copies of SMN1 are on the same chromosome.
Inheritance: Autosomal recessive.
Cause: Pathogenic variants in the SMN1 gene.
Variants Tested: For copy number: SMN1 (NM_000344.3) exon 7 c.840C and exon 8 c.*239G, and SMN2 (NM_017411.3) exon 7 c.840T. For haplotype associated with SMN1 duplication (silent carriers):  SMN1 c.*3+80T>G (rs143838139).
Clinical sensitivity: 95-98 percent in individuals affected with SMA. Detection rate for carrier screening is 90 percent in African Americans, 93 percent in Ashkenazi Jewish, 93 percent in Asians, 95 percent in Caucasians, and 93 percent in Hispanics.
Methodology:  Multiplex probe ligation-dependent amplification (MLPA) to detect SMN1 and SMN2 copy number and presence or absence of the SMN1 linked variant c.*3+80T>G (rs143838139).
Analytical sensitivity and specificity:  99 percent.
Limitations: Diagnostic errors can occur due to rare sequence variations. Single base pair substitutions, small deletions/duplications, regulatory region mutations, and deep intronic mutations will not be detected. This test is unable to determine chromosomal phase of SMN1 or SMN2 copies. Even if the linked variant associated with SMN1 duplication is detected, the test cannot definitively differentiate between 1+ copies of SMN1 on each chromosome from 2+ copies of SMN1 on one chromosome and none on the other (silent carriers).

This test was developed and its performance characteristics determined by ARUP Laboratories. It has not been cleared or approved by the US Food and Drug Administration. This test was performed in a CLIA certified laboratory and is intended for clinical purposes.

Counseling and informed consent are recommended for genetic testing. Consent forms are available online.