Clinical Information

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by motor neuron degeneration leading to muscular atrophy with progressive paralysis. It is a genetically complex condition that is traditionally divided into 5 subtypes, depending on the age at which symptoms present and the motor milestones that are achieved. Presentation can range from in utero joint contractures and lack of fetal movement (type 0), to loss of ambulation in adolescence or adulthood (Type IV). All patients with SMA develop symmetrical loss of muscle control, most commonly affecting proximal muscles. The American College of Medical Genetics and Genomics (ACMG) and The American Congress of Obstetricians and Gynecologists (ACOG) currently recommend offering SMA carrier screening to all couples, regardless of race or ethnicity, before conception or early in pregnancy.

The most common form of SMA is associated with the loss of survival motor neuron (SMN) protein, which is encoded by 2 or more genes on chromosome 5. The majority of SMN protein is expressed by the SMN1 gene but a small portion of SMN is also contributed by the SMN2 gene. In fact, SMN1 produces more than 90% of SMN protein, while SMN2 produces less than 10% of residual SMN protein. This occurs because SMN2 differs from SMN1 by 5 nucleotide changes, one of which leads to alternative exon 7 splicing, and a reduction of SMN2 expression. Most individuals have 2 copies of SMN1, but individuals with as many as 5 copies of SMN1 have been observed. In addition, individuals may also have 0 to 5 copies of SMN2.

SMA is most commonly caused by a homozygous deletion of exon 7 in SMN1. However, some patients with this disorder may be compound heterozygotes, with a deletion of 1 copy of SMN1 and a point alteration in the other allele. The severity of a patient's disease is associated with the number of copies of SMN2 that are present and 3 or more SMN2 copies are associated with a milder SMA phenotype.

As the SMA test is a quantitative assay for the number of SMN1 exon 7 deletions, any result showing 2 or more SMN1 copies may, in fact, have 2 copies of SMN1 in cis (on the same chromosome) and a copy of SMN1 with the exon 7 deletion on the other chromosome (in trans). This is called the "2+0" carrier genotype. The frequency of the "2+0" carrier genotype differs by ancestry. Previously, it was not possible to distinguish a "2+0" carrier from an individual with one copy of SMN1 on each chromosome. However, following a study performed by Luo et al,(2) it is now possible to provide an adjusted genetic residual carrier risk specific to one's ancestry, based on the presence or absence of the SMN1 alteration g.27134T>G. The presence of this alteration is linked to being a "2+0" carrier in the Ashkenazi Jewish and Asian populations, and it increases the chances that one is a "2+0" carrier in other populations. See the table below for details.

SMA carrier residual risk estimates.(2)