Clinical Information

Because an individual can be a carrier for an autosomal recessive condition without showing signs or symptoms, there is often no family history of such disorders. Therefore, without a family history, a reproductive couple may not know if they have an increased risk to have a child with any given genetic disorder. Carrier screening either before or during a pregnancy can help a reproductive couple further understand their risk to have a child with a genetic condition.

Carrier screening for genetic variants associated with cystic fibrosis (CF) and spinal muscular atrophy (SMA) are considered standard of care by American College of Obstetricians and Gynecologists (ACOG) and American College of Medical Genetics and Genomics (ACMG) for all couples regardless of ancestry.(1,2)

Cystic Fibrosis:

CF, in the classic form, is a severe autosomal recessive disorder characterized by a varied degree of chronic obstructive lung disease and pancreatic enzyme insufficiency. The incidence of CF varies markedly among different populations, as does the genetic variant detection rate for the variant screening assay. To date, over 1500 variants have been described within the gene that causes CF, named cystic fibrosis transmembrane conductance regulator (CFTR). The most common variant, deltaF508, accounts for approximately 67% of the variants worldwide and approximately 70% to 75% in the North American population of Northern European descent. Most of the remaining variants are rare, although some show a relatively higher prevalence in certain ethnic groups or in certain atypical presentations of CF such as congenital bilateral absence of the vas deferens (CBAVD). Genetic variants detected by this assay include the 23 variants recommended by the ACMG as well as over 450 other variants.

 

Of note, CFTR potentiator therapies may improve clinical outcomes for patients with a clinical diagnosis of CF and at least one copy of a select subset of variants.

 

Detection rates for several ethnic and racial groups are listed in the table below. Note that interpretation of test results and risk calculations are also dependent on clinical information and family history.

*Rates are for classic CF. Rates are lower for atypical forms of CF and for CBAVD.

**Does not apply to individuals of Japanese ancestry.

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 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 about 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 one 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 this test is a quantitative assay for the number of SMN1 exon 7 deletions, any result showing 2 SMN1 copies may, in fact, have 2 normal 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,(3) 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 polymorphism g.27134T>G. The presence of this polymorphism 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.

Table. SMA carrier residual risk estimates.(3)

For details regarding the specific variants identified by this test see Targeted Variants Detected by Focused Carrier Screening Tests.