Family History Can Be Key in Identifying Silent Carriers of SMA

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A family and medical history examination was crucial in the genetic counseling given a 28-year-old pregnant woman with two previous children with spinal muscular atrophy (SMA), whose standard genetic testing classified her as a non-carrier of the disease, a case study shows.

This case highlights the limitations of standard carrier screening to identify so-called “silent carriers,” supporting referral to a genetic specialist when genetic tests are inconsistent with family and clinical evidence, the researchers noted.

The study, “Case report of pregnancy management and genetic evaluation after negative carrier screening for spinal muscular atrophy in an affected family,” was published in the journal Case Reports in Women’s Health.

Each person has 46 chromosomes — rodlike structures where genes are located — arranged in 23 pairs, within which one chromosome is inherited from the mother and the other from the father.

Nearly all SMA cases are caused by the complete loss of exon 7 in both copies of the SMN1 gene — again, one from the mother and one from the father. Exons are the sections of a gene that contain the information to generate proteins.

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Notably, the number of copies of a “backup” SMN gene, SMN2, influences SMA severity, with a higher number typically predicting milder disease.

While people with only one mutated SMN1 copy do not develop the disease, they are called carriers and can transmit the faulty gene to their children. Given the high frequency of SMA carriers in the population (1 in 50 people across all ethnicities), identifying carriers is essential for genetic counseling of adults who are planning families.

Identification relies on an accurate determination of the number of SMN1 exon 7 copies. While most carriers have only one exon 7 copy, others lack the SMN1 gene in one of their chromosomes, having instead two working SMN1 copies in the other. These people, known as silent carriers, may be wrongly identified as non-carriers.

To identify silent carriers, researchers can search for the presence of specific mutations associated with the presence of two SMN1 copies in one chromosome, including the g.27134T>G mutation. However, this is “most accurate in Ashkenazi Jewish and Asian populations and not nearly as accurate in other ethnic populations,” the researchers wrote.

Identifying carriers is additionally challenged by the fact that 4% of SMA cases are due to mutations other than exon 7 deletion and that are not included in standard genetic screening. An estimated 2% of SMA patients also carry de novo mutations, meaning mutations that were not inherited and developed for the first time in the affected person.

Therefore, the limitations of standard screening can leave families — especially those who are not of Ashkenazi or Asian descent — “at significant residual risk to have a child affected with SMA and unprepared to navigate effective diagnosis and treatment,” the researchers wrote.

Researchers in Texas described the case of a 28-year-old Hispanic woman who had two children with SMA and had tested negative in standard carrier screening.

The woman, pregnant through a different partner from her previous children, was referred to the clinic for genetic counseling to discuss her negative carrier result and possibility for another affected child.

She also wanted a prenatal SMA diagnosis, so to access appropriate treatment should her child be affected.

Given that previous standard testing showed the presence of two working SMN1 copies and the absence of the g.27134T>G mutation, her likelihood of being a silent carrier was estimated to be 0.05%.

As such, the researchers recommended additional genetic testing to look for other disease-causing mutations than exon 7 deletion. Results showed no such mutation and confirmed the presence of two SMN1 gene copies, although the test did not assess whether they were located in the same chromosome.

Despite the low predicted risk, the patient was considered a silent carrier for SMA based on family history of two affected children — considered very unlikely to be caused by de novo mutations in both cases.

Carrier screening for her new partner led to similar results, with an estimated 0.05% risk of being a silent carrier. Subsequent diagnostic testing for the fetus revealed three copies of SMN1 and no SMA-causing mutations.

Results confirmed that the woman was a silent carrier, contributing two SMN1 copies in one chromosome to her developing fetus, and that her partner was not a carrier, contributing one copy.

Findings also indicated that their future children were not at an increased risk of SMA, but would have a 50% chance of being carriers of the condition; a condition characterized by inheriting the SMN1-absent chromosome from the mother.

This case emphasizes that “carrier screening results are not diagnostic and only estimate risk for carrier status,” the researchers wrote, adding that “patient results must be reviewed through the lens of family and medical history” for a full understanding.

“While this patient and her new partner had received identical carrier screening results, their respective family histories clearly led to a change in the way they were interpreted and highlight the need for follow-up testing that was more comprehensive to determine fetal risk,” they added.

“Referral to a genetic counselor or genetics specialist should be considered when a history is suggestive of carrier status inconsistent with genetic screening,” the researchers concluded.