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Incorporating Risk Modifier Into Screening May Identify More Potential SMA Carriers


Although most SMA carriers can be identified through routine SMN1 copy number assessment data, approximately 4% of carriers who harbor 2 copies of SMN1 can go undetected.

Researchers of a new study indicate that patients with 2 copies of the SMN1 gene and an additional risk modifier are less likely to be counseled on their risk of being a carrier for spinal muscular atrophy (SMA) compared with classic carriers.

They published their findings in a new issue of Molecular Genetics and Genomic Medicine.

Although the majority of SMA carriers can be identified through routine SMN1 copy number assessment data, the approximately 4% who harbor 2 copies of SMN1 can go undetected. One year prior to this study, the researchers incorporated the detection of the c.*3+80>G risk-modifying single nucleotide polymorphism (SNP) into their SMA carrier screening program to strengthen the sensitivity of their testing.

With their modified screening, the researchers were able to detect an additional 40 patients at risk of being carriers. While all 22 patients with a single copy of SMN1 were consulted, 31 (77.5%) of the 40 women who harbored 2 copies of SMN1 and tested positive for the c.*3+80T>G risk-modifying SNP were consulted about their increased risk of being a carrier for SMA.

“It is unclear why the remaining 22.5% of individuals were not appropriately counseled. We acknowledge the result may have been discussed by the provider but not documented in the electronic medical record,” wrote the researchers. “However, several other factors could explain this discrepancy, including the recent introduction of this test, difficulties in a provider explaining the meaning of a risk-modifying SNP to patients, or the possibility that the patient did not identify with one of the characterized populations.”

Among the 31 cases, 30 of the fathers received a recommendation to receive SMA carrier testing. According to the researchers, in the 1 case where the father was not recommended to get tested, the ethnicities of the couple were not considered to be high enough to warrant testing.

Across the 52 couples who received counseling for an increased risk of SMA, 22 (42%) chose to have the father be tested at the group’s institution. In all of these cases, none of the fathers were identified to be SMA carriers or to be at an increased risk of being a carrier.

“There are several possible reasons why follow-up partner testing was low, including testing done at an alternative laboratory, out-of-pocket testing costs, limited parental understanding of the significance or rationale for added testing, uncertain paternity, or a judgment that the increased risk was not significant,” explained the researchers. “The latter reason may be pertinent to those of Hispanic descent where the residual risk of being a carrier remains comparatively low (1 in 139.6).”

Similar to Latino/Hispanic patients, Caucasian and Mexican/Mexican-American patients had relatively low levels of the SNP. Among Asian patients, who accounted for 5.4% of patients, there was no detection of the SNP. African patients accounted for the highest prevalence (46.71%) of the SNP.

The researchers noted that although the rates of White and Asian patients testing positive for the SNP were similar to previous findings, there was an approximate 5% deviation in the positive rate among African, Latino/Hispanic, and Mexican patients. This finding, said the researchers, could be due to how populations are recorded at their institution or due to local/regional difference in immigrant populations.


Ware G, Miller C, Jones D, Avenarius M. The clinical utility of a risk-modifying SNP to detect carriers for spinal muscular atrophy with increased sensitivity. Mol Genet Genomic Med. Published online March 15, 2022. doi:10.1002/mgg3.1897

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