In This Issue

Expanded carrier screening detects more at-risk couples

Many parents-to-be wonder whether their kids will be healthy. Carrier screening (CS) lets people find out the chance of passing on a genetic condition to their children. Traditionally, CS targeted specific genetic diseases prevalent in defined racial/ethnic populations. This approach, however, can miss potential carriers. In this issue, Westemeyer and colleagues show that, compared with standard screening, expanded CS in a pan-ethnic population is able to detect more at-risk couples. To conduct the retrospective analysis, clinicians provided the researchers with de-identified next-generation sequencing–based results from CS panels that included up to 274 genetic diseases along with race/ethnicity information from more than 380,000 individuals. The researchers then compared observed carrier frequencies with published, expected carrier frequencies. They found that observed carrier rates were significantly different than expected for nearly half of all genes screened. The expanded CS also detected more carriers than disease-specific panels. For example, the standard panel for detecting variants in CTFR associated with cystic fibrosis would have missed 44% of carriers, as most positive CTFR variants (95%) were not included in the targeted genotyping panel. The panel would have missed four of the five most common CTFR variants observed among East Asians and South East Asians and three of the five most common variants among African Americans. Finally, the researchers calculated the projected at-risk couple carrier frequency for 274 diseases. They found that 2.3% of couples would be expected to be at risk, affecting 0.6% of theoretical pregnancies when assuming random couple pairing across ethnicities and no prior knowledge of risk status. Risk ranged from 1.7% (Hispanic) to 5.9% (Ashkenazi Jewish) for couple pairing within race/ethnic groups, affecting 0.5% (Hispanic) to 1.8% (Ashkenazi Jewish) of theoretical pregnancies. The researchers conclude that there is benefit to applying expanded CS to all individuals and that targeted CS based on ethnicity and family history may warrant re-examination. —V. L. Dengler, News Editor

Spinal muscular atrophy incidence lower than expected in New York State

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Controlling head movement and sitting up unassisted are major developmental milestones for infants. But for babies with the most serious form of spinal muscular atrophy (SMA), a genetic condition that causes the motor neurons that control muscle movement to die, these hallmarks often remain unmet. The condition can also cause respiratory complications and is a common genetic cause of death in infants and children. Incidence estimates for SMA range from 1 in 6000 to 1 in 11,000 live births worldwide. Kay and colleagues, on the basis of results from a population-based newborn screening program implemented in New York State (NYS), found that the incidence may be lower. NYS implemented a universal SMA screening program for newborns in 2018. SMA screening programs facilitate universal and timely diagnosis when lifesaving treatments are most effective. Over the course of the program’s first year, more than 225,000 infants were screened by quantitative polymerase chain reaction for the most common genetic variant underlying SMA, deletion of exon 7 in the gene SMN1. Eight infants were homozygous for the recessive condition, corresponding to an incidence of 1 in 28,137. This rate is 2.6- to 4.7-fold lower than expected compared with the often-cited incidence of 1 in 6000 to 1 in 11,000. When the researchers included screening data through February 2020 in their analysis, incidence bumped up to about 1 in 21,000. The researchers suggest that the lower incidence in NYS is due in part to biased or imprecise prior estimates. For example, previous SMA incidence estimates were derived from small European subpopulations, which are not representative of the US population. Additionally, the authors suggest that informed reproductive decisions likely contributed to the lower than expected occurrence. The authors conclude that increased accuracy in establishing true SMA incidence will come with time as further data from other screening programs become available. —V. L. Dengler, News Editor


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Dengler, V. In This Issue. Genet Med 22, 1283 (2020).

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