Incidental molecular diagnoses and heterozygous risk alleles in a carrier screening cohort

Expanded pan-ethnic carrier screening is an effective tool for the management of reproductive risk. However, growth in the number of conditions screened, in combination with increasingly more comprehensive test methodologies, can lead to the detection of genetic findings that may affect the health of the tested individual. The objective of this study was to investigate the frequency of pathogenic genotypes in a presumed healthy carrier screening cohort to facilitate broader discussions regarding disclosure of genetic information from carrier screening.

A retrospective analysis of 73,755 targeted carrier screens was performed to identify individuals with pathogenic genotypes and heterozygous risk alleles.

In this study, we identified 79 individuals (0.11%) with pathogenic genotypes associated with moderate to profound autosomal recessive or X-linked conditions. In addition, 10 cases had chromosome X dosage abnormalities suggestive of a sex chromosome abnormality. Heterozygote risk alleles represented the majority of ancillary findings in this cohort, including 280 female carriers of FMR1 premutation alleles, 15 heterozygous females with pathogenic DMD variants, and 174 heterozygotes with pathogenic variants in genes that may confer increased risk for somatic malignancies in the heterozygous state.

These data suggest that nearly 1% of individuals undergoing carrier screening will have a finding that may require clinical evaluation or surveillance.