Beyond the panel: preconception screening in consanguineous couples using the TruSight One "clinical exome"

To provide proof of concept by broadening preconception screening beyond targeted testing to inform reproductive risk in consanguineous couples.

Consanguineous couples were screened for autosomal recessive and X-linked disorders using the TruSight One panel of 4,813 genes associated with human disease.

We recruited 22 couples, of whom 15 elected to have sequencing. We found four couples to be at risk of autosomal recessive disorders, including one with a child affected by Poretti-Boltshauser syndrome (a diagnosis not made prior to the study) and another previously known to carry a β-globin variant. Two couples were found to carry variants unrelated to known family history. These variants were in the genes C5orf42 (associated with Joubert syndrome and orofaciodigital syndrome) and GYS2 (associated with glycogen synthase deficiency). One known variant was not detected-a single exon deletion in FAM20C. We would not expect to identify this variant with the methodology employed. Of the four variants identified, only the β-globin variant would have been found using available commercial preconception screening panels.

Preconception screening of consanguineous couples for recessive and X-linked disorders using genomic sequencing is practicable, and is likely to detect many more at-risk couples than any targeted panel could achieve. A couples-based approach greatly reduces the associated analysis and counselling burden.