In some inherited conditions, both copies of a gene must be altered (“variant”) to cause symptoms; these are known as autosomal recessive disorders. Some patients with suspected autosomal recessive disorders were recruited for whole genome sequencing (WGS) through the 100,000 Genomes Project after only one causative variant was detected. Clinical testing may not detect some alterations, such as those outside of the protein-coding region, or complex alterations; this study looked for the second causative variant, specifically focussing on variant types which clinical testing might not detect.

Second causative variants were found for 8/31 patients to give full genetic diagnosis, with some cases requiring additional investigations to resolve the exact variant. This study shows how WGS can uncover new and complex causative genetic variants in autosomal recessive disorders and provides some strategies for investigation. (By A Rachel Moore, https://jmg.bmj.com/content/early/2023/08/09/jmg-2023-109362 )