Systematic evaluation of incomplete penetrance in 4,325 rare disease families reveals divergent transcriptional networks in CHD8 pathology

CHD8

CHD8 haploinsufficiency with a positive episignature in both the proband and his unaffected mother, but divergent downstream transcriptional effects

This preprint presents a pipeline to systematically investigate inherited variants as the cause of rare disease in 4,325 families (affected proband and unaffected parents) from the Broad Center for Mendelian Genomics (GREGoR Consortium). In 81 families the proband carried a putative disease-causing variant inherited from a reportedly unaffected parent; clinical re-evaluation considered the variant diagnostic in 30 families, including six previously missed diagnoses. Inherited incomplete-penetrance variants accounted for 1.6% of diagnosed cases, an overall yield of 0.4% in the cohort. In one family with an inherited CHD8 frameshift variant, the CHD8 methylation episignature was positive in the male proband but also in the reportedly unaffected mother, and transcriptomic analysis showed divergent downstream effects despite similar haploinsufficiency.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The finding that at least 1 in 60 diagnostic variants is inherited from a reportedly unaffected parent is a safeguard against overly strict filtering of inherited variants in trio analysis. The positive episignature in an unaffected mother is a reminder that an episignature confirms a variant's molecular effect, not phenotypic expression. This is a preprint, and the multi-omic follow-up rests on a single family.

Analysis by Dr Thibaut Benquey