Thread by @ksamocha

Gabrielle Lemire up next on how genome sequecing can be more than just a fancy exome. #GRD23

Genomes are more expensive than exomes and have a higher analytical burden, but could offer additional benefit. Want to evaluate that benefit here.

Gabrielle Lemire #GRD23: 744 families with short read genome sequencing, some also have RNAseq.

Need genomes for deep intronic variants, tandem repeats, small/intronic CNVs, or coding variants in regions that weren't well covered in exome sequencing.

Gabrielle Lemire #GRD23: Patients coming both from the Center for Mendelian Genomics (academic collaboration) and the Rare Genomes Project (direct to patients study).

Solve rate was 26% (196/744). Most solves in established disease genes. 57 of the solves *required* genomes.

Gabrielle Lemire #GRD23: Most of the genome-required solves involved structural variants or deep intronic non-coding variants.

One example of a deletion of part of a single exon in FBN1. Notes that they may have been able to see it in the exome data, but reads didn't pass QC.

Gabrielle Lemire #GRD23: For the 139 solves that should have been detectable in exome sequencing -- about half were missed before + would have been detected via exome re-analysis (e.g., new gene).

Notes that the majority of the cohort remains undiagnosed after genome sequencing