The limits of Mendelian assumptions in genomic diagnostics: Evidence from longread whole genome sequencing and exome analysis

Presenting Author: Erica Smith, PhD

Take home points:

Some candidate findings identified on long read WGS do not follow the assumptions of Mendelian inheritance, being inherited from "healthy" parents or rather common in population databases.
Similarly, in 16,500 consecutive previous diagnostic exome cases, there is also supporting evidence for incomplete penetrance and variable expressivity -- more than half of inherited P/LP variants were transmitted from a reportedly healthy parent.
Case-level analysis of exome or genome sequencing should de-prioritize family-inheritance based filtering and should account for variable disease penetrance to optimize diagnoses.

Authors: Erica D Smith; Greta Pitsava; Krista Bluske; Changrui Xiao; Rebekah Barrick; Ivan De Dios; Kirsten Blanco; Elizabeth Chao; Kelly Radtke; Eric Vilain; Emmanuèle C. Délot; Seth Berger; Rachid Karam
Collaborators: Children's Hospital of Orange County, CA (CHOC); University of California, Irvine
Conference: ASHG 2025
Date: Thursday, Oct 16, 2025 2:30pm - 4:30pm

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