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

Clinical Genomics

Session:

#7031

Date:

Thursday, Oct 16, 2025 2:30pm – 4:30pm

Conference:

Authors:

Changrui Xiao, Elizabeth Chao, Emmanuèle C. Délot, Erica D Smith, Eric Vilain, Greta Pitsava, Ivan De Dios, Kelly Radtke, Kirsten Blanco, Krista Bluske, Rachid Karam, PhD, Rebekah Barrick, Seth Berger

Collaborators:

Children's Hospital of Orange County, CA (CHOC)

University of California, Irvine

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.

Abstract Poster