What Can Go Wrong in the Non-coding Genome and How to Interpret Whole Genome Sequencing Data

Overview

Journal Med Genet

Publisher De Gruyter

Specialties Genetics
Medical Ethics

Date 2024 Jun 5

PMID 38836035

Authors

Heiko Krude

Stefan Mundlos

Nancy Christine Oien

Robert Opitz

Markus Schuelke

Affiliations

Soon will be listed here.

Abstract

Whole exome sequencing discovers causative mutations in less than 50 % of rare disease patients, suggesting the presence of additional mutations in the non-coding genome. So far, non-coding mutations have been identified in less than 0.2 % of individuals with genetic diseases listed in the ClinVar database and exhibit highly diverse molecular mechanisms. In contrast to our capability to sequence the whole genome, our ability to discover and functionally confirm such non-coding mutations is lagging behind severely. We discuss the problems and present examples of confirmed mutations in deep intronic sequences, non-coding triplet repeats, enhancers, and larger structural variants and highlight their proposed disease mechanisms. Finally, we discuss the type of data that would be required to establish non-coding mutation detection in routine diagnostics.

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