“…Thus far, however, pathogenic variants in genes have only been identified in 20%–40% of these conditions, with most located in protein-coding regions ( NIH, 2022 ; Shire, 2013 ). Non-protein-coding sequences occupy 98% of the human genome and, depending on their localization and specific interactions with DNA, RNA, and proteins, play key regulatory roles in nearly 93% of diseases ( Ding et al, 2021 ; Hindorff et al, 2009 ; Liu et al, 2020 ; Statello et al, 2021 ). Non-Mendelian inheritance patterns (e.g., oligogenic inheritance), gene-environment interactions, epigenetics, and other chemical modifications of biomolecules (e.g., glycosylation) also warrant further attention to understand the pathogenic mechanisms underlying undiagnosed and rare diseases ( Fitz-James & Cavalli, 2022 ; Kousi & Katsanis, 2015 ; Oh & Petronis, 2021 ; Wang et al, 2020 ).…”