Mapping molecular genome-editing opportunities across Mendelian disorders using ClinVar and GenCC
Year: 2026
Type: preprint
Abstract: Catalog-wide estimates of genome-editing correctability may conflate nucleotide chemistry, confidence in disease attribution, target-sequence feasibility, and therapeutic effectiveness. We integrated frozen ClinVar variant classifications with Gene Curation Coalition (GenCC) assertions to analyze 6,968 high-confidence gene–disease–mode-of-inheritance relationships. Filtering 9,345,867 ClinVar source rows yielded 312,679 unique qualifying variants, of which 168,648 were sequence-resolved single-nucleotide variants (SNVs); 92,687 (54.96%) exhibited canonical adenine/cytosine base-editor reaction chemistry for hypothetical alternate-to-reference correction. Exact disease linkage, unique relationship assignment, and ClinVar review confidence of at least two stars retained 46,786 of 269,669 variant–relationship association edges. Within the stringent cohort, 2,396 relationships contained a chemistry-compatible SNV and 1,763 contained short-indel evidence; 1,427 overlapped, yielding 2,732/6,968 (39.21%) nonredundant molecular-class candidates. Variant documentation was highly unequal (Gini coefficient 0.805), with the most extensively annotated 1% of relationships contributing 28.18% of association edges. In a GRCh38-validated chromosome 21 pilot, 373 of 1,071 chemistry-compatible SNVs had an NGG PAM and an eligible modeled editing-window position; 169 lacked additional modeled same-class bystanders. A purposive translational benchmark highlighted interventions directed at compensatory or alternative loci. The results define evidence-linked molecular substrates for experimental prioritization, not the fraction of Mendelian disorders with technically deliverable or clinically validated genome-editing therapies. Article summary The analysis integrates public human genetic-variant classifications with curated gene–disease associations to identify molecular changes relevant to genome editing. A stringent evidence filter revealed 2,732 of 6,968 relationships with a documented base-editing chemistry or short-indel candidate. Sequence screening of chromosome 21 demonstrated substantial targeting constraints, and the number of candidate relationships was sensitive to variant ascertainment and disease-linkage rules. These results provide a reproducible starting point for prioritizing editing experiments. They do not establish that an equivalent fraction of genetic disorders has deliverable, safe, or effective genome-editing therapy.
Source: Research Square
Author: Achab-Awelana Ernest
Institution: Kwame Nkrumah University of Science and Technology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225789943