Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy.
Nat Genet
; 56(4): 585-594, 2024 Apr.
Article
in En
| MEDLINE
| ID: mdl-38553553
ABSTRACT
We performed whole-genome sequencing (WGS) in 327 children with cerebral palsy (CP) and their biological parents. We classified 37 of 327 (11.3%) children as having pathogenic/likely pathogenic (P/LP) variants and 58 of 327 (17.7%) as having variants of uncertain significance. Multiple classes of P/LP variants included single-nucleotide variants (SNVs)/indels (6.7%), copy number variations (3.4%) and mitochondrial mutations (1.5%). The COL4A1 gene had the most P/LP SNVs. We also analyzed two pediatric control cohorts (n = 203 trios and n = 89 sib-pair families) to provide a baseline for de novo mutation rates and genetic burden analyses, the latter of which demonstrated associations between de novo deleterious variants and genes related to the nervous system. An enrichment analysis revealed previously undescribed plausible candidate CP genes (SMOC1, KDM5B, BCL11A and CYP51A1). A multifactorial CP risk profile and substantial presence of P/LP variants combine to support WGS in the diagnostic work-up across all CP and related phenotypes.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cerebral Palsy
/
DNA Copy Number Variations
Limits:
Child
/
Humans
Language:
En
Journal:
Nat Genet
Journal subject:
GENETICA MEDICA
Year:
2024
Type:
Article
Affiliation country:
Canada