Recessive genomic and phenotypic variation in consanguineous families with cerebral palsy.
PMID 41282771 | PMCID PMC12637781 | DOI 10.1101/2025.11.04.25339178 · medRxiv : the preprint server for health sciences · 2025
Cerebral palsy (CP) is a neurodevelopmental disorder of motor function, with genetic etiologies, particularly de novo variants, identified in approximately one-third of cases. The contribution of consanguinity - long-recognized as a CP risk factor - has remained undefined. Here, we report findings from 188 primarily consanguineous Middle Eastern families with CP and identified putative causative genes in nearly three-quarters. The majority demonstrated recessive inheritance, although multi-level consanguinity and multilocus pathogenic variants complicated Mendelian assortment analyses. We identified 110 known CP-associated genes - five with phenotypic expansions and three others exhibiting new recessive inheritance patterns - and 24 novel candidates. We characterized ten candidates as high-confidence based on independent replication and protein modeling. We experimentally validated a role for SUCO variants in CP and newly identified a role for mid-gestational migrating excitatory neurons in the disorder. These findings highlight new genes, pathways, and phenotypes that reveal striking genomic diversity in CP.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | CP | “Cerebral palsy (CP) is a neurodevelopmental disorder of motor function, with genetic etiologies, particularly de novo variants, identified in approximately one-third of cases.” | 0.98 | hgnc_dict_v1 |
| gene | SUCO | “We experimentally validated a role for SUCO variants in CP and newly identified a role for mid-gestational migrating excitatory neurons in the disorder.” | 0.98 | hgnc_dict_v1 |
| phenotype | neurodevelopmental disorder | “Cerebral palsy (CP) is a neurodevelopmental disorder of motor function, with genetic etiologies, particularly de novo variants, identified in approximately one-third of cases.” | 0.98 | phenotype_alias_lexicon_v2 |
| population | Population | “Recessive genomic and phenotypic variation in consanguineous families with cerebral palsy. The contribution of consanguinity - long-recognized as a CP risk factor - has remained undefined. Here, we report findings from 188 primarily consanguineous Middle Eastern families with CP and identified putative causative genes in nearly three-quarters. The majority demonstrated recessive inheritance, although multi-level consanguinity and multilocus pathogenic variants complicated Mendelian assortment analyses.” | 0.80 | saudi_context_rules_v1 |