Recessive genomic and phenotypic variation in consanguineous families with cerebral palsy
Bisarad, P.; Wang, Y.-C.; Skidmore, P. T.; Galaz-Montoya, C. I.; Lewis, S. A.; Alhaddad, B.; Kong, N.; Julian, D.; Magee, H.; Kruer, T. N.; Xie, Y.; Zhang, W.; Li, B.; Rajabpour, F. V.; Liu, J.; Revanur, A.; Bakur, K.; Firouzabadi, S. G.; Sharbatkhori, S.; Tafakhori, A.; Taghiabadi, E.; Nezaminargabad, E.; Vosoogh, S.; Jamshidi, J.; Arefnia, S.; Hosseini, S. A.; Khajehmirzaei, A.; Jamali, F.; Ahmadifard, A.; Khodadadi, H.; Daneshmand, P.; Bohlega, S.; Maddirevula, S.; Nadeef, S. S.; Hashem, M. O.; Salih, M. A.; Mohmed, I. N.; Sticht, H.; Morias, S. P.; Damasio, J.; Santos, M.; Loureiro, J. L.;
Show abstract
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.
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