A cardiovascular, craniofacial, and neurodevelopmental disorder caused by loss-of-function variants in the eIF3 complex component genes EIF3A and EIF3B.

Syndromic cardiac malformations can result in morbidity, yet their genetic etiology is only understood for a subset of individuals. Genome sequencing efforts in congenital anomaly cohorts may identify disease-associated variants in previously unrecognized genes. Through international matchmaking efforts, we identified eighteen individuals in total with de novo or loss-of-function variants in EIF3A (n = 4) or EIF3B (n = 14). The clinical phenotype varied but predominantly included cardiac defects, craniofacial dysmorphisms, mild developmental delays, and behavioral abnormalities. These genes encode core subunits of the eukaryotic initiation factor 3 (eIF3) complex, which plays a critical role in binding mRNA transcripts to the 40S ribosomal subunit during translation initiation. Both genes are highly constrained against loss of function, and animal models have demonstrated that disruptions in the eIF3 complex result in a range of developmental defects, including cardiovascular malformations. Additionally, EIF3B is located within the minimally overlapping region implicated in cardiac anomalies associated with 7p22.3 microdeletions. We sought to further study the role of these genes in syndromic congenital heart disease. To explore their functional impact, we generated zebrafish models with mutations in the orthologous eif3s10 and eif3ba genes, which resulted in developmental abnormalities, including thin heart tubes, lack of craniofacial cartilage, and embryonic lethality. We propose that pathogenic variants in EIF3A, as well as pathogenic variants or microdeletions involving EIF3B, cause a distinct autosomal-dominant neurodevelopmental syndrome characterized by cardiovascular and craniofacial manifestations.