155: eIF3A/EIF3B haploinsufficiency and a syndromic cause of CHD

Erkut E et al., The American Journal of Human Genetics - This episode examines an international cohort of 18 individuals with de novo or loss-of-function variants in EIF3A or EIF3B who present with congenital heart defects, craniofacial differences, and mild neurodevelopmental features, and reviews zebrafish CRISPR models that recapitulate key aspects of the human phenotype. Key terms: EIF3A, EIF3B, congenital heart disease, craniofacial dysmorphism, zebrafish model.

Study Highlights:
An international clinical series identified 18 individuals with de novo or predicted loss-of-function variants in EIF3A (n=4) or EIF3B (n=14) presenting mainly with congenital heart defects, craniofacial dysmorphisms, and mild neurodevelopmental features. Most variants are predicted to act via haploinsufficiency. CRISPR-Cas9 zebrafish mutants of orthologous eif3s10 and eif3ba showed hypoplastic heart tubes, absent craniofacial cartilage, microcephaly, coloboma, increased apoptosis, and embryonic lethality. The combined human and zebrafish data support EIF3A and EIF3B loss as the cause of a distinct autosomal-dominant neurocristopathy-like syndrome.

Conclusion:
Haploinsufficiency of EIF3A or EIF3B defines an autosomal-dominant syndrome with cardiac, craniofacial, and neurodevelopmental manifestations; both genes should be considered in genetic testing for congenital heart disease and related syndromes.

Music:
Enjoy the music based on this article at the end of the episode.

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

First author:
Erkut E

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2025.09.008

Reference:
Erkut E, Somerville C, Schwartz MLB, et al. A cardiovascular, craniofacial, and neurodevelopmental disorder caused by loss-of-function variants in the eIF3 complex component genes EIF3A and EIF3B. Am J Hum Genet. 2025;112:1–18. doi:10.1016/j.ajhg.2025.09.008

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode link: https://basebybase.com/episodes/eif3a-eif3b-loss-of-function-a-cardiocraniofacial-neurodevelopmental-syndrome