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

Esra Erkut¹, Cherith Somerville², Marci L B Schwartz³, Laura McDonald⁴, Qiliang Ding², Olivia M Moran³, Xin Chen², Roozbeh Manshaei², Anne-Sophie Riedijk⁴, Marie-Therese Schnürer⁴, Daniel C Koboldt⁵, Stylianos E Antonarakis⁶, Emma C Bedoukian⁷, Xavier Blanc⁶, Laura K Conlin⁷, Helen Cox⁸, Karin E M Diderich⁹, Bri Dingmann¹⁰, Christèle Dubourg¹¹, Frances Elmslie¹², Luis F Escobar¹³, Rachel Gosselin¹⁴, Maria J Guillen Sacoto¹⁵, Cynthia D Haag¹⁶, Lisa Herzig¹⁰, Ramanand Jeeneea⁸, Priti Kenia¹⁷, Konstantinos Kolokotronis¹⁸, Anna M Kopps¹⁹, Christin Kupper¹⁸, Hayley Lees²⁰, Jacqueline Leonard⁷, Jonathan Levy²¹, Rebecca Littlejohn²², Demian Mayer¹⁹, Scott D McLean²², Nikhil Pattani¹², Laurence Perrin²¹, Véronique Pingault²³, Chloé Quelin²⁴, Emmanuelle Ranza⁶, Anita Rauch¹⁸, Sara L Reichert⁷, Joana Rosmaninho-Salgado²⁵, Cara Skraban⁷, Sérgio Sousa²⁵, Melissa Stuebben²², Paolo Zanoni²⁶, Raymond H Kim²⁷, Ian C Scott²⁸, Rebekah K Jobling²⁹

Affiliations

¹ Program in Developmental, Stem Cell & Cancer Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
² Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
³ Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Program in Developmental, Stem Cell & Cancer Biology, The Hospital for Sick Children, Toronto, ON, Canada.
⁵ The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA.
⁶ Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland.
⁷ Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸ Birmingham Women's and Children's Hospital, Birmingham, UK.
⁹ Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
¹⁰ Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
¹¹ Service de Génétique Moléculaire et Génomique, CHU Pontchaillou, Rennes, France.
¹² St George's University Hospitals NHS Foundation Trust, London, UK.
¹³ Medical Genetics, Peyton Manning Children's Hospital, Ascension Health, Indianapolis, IN, USA.
¹⁴ Division of Genetic and Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA.
¹⁵ GeneDx LLC, Gaithersburg, MD, USA.
¹⁶ Medical Genetics, Ascension St. Vincent, Indianapolis, IN, USA.
¹⁷ Birmingham Women's and Children's NHS Trust, Birmingham, UK.
¹⁸ Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
¹⁹ Genetica AG, Zurich, Switzerland.
²⁰ Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
²¹ Genetics Department, AP-HP, Robert Debré University Hospital, Paris, France.
²² Baylor College of Medicine, Houston, TX, USA.
²³ Service de Médecine Génomique des Maladies Rares, AP-HP, Hôpital Necker, Université Paris Cité, Paris, France.
²⁴ Service de Génétique Clinique, CLAD Ouest, CHU Rennes, Rennes, France.
²⁵ Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
²⁶ Genetica AG, Zurich, Switzerland; Luzerner Kantonsspital, Lucerne, Switzerland.
²⁷ Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada; Fred A. Litwin Family Centre in Genetic Medicine, University Health Network, Department of Medicine, University Health Network, Toronto, ON, Canada.
²⁸ Program in Developmental, Stem Cell & Cancer Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. Electronic address: ian.scott@sickkids.ca.
²⁹ Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada; Genome Diagnostics, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address: rebekah.jobling@sickkids.ca.

PMID: 41033306
DOI: 10.1016/j.ajhg.2025.09.008

Free article

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

Esra Erkut et al. Am J Hum Genet. 2025.

Free article

. 2025 Nov 6;112(11):2625-2642.

doi: 10.1016/j.ajhg.2025.09.008. Epub 2025 Sep 30.

Authors

Affiliations

¹ Program in Developmental, Stem Cell & Cancer Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
² Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
³ Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Program in Developmental, Stem Cell & Cancer Biology, The Hospital for Sick Children, Toronto, ON, Canada.
⁵ The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA.
⁶ Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland.
⁷ Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸ Birmingham Women's and Children's Hospital, Birmingham, UK.
⁹ Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
¹⁰ Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
¹¹ Service de Génétique Moléculaire et Génomique, CHU Pontchaillou, Rennes, France.
¹² St George's University Hospitals NHS Foundation Trust, London, UK.
¹³ Medical Genetics, Peyton Manning Children's Hospital, Ascension Health, Indianapolis, IN, USA.
¹⁴ Division of Genetic and Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA.
¹⁵ GeneDx LLC, Gaithersburg, MD, USA.
¹⁶ Medical Genetics, Ascension St. Vincent, Indianapolis, IN, USA.
¹⁷ Birmingham Women's and Children's NHS Trust, Birmingham, UK.
¹⁸ Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
¹⁹ Genetica AG, Zurich, Switzerland.
²⁰ Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
²¹ Genetics Department, AP-HP, Robert Debré University Hospital, Paris, France.
²² Baylor College of Medicine, Houston, TX, USA.
²³ Service de Médecine Génomique des Maladies Rares, AP-HP, Hôpital Necker, Université Paris Cité, Paris, France.
²⁴ Service de Génétique Clinique, CLAD Ouest, CHU Rennes, Rennes, France.
²⁵ Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
²⁶ Genetica AG, Zurich, Switzerland; Luzerner Kantonsspital, Lucerne, Switzerland.
²⁷ Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada; Fred A. Litwin Family Centre in Genetic Medicine, University Health Network, Department of Medicine, University Health Network, Toronto, ON, Canada.
²⁸ Program in Developmental, Stem Cell & Cancer Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. Electronic address: ian.scott@sickkids.ca.
²⁹ Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada; Genome Diagnostics, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address: rebekah.jobling@sickkids.ca.

PMID: 41033306
DOI: 10.1016/j.ajhg.2025.09.008

Abstract

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.

Keywords: 7p22.3 microdeletions; EIF3A; EIF3B; congenital heart disease; craniofacial; eIF3; neurodevelopmental; syndromic CHD; tetralogy of Fallot; zebrafish models.

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Conflict of interest statement

Declaration of interests S.E.A. and E.R. are cofounders of Medigenome, Swiss Institute of Genomic Medicine. M.J.G.S. is an employee and may own stock in GeneDx.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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Medical