Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy

Maimuna S Paul; Anna R Duncan; Casie A Genetti; Hongling Pan; Adam Jackson; Patricia E Grant; Jiahai Shi; Michele Pinelli; Nicola Brunetti-Pierri; Alexandra Garza-Flores; Dave Shahani; Russell P Saneto; Giuseppe Zampino; Chiara Leoni; Emanuele Agolini; Antonio Novelli; Ulrike Blümlein; Tobias B Haack; Wolfram Heinritz; Eva Matzker; Bader Alhaddad; Rami Abou Jamra; Tobias Bartolomaeus; Saber AlHamdan; Raphael Carapito; Bertrand Isidor; Seiamak Bahram; Alyssa Ritter; Kosuke Izumi; Ben Pode Shakked; Ortal Barel; Bruria Ben Zeev; Amber Begtrup; Deanna Alexis Carere; Sureni V Mullegama; Timothy Blake Palculict; Daniel G Calame; Katharina Schwan; Alicia R P Aycinena; Rasa Traberg; Genomics England Research Consortium; Sofia Douzgou; Harrison Pirt; Naila Ismayilova; Siddharth Banka; Hsiao-Tuan Chao; Pankaj B Agrawal

doi:10.1016/j.ajhg.2022.11.011

Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy

Am J Hum Genet. 2023 Jan 5;110(1):120-145. doi: 10.1016/j.ajhg.2022.11.011. Epub 2022 Dec 16.

Authors

Maimuna S Paul¹, Anna R Duncan², Casie A Genetti³, Hongling Pan⁴, Adam Jackson⁵, Patricia E Grant⁶, Jiahai Shi⁷, Michele Pinelli⁸, Nicola Brunetti-Pierri⁸, Alexandra Garza-Flores⁹, Dave Shahani¹⁰, Russell P Saneto¹¹, Giuseppe Zampino¹², Chiara Leoni¹³, Emanuele Agolini¹⁴, Antonio Novelli¹⁴, Ulrike Blümlein¹⁵, Tobias B Haack¹⁶, Wolfram Heinritz¹⁷, Eva Matzker¹⁵, Bader Alhaddad¹⁸, Rami Abou Jamra¹⁹, Tobias Bartolomaeus¹⁹, Saber AlHamdan²⁰, Raphael Carapito²¹, Bertrand Isidor²², Seiamak Bahram²¹, Alyssa Ritter²³, Kosuke Izumi²³, Ben Pode Shakked²⁴, Ortal Barel²⁵, Bruria Ben Zeev²⁴, Amber Begtrup²⁶, Deanna Alexis Carere²⁶, Sureni V Mullegama²⁶, Timothy Blake Palculict²⁶, Daniel G Calame²⁷, Katharina Schwan²⁸, Alicia R P Aycinena²⁸, Rasa Traberg²⁹; Genomics England Research Consortium; Sofia Douzgou³⁰, Harrison Pirt³¹, Naila Ismayilova³², Siddharth Banka⁵, Hsiao-Tuan Chao³³, Pankaj B Agrawal³⁴

Affiliations

¹ Department of Pediatrics, Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
² Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Division of Neonatology and Newborn Medicine, Massachusetts General Hospital for Children, Boston, MA, USA.
³ Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
⁴ Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁵ Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
⁶ Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiology, Boston Children's Hospital, Boston, MA, USA.
⁷ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁸ Telethon Institute of Genetics and Medicine, Pozzuoli, Italy; Department of Translational Medicine, University of Naples "Federico II", Naples, Italy.
⁹ Department of Clinical Genetics, Cook Children's Hospital, Fort Worth, TX, USA.
¹⁰ Department of Neurology and Epileptology, Cook Children's Hospital, Fort Worth, TX 76104, USA.
¹¹ Neuroscience Institute, Center for Integrative Brain Research, Departments of Pediatric Neurology and Neurology Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
¹² Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy; Catholic University of the Sacred Heart, Faculty of Medicine and Surgery, Rome, Italy.
¹³ Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy.
¹⁴ Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹⁵ Department of Pediatrics, Carl-Thiem-Klinikum Cottbus, Cottbus, Germany.
¹⁶ Institute of Human Genetics, Technical University of Munich, 81675 Munich, Germany; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany.
¹⁷ Praxis für Humangenetik Cottbus, 03048 Cottbus, Germany.
¹⁸ Institute of Human Genetics, Technical University of Munich, 81675 Munich, Germany.
¹⁹ Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany.
²⁰ Al Qrayya, Syria.
²¹ Laboratoire 'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), ITI TRANSPLANTEX NG, Université de Strasbourg, 67085 Strasbourg, France; Service d'Immunologie Biologique, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, 1 Place de l'Hôpital, 67091, Strasbourg, France.
²² Service de Génétique Médicale, Hôpital Hôtel-Dieu, Centre Hospitalier Universitaire de Nantes, Nantes, France.
²³ Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
²⁴ Pediatric Neurology Department, The Edmond and Lilly Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
²⁵ Pediatric Neurology Department, The Edmond and Lilly Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.
²⁶ Clinical Genomics Program, GeneDx, Gaithersburg, MD 20877, USA.
²⁷ Section of Pediatric Neurology and Developmental Neurosciences, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
²⁸ Kaiser Permanente, San Francisco, CA, USA.
²⁹ Department of Genetics and Molecular Medicine, Hospital of Lithuanian University of Health Sciences Kauno klinikos, Kaunas, Lithuania.
³⁰ Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
³¹ Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK.
³² Department of Paediatric Neurology, Chelsea and Westminster NHS Foundation Trust, London, UK.
³³ Department of Pediatrics, Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA; McNair Medical Institute, The Robert and Janice McNair Foundation, Houston, TX, USA. Electronic address: hc140077@bcm.edu.
³⁴ Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: pankaj.agrawal@enders.tch.harvard.edu.

Abstract

Eukaryotic initiation factor-4A2 (EIF4A2) is an ATP-dependent RNA helicase and a member of the DEAD-box protein family that recognizes the 5' cap structure of mRNAs, allows mRNA to bind to the ribosome, and plays an important role in microRNA-regulated gene repression. Here, we report on 15 individuals from 14 families presenting with global developmental delay, intellectual disability, hypotonia, epilepsy, and structural brain anomalies, all of whom have extremely rare de novo mono-allelic or inherited bi-allelic variants in EIF4A2. Neurodegeneration was predominantly reported in individuals with bi-allelic variants. Molecular modeling predicts these variants would perturb structural interactions in key protein domains. To determine the pathogenicity of the EIF4A2 variants in vivo, we examined the mono-allelic variants in Drosophila melanogaster (fruit fly) and identified variant-specific behavioral and developmental defects. The fruit fly homolog of EIF4A2 is eIF4A, a negative regulator of decapentaplegic (dpp) signaling that regulates embryo patterning, eye and wing morphogenesis, and stem cell identity determination. Our loss-of-function (LOF) rescue assay demonstrated a pupal lethality phenotype induced by loss of eIF4A, which was fully rescued with human EIF4A2 wild-type (WT) cDNA expression. In comparison, the EIF4A2 variant cDNAs failed or incompletely rescued the lethality. Overall, our findings reveal that EIF4A2 variants cause a genetic neurodevelopmental syndrome with both LOF and gain of function as underlying mechanisms.

Keywords: DEAD-box protein; Drosophila; epilepsy; neurodevelopmental disorder; transcription factor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Drosophila / genetics
Drosophila Proteins* / genetics
Drosophila melanogaster / genetics
Drosophila melanogaster / metabolism
Epilepsy* / genetics
Eukaryotic Initiation Factor-4A / genetics
Humans
Intellectual Disability* / genetics
Muscle Hypotonia / genetics
Neurodevelopmental Disorders* / genetics
RNA, Messenger / genetics
RNA, Messenger / metabolism

Substances

dpp protein, Drosophila
Drosophila Proteins
EIF4A2 protein, human
Eukaryotic Initiation Factor-4A
RNA, Messenger
eIF4A protein, Drosophila

Abstract

Publication types

MeSH terms

Substances

Grants and funding