Ulrike Hüffmeier1, Cornelia Kraus2, Miriam S Reuter2, Steffen Uebe2, Mary-Alice Abbott3, Syed A Ahmed4, Kristyn L Rawson4, Eileen Barr5, Hong Li5, Ange-Line Bruel6,7, Laurence Faivre6,8, Frédéric Tran Mau-Them6,7, Christina Botti9, Susan Brooks9, Kaitlyn Burns10, D Isum Ward10, Marina Dutra-Clarke11, Julian A Martinez-Agosto11,12, Hane Lee12,13, Stanley F Nelson11,12,13, Pia Zacher14,15, Rami Abou Jamra14, Chiara Klöckner14, Julie McGaughran16,17, Jürgen Kohlhase18, Sarah Schuhmann2, Ellen Moran19, John Pappas20, Annick Raas-Rothschild21,22, Maria J Guillen Sacoto23, Lindsay B Henderson23, Timothy Blake Palculict23, Sureni V Mullegama23, Houda Zghal Elloumi23, Adi Reich23, Samantha A Schrier Vergano24, Erica Wahl25, André Reis2, Christiane Zweier2,26. 1. Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 10, 91054, Erlangen, Germany. ulrike.hueffmeier@uk-erlangen.de. 2. Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 10, 91054, Erlangen, Germany. 3. Medical Genetics, Department of Pediatrics, University of Massachusetts Medical School - Baystate, Springfield, MA, USA. 4. Department of Genetics, Southern California Permanente Medical Group, Kaiser Permanente, Riverside, CA, USA. 5. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA. 6. UMR-Inserm 1231 GAD Team, Génétique des Anomalies du développement, Université de Bourgogne Franche-Comté, 21000, Dijon, France. 7. Laboratoire de Génétique Chromosomique et Moléculaire, UF Innovation en diagnostic génomique des maladies rares, Plateau de Biologie Hospitalo-Universitaire, Centre Hospitalier Universitaire de Dijon, Dijon, France. 8. Centre de Génétique, Centre de Référence «Anomalies du Développement et Syndromes Malformatifs» et FHU TRANSLAD, Hôpital D'Enfants, Centre Hospitalier Universitaire de Dijon, Dijon, France. 9. Division of Medical Genetics, Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA. 10. Sanford Health, Sioux Falls, SD, USA. 11. Division of Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095, USA. 12. Department of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095, USA. 13. Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095, USA. 14. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany. 15. Epilepsy Center Kleinwachau, Radeberg, Germany. 16. Genetic Health Queensland, Royal Brisbane and Woman's Hospital, Brisbane, Australia. 17. School of Medicine, The University of Queensland, St Lucia, Brisbane, Australia. 18. Synlab Human Genetics Freiburg, Freiburg, Germany. 19. Clinical Genetics, Hassenfeld Children's Hospital at NYU Langone, NYU Langone, Orthopedic Hospital, New York, NY, USA. 20. Division of Clinical Genetic Services, Department of Pediatrics, NYU Grossman School of Medicine, New York, NY, USA. 21. Sackler School of Medicine at Tel Aviv University, Tel Aviv, Israel. 22. Institute of Rare Diseases, Edmond & Lily Safra Children Hospital, Tel Hashomer, Israel. 23. GeneDx, Gaithersburg, MD, 20877, USA. 24. Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA, USA. 25. Division of Genetics, UBMD Pediatrics, Buffalo, NY, USA. 26. Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Abstract
BACKGROUND: An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients. RESULTS: 21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals' facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype-phenotype correlation. CONCLUSIONS: Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.
BACKGROUND: An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients. RESULTS: 21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals' facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype-phenotype correlation. CONCLUSIONS: Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.
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