EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum

• Authors: Ulrike Hueffmeier, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU); Cornelia Kraus, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU); Miriam S Reuter, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU); Steffen Uebe, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU); Mary-Alice Abbott, University of Massachusetts; Syed A Ahmed, Kaiser Permanente; Kristyn L Rawson, Kaiser Permanente; Eileen Barr, Emory University; Hong Li, Emory University; Ange-Line Bruel, Université de Bourgogne Franche-Comté; Laurence Faivre, Université de Bourgogne Franche-Comté; Frédéric T Mau-Them, Université de Bourgogne Franche-Comté; Christina Botti, Rutgers Robert Wood Johnson Med Sch; Susan Brooks, Rutgers Robert Wood Johnson Med Sch; Kaitlyn Burns, Sanford Health, Sioux Falls; Isum D Ward, Sanford Health, Sioux Falls; Marina Dutra-Clarke, University of California Los Angeles; Julian A Martinez-Agosto, University of California Los Angeles; Hane Lee, University of California Los Angeles; Stanley F Nelson, University of California Los Angeles; Pia Zacher, Leipzig University; Rami Abou Jamra, Leipzig University; Chiara Kloeckner, Leipzig University; Julie McGaughran, Royal Brisbane & Womans Hospital; Jürgen Kohlhase, Synlab Human Genet Freiburg; Sarah Schuhmann, Friedrich Alexander Univ Erlangen Nurnberg FAU; Ellen Moran, NYU Langone; John Pappas, NYU Grossman School of Medicine; Annick Raas-Rothschild, Tel Aviv University; Maria Guilen J Sacoto, GeneDx, Gaithersburg, MD; Linday B Henderson, GeneDx, Gaithersburg, MD; Timothy B Palculict, GeneDx, Gaithersburg, MD; Sureni Mullegama, GeneDx, Gaithersburg, MD; Houda Z Elloumi, GeneDx, Gaithersburg, MD; Adi Reich, GeneDx, Gaithersburg, MD; Samantha Schrier A Vergano, Childrens Hosp Kings Daughters; Erica Wahl, UBMD Pediat; André Reis, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU); Christiane Zweier, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
• Journal Title: ORPHANET JOURNAL OF RARE DISEASES
• Volume: Volume 16, Number 1
• Publisher: BMC | 2021-03-18, Pages 136-136
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1186/s13023-021-01744-1
• Subjects: Health Sciences, Medicine and Surgery; Biology, Genetics
• Keywords: Science & Technology; Life Sciences & Biomedicine; Genetics & Heredity; Medicine, Research & Experimental; Research & Experimental Medicine; EIF3F gene; Neurodevelopmental disorder; Short stature; Deafness; Behavioral difficulties; Altered muscular tone

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.