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EIF3F-related neurodevelopmental disorder: delineating and expanding the phenotypic and molecular spectrum
  • +37
  • Ulrike Hueffmeier,
  • Cornelia Kraus,
  • Miriam Reuter,
  • Steffen Uebe,
  • Mary-Alice Abbott,
  • Syed Ahmed,
  • Kristyn Rawson,
  • Eileen Barr,
  • Hong Li,
  • ange-line bruel,
  • Laurence Faivre,
  • Frederic Tran Mau Them,
  • Christina Botti,
  • Susan Brooks,
  • Kaitlyn Burns,
  • Isum Ward,
  • Marina Dutra-Clarke,
  • Julian Martinez-Agosto,
  • Hane Lee,
  • Stanley Nelson,
  • UCLA California Center for Rare Disease,
  • Pia Zacher,
  • Rami Abou Jamra,
  • Chiara Klöckner,
  • Julie MacGaughran,
  • Juergen Kohlhase,
  • Sarah Schuhmann,
  • Ellen Moran,
  • John Pappas,
  • Annick Rothschild,
  • Maria Guillen Sacoto,
  • Lindsay Henderson,
  • Timothy Palculict,
  • Sureni Mullegama,
  • Houda Elloumi,
  • Adi Reich,
  • Samantha Schrier Vergano,
  • Erica Wahl,
  • André Reis,
  • Christiane Zweier
Ulrike Hueffmeier
Friedrich-Alexander-Universitaet Erlangen-Nuernberg

Corresponding Author:ulrike.hueffmeier@uk-erlangen.de

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Cornelia Kraus
Friedrich-Alexander University Erlangen-Nuremberg
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Miriam Reuter
Friedrich-Alexander-Universitaet Erlangen-Nuernberg
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Steffen Uebe
Friedrich-Alexander-Universität Erlangen-Nürnberg
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Mary-Alice Abbott
University of Massachusetts Medical School – Baystate
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Syed Ahmed
Department of Genetics, Southern California Permanente Medical Group, Kaiser Permanente
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Kristyn Rawson
Department of Genetics, Southern California Permanente Medical Group, Kaiser Permanente
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Eileen Barr
Emory University School of Medicine
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Hong Li
Emory university, school of medicine
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ange-line bruel
INSERM U1231 GAD
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Laurence Faivre
Dijon Hospital
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Frederic Tran Mau Them
Université de Bourgogne-Franche Comté, FHU TRANSLAD
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Christina Botti
Division of Medical Genetics, Department of Pediatrics, Rutgers Robert Wood Johnson Medical School
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Susan Brooks
Division of Medical Genetics, Department of Pediatrics, Rutgers Robert Wood Johnson Medical School
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Kaitlyn Burns
Sanford Health
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Isum Ward
Sanford Health
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Marina Dutra-Clarke
Division of Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles
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Julian Martinez-Agosto
University of California Los Angeles
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Hane Lee
Pathology and Laboratory Medicine
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Stanley Nelson
Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles
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UCLA California Center for Rare Disease
David Geffen School of Medicine, University of California at Los Angeles, Los Angeles
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Pia Zacher
University of Leipzig Medical Center
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Rami Abou Jamra
Leipzig University
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Chiara Klöckner
University of Leipzig Medical Center
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Julie MacGaughran
University of Queensland
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Juergen Kohlhase
SYNLAB Center for Human Genetics Freiburg
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Sarah Schuhmann
Friedrich-Alexander-Universitat Erlangen-Nurnberg Medizinische Fakultat
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Ellen Moran
Clinical Genetics, Hassenfeld Children’s Hospital at NYU Langone, NYU Langone, Orthopedic Hospital
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John Pappas
New York University School of Medicine
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Annick Rothschild
Sheba medical center
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Maria Guillen Sacoto
GeneDx
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Lindsay Henderson
GeneDx
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Timothy Palculict
GeneDx
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Sureni Mullegama
GeneDx
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Houda Elloumi
GeneDx
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Adi Reich
GeneDx
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Samantha Schrier Vergano
Children's Hospital of The King's Daughters
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Erica Wahl
UBMD Pediatrics, Division of Genetics
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André Reis
University Hospital Erlangen
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Christiane Zweier
Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg
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Abstract

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 delineate and expand the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined 21 affected individuals, homozygous (20/21) or compound heterozygous (1/21) for c.694T>G/ p.(Phe232Val) in EIF3F. Haplotype analyses in 12 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. Our study expands the phenotypic and molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.