title: Genetic and clinical heterogeneity in eIF2B-related disorder.
abstract: Eukaryotic initiation factor 2B (eIF2B)-related disorders are heritable white matter disorders with a variable clinical phenotype (including vanishing white matter disease and ovarioleukodystrophy) and an equally heterogeneous genotype. We report 9 novel mutations in the EIF2B genes in our subject population, increasing the number of known mutations to more than 120. Using homology modeling, we have analyzed the impact of novel mutations on the 5 subunits of the eIF2B protein. Although recurrent mutations have been found at CpG dinucleotides in the EIF2B genes, the high incidence of private or low frequency mutations increases the challenge of providing rapid genetic confirmation of this disorder, and limits the application of EIF2B screening in cases of undiagnosed leukodystrophy.
authors.affiliation: Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine, Washington, DC 20010, USA.
authors.forename: Jelena
authors.initials: J
authors.lastname: Maletkovic
authors.forename: Raphael
authors.initials: R
authors.lastname: Schiffmann
authors.forename: J Rafael
authors.initials: JR
authors.lastname: Gorospe
authors.forename: Erynn S
authors.initials: ES
authors.lastname: Gordon
authors.forename: Michelle
authors.initials: M
authors.lastname: Mintz
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Gulay
authors.initials: G
authors.lastname: Alper
authors.forename: David R
authors.initials: DR
authors.lastname: Lynch
authors.forename: Bhim S
authors.initials: BS
authors.lastname: Singhal
authors.forename: Cary
authors.initials: C
authors.lastname: Harding
authors.forename: Hernan
authors.initials: H
authors.lastname: Amartino
authors.forename: Candida M
authors.initials: CM
authors.lastname: Brown
authors.forename: Alicia
authors.initials: A
authors.lastname: Chan
authors.forename: Deborah
authors.initials: D
authors.lastname: Renaud
authors.forename: Michael
authors.initials: M
authors.lastname: Geraghty
authors.forename: Lloyd
authors.initials: L
authors.lastname: Jensen
authors.forename: Nesrin
authors.initials: N
authors.lastname: Senbil
authors.forename: Nadja
authors.initials: N
authors.lastname: Kadom
authors.forename: Javad
authors.initials: J
authors.lastname: Nazarian
authors.lastname: Yuanjian Feng
authors.lastname: Zuyi Wang
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartka
authors.forename: Hiroki
authors.initials: H
authors.lastname: Morizono
authors.forename: Adeline
authors.initials: A
authors.lastname: Vanderver
mesh_terms: D000293:Adolescent; D000328:Adult; D001927:Brain Diseases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics; D040681:Structural Homology, Protein
chemical_list: D020717:Eukaryotic Initiation Factor-2B; D021122:Protein Subunits