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

• Published in: Orphanet journal of rare diseases 2021-03, Vol.16 (1), p.136-136, Article 136
• Main Authors: Hüffmeier, Ulrike, Kraus, Cornelia, Reuter, Miriam S, Uebe, Steffen, Abbott, Mary-Alice, Ahmed, Syed A, Rawson, Kristyn L, Barr, Eileen, Li, Hong, Bruel, Ange-Line, Faivre, Laurence, Tran Mau-Them, Frédéric, Botti, Christina, Brooks, Susan, Burns, Kaitlyn, Ward, D Isum, Dutra-Clarke, Marina, Martinez-Agosto, Julian A, Lee, Hane, Nelson, Stanley F, Zacher, Pia, Abou Jamra, Rami, Klöckner, Chiara, McGaughran, Julie, Kohlhase, Jürgen, Schuhmann, Sarah, Moran, Ellen, Pappas, John, Raas-Rothschild, Annick, Sacoto, Maria J Guillen, Henderson, Lindsay B, Palculict, Timothy Blake, Mullegama, Sureni V, Zghal Elloumi, Houda, Reich, Adi, Schrier Vergano, Samantha A, Wahl, Erica, Reis, André, Zweier, Christiane
• Format: Article
• Language: English
• Subjects: Age; Altered muscular tone; Autism; Behavioral difficulties; Cell cycle; Child development deviations; Cleft Lip; Cleft lip/palate; Cleft Palate; Congenital diseases; Deafness; Developmental disabilities; Diagnosis; EIF3F gene; Epilepsy; Eukaryotic Initiation Factor-3; Families & family life; Genetic aspects; Genetic disorders; Genetic variation; Genomes; Genotypes; Haplotypes; Hearing loss; Humans; Intellectual disabilities; Intellectual Disability - genetics; Medical imaging; Medical research; Medicine, Experimental; Mental illness; Microcephaly; Microencephaly; Nervous system diseases; Neurodevelopmental disorder; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Parents & parenting; Phenotype; Phenotypes; Rare diseases; Short stature; Speech
• ISSN: 1750-1172; 1750-1172
• DOI: 10.1186/s13023-021-01744-1

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. 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. Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.