Abstract
BackgroundAn 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.Results21 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.ConclusionsOur study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.
Highlights
Bi-allelic variants in the EIF3F gene have recently been published as the cause for a syndromic neurodevelopmental disorder (NDD) (OMIM #618,295: intellectual developmental disorder, autosomal recessive 67)
EIF3F variants were identified by sequencing of autism/ intellectual disability gene panels, whole exome sequencing (WES) or whole genome sequencing, performed as a clinical test or within a research project as described previously [4, 12, 13], or by Sanger sequencing for co-segregation testing in core family members, as presented in Additional file 1: Table S1 and Additional file 2: Fig. S1
Genotypes of rs12278319 in mother of P10 and of rs79714374 and rs12420464 in the affected individual of P17 could be inferred in single individuals of P10, P17 due to available genotypes in other core family members, and the ones of two SNPs in P4 could be deduced to one of the haplotypes identified in 1818 WES data
Summary
Bi-allelic variants in the EIF3F gene have recently been published as the cause for a syndromic neurodevelopmental disorder (NDD) (OMIM #618,295: intellectual developmental disorder, autosomal recessive 67). Variants were identified by a large exome-wide recessive burden analysis of > 4500 families with no previous molecular diagnosis [9]. All nine affected individuals from seven families carried the same homozygous EIF3F missense variant c.694T>G/p.(Phe232Val). Beside variable intellectual disability (ID) in all individuals, epilepsy occurred in six, and behavioral problems or sensorineural hearing loss in three individuals, respectively [9]. 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, character‐ ized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phe‐ notypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients
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