eP198: EIF3F compound heterozygous genotype-phenotype association

Phenotypes for newly described gene-disease associations often undergo rapid evolution as additional cases are described. The expansion of exome and genome sequencing has contributed to this phenomenon by allowing ascertainment of diseases based on genotype rather than phenotype. We describe an example of phenotype expansion for the EIF3F gene, which encodes an essential subunit of the mammalian eukaryotic initiation factor (eIF2B) complex. EIF2F is important for translation regulation and is involved in cell proliferation and growth, cell cycle control, differentiation, and apoptosis. EIF3F gene has been implicated in severe autosomal recessive neurodegenerative disorders, including the disorder "Mental retardation, autosomal recessive 67” (OMIM #618295), which includes cognitive impairment, hearing loss and seizures. We describe a newly diagnosed case with white matter changes not previously associated with the disorder. The proband is a 4 year- and 11 month-old Romanian boy born to healthy, non-consanguineous parents. There was no family history of known congenital anomalies, genetic disorders, epilepsy, or intellectual disability. A 12-week ultrasound identified increased nuchal translucency (3.8 mm). Amniocentesis was performed at 16 weeks; QF-PCR and karyotype revealed normal results. Subsequent ultrasound evaluations yielded normal results. Decreased fetal movement was noted. Apgar scores were 9 at both 1- and 5-min. Birth weight was 3,200 g (10th centile), length was 50 cm (25th centile), and occipital frontal diameter (OFD) was 33cm (45th centile). Physical examination revealed muscular hypotonia, hypospadias, and 2,3-foot syndactyly. Newborn hearing screening was abnormal. Congenital visual impairment with nystagmus and convergent strabismus were present. Extensive metabolic screening and an electroencephalogram (EEG) study performed during the neonatal period were normal. During the first months of life, the patient showed severe hypotonia, global developmental delay (motor, cognitive and speech), muscular hypotonia, dysmorphic facial features (skin and hair hypopigmentation, micrognathia, and hand brachydactyly). Hearing assessment at the age of 6 months identified mild bilateral neuro-sensorial hearing loss with a 60 dB threshold (ABR test with anesthesia). At the age of 9 months, a 1.5T brain MRI revealed extensive supratentorial leukodystrophy. Genomic evaluation included a CGH high resolution micro array (aCGH), exome sequencing and genome sequencing. The aCGH study detected a region of absent heterozygosity in 2q11.1q11.2. Exome and genome sequencing were initially negative, but detected two heterozygous variants in the EIF3F gene on reanalysis of the genome 36 months after the initial interpretation. Clinical features reported to be associated with EIF3F gene variants include intellectual disability, epilepsy, behavioral problems, sensorineural hearing loss, congenital anomalies (cleft lip and palate, congenital lobar emphysema, anal stenosis, and undescended testis), neurological symptoms and non-specific brain MRI changes. Similar findings were identified in our patient, with the addition of white matter changes. Our paper provides a detailed clinical presentation of boy affected with autosomal recessive Mental retardation type 67 (MRT67, OMIM 618295) and expands the mutational spectrum associated with this extremely rare genetic condition. This is the first case of MRT67 identified in Romania.