ClinVar Genomic variation as it relates to human health

Global developmental delay (present) , Abnormal facial shape (present) , Delayed fine motor development (present) , Intellectual disability (present) , Delayed speech and language development (present) , Autistic behavior (present) , Abnormal facial shape (present) , Intellectual disability (present) , Seizure (present) , Delayed gross motor development (present) , Epicanthus (present) , Seizure (present) , Generalized hypotonia (present) , Thick vermilion border (present) (less)

In 2 sibs with developmental and epileptic encephalopathy-47 (DEE47; 617166), Siekierska et al. (2016) identified a de novo heterozygous C-to-T transition (chr3.192,053,223C-T, GRCh37) in the FGF12 gene, resulting in an arg114-to-his (R114H) substitution in the A-isoform and an arg52-to-his (R52H) substitution in the B-isoform. The mutation, which was found by exome sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. It was also not present in either parent, suggesting germline mosaicism. The substitution occurs at a highly conserved residue that binds the cytoplasmic tail of voltage-gated sodium channels necessary for modulation of fast inactivation. In vitro functional expression studies in neuronal cells showed that both the R114H and R52H variants strongly changed the voltage dependence of inactivation gating, resulting in a gain-of-function effect and increased neuronal excitability. Additional experiments with different substitutions of the arg114 residue indicated that the loss of arginine side-chain interactions with the channel likely causes impaired function. Transfection of the orthologous mutation in zebrafish caused epileptiform activity in larval optic tecta. Al-Mehmadi et al. (2016) identified a de novo heterozygous R52H mutation in the FGF12 gene in 3 unrelated patients with DEE47. Whole-exome or whole-genome sequencing in these patients detected a c.155G-A transition (c.155G-A, NM_004113.5); the mutation was confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that their findings, combined with the report of Siekierska et al. (2016), suggested that DEE47 is an FGF12 R52H mutation-specific disease. The patients had onset of seizures in the first days to weeks of life. Guella et al. (2016) identified a de novo heterozygous c.155G-A transition in the FGF12 gene, resulting in an R52H substitution, in 2 unrelated patients with DEE47. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies and studies of patient cells were not performed. Guella et al. (2016) noted that 1 of the patients had normal development and neurologic examination at age 11 months, which may have resulted from early successful treatment with phenytoin at 20 days of age. By whole-exome sequencing in 2 unrelated Japanese patients with DEE47 (617166), Takeguchi et al. (2018) identified a heterozygous c.341G-A transition (c.341G-A, NM_021032.4) in the FGF12 gene, resulting in an R114H substitution. In patient 1, the mutation was inherited from a phenotypically normal mother who was mosaic for the mutation; in patient 2, the mutation occurred de novo. (less)

Abnormality of the amniotic fluid (present) , Prenatal maternal abnormality (present) , Premature birth (present) , Abnormality of eye movement (present) , Hypermetropia (present) , Cognitive impairment (present) , Abnormality of coordination (present) , EEG abnormality (present) , Encephalopathy (present) , Generalized hypotonia (present) , Memory impairment (present) , Seizures (present) , Feeding difficulties (present) , Abnormality of esophagus morphology (present) , Abnormality of the stomach (present) , Abnormality of the large intestine (present) (less)