Objectives: The association of developmental delay and epilepsy has been long reported in multiple neurological diseases of childhood. The substantial recent technological advances in genetic diagnosis have identified numerous pathogenic variants on genes involved in neurodevelopment in such patients. Among those, heterozygous gain-of-function variants in RNF13 leading to altered signaling of the endoplasmic reticulum stress response, have been recently reported in three children with congenital microcephaly, encephalopathy with epilepsy, blindness, and failure to thrive. None of these patients presented with movement disorders.
Content: We, here, report a child with early-onset global developmental delay, acquired microcephaly, failure to thrive, infantile spasms, focal seizures, and gastrointestinal dysfunction who also presented at 3 years with a choreodystonic movement disorder. An extended metabolic workup was normal. Brain MRI did not reveal significant abnormalities. Genetic analyses that included trio whole-exome sequencing revealed a heterozygous de novo c.932delT:(p.Leu311TyrfsTer2) variant in RNF13. The variant is located near the other pathogenic variants reported previously. It creates a frameshift near the carboxyl terminus of the predicted protein sequence (codon, 311/380), producing an abnormal protein with a postulated gain of function effect.
Conclusion: RNF13 variants are involved in a complex neurodevelopmental disorder hitherto only very rarely reported. To our knowledge, our patient is the fourth described so far. In addition to previously reported clinical features, the phenotype of this child also included a choreodystonic movement disorder. The RNF13 should be added to the panel of genes, specifically analyzed in patients who present with abnormal movements, in addition to those involved in encephalopathy and early-onset epilepsy.
