Gonadal mosaicism in GNAO1 causing neurodevelopmental disorder with involuntary movements; two additional variants.

Background: encodes an alpha subunit of the heterotrimeric guanine nucleotide-binding proteins (G proteins). Mutations in result in two clinical phenotypes: Early infantile epileptic encephalopathy 17 (EEIE17-OMIM #615473) and Neurodevelopmental disorder with involuntary movements (NEDIM-OMIM #617493). Both are inherited as autosomal dominant disorders and originate mainly as de novo. Only a few are reported as gonadal mosaicism.

Materials And Methods: We recruited and retrospectively reviewed five patients from two families seen at King Faisal Specialist Hospital and Research Centre in Riyadh (KFSHRC).

Results: All patients presented with severe neurodevelopmental disorder, followed by progressive dystonia and hyperkinetic movements. In addition, none of the patients had seizures which was consistent with NEDIM phenotype. The specific diagnosis was not clinically entertained and was only found on whole exome sequencing (WES), which identified two variants (c.724-8G > A & c.709G > A). Both variants were previously reported as pathogenic de novo in patients with NEDIM, and one was reported as parental gonadal mosaicism.

Conclusion: We report these variants as additional variants in gene that may be inherited as parental gonadal mosaicism. Both variants resulted in NEDIM with no observed clinical differences in the severity than the reported cases. This noticeable reported association between gene associated disorders and gonadal mosaicism should be considered in reproductive genetic counselling of affected families. Furthermore, in view of these reports, more studies with prospective data collection to explore the association between and gonadal mosaicism and the underlying mechanisms will be necessary.