Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Apr 18:31:100864.
doi: 10.1016/j.ymgmr.2022.100864. eCollection 2022 Jun.

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

Zainab Al Masseri  1 , Moeenaldeen AlSayed  1   2
Affiliations

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

Zainab Al Masseri et al. Mol Genet Metab Rep. .

Abstract

Background: GNAO1 encodes an alpha subunit of the heterotrimeric guanine nucleotide-binding proteins (G proteins). Mutations in GNAO1 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 GNAO1 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 GNAO1 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 GNAO1 and gonadal mosaicism and the underlying mechanisms will be necessary.

Keywords: Chorea; Dystonia; EEIE17; EEIE17, Early infantile epileptic encephalopathy 17; Gonadal; Involuntary; Mosaicism; Movements; NEDIM; NEDIM, Neurodevelopmental disorder with involuntary movements; Neurodevelopmental.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing financial interests.

Figures

Fig. 1
Fig. 1
Pedigrees of the two families with GANO1.
See this image and copyright information in PMC

References

    1. Blumkin L., Lerman-Sagie T., Westenberger A., et al. Multiple causes of pediatric early onset chorea-clinical and genetic approach. Neuropediatrics. 2018;49:246–255. doi: 10.1055/s-0038-1645884. - DOI - PubMed
    1. Worley P.F., Baraban J.M., Van Dop C., Neer E.J., Snyder S.H. Go, a guanine nucleotide-binding protein: immunohistochemical localization in rat brain resembles distribution of second messenger systems. Proc. Natl. Acad. Sci. U. S. A. 1986;83:4561–4565. doi: 10.1073/pnas.83.12.4561. - DOI - PMC - PubMed
    1. Nakamura K., Kodera H., Akita T., et al. De novo mutations in GNAO1, encoding a Gαo subunit of heterotrimeric G proteins, cause epileptic encephalopathy. Am. J. Hum. Genet. 2013;93:496–505. 10.1016%2Fj.ajhg.2013.07.014. - PMC - PubMed
    1. Kulkarni N., Tang S., Bhardwaj R., Bernes S., Grebe T.A. Progressive movement disorder in brothers carrying a GNAO1 mutation responsive to deep brain stimulation. J. Child Neurol. 2016;31:211–214. doi: 10.1177/0883073815587945. - DOI - PubMed
    1. Menke L.A., Engelen M., Alders M., Odekerken V.J.J., Baas F., Cobben J.M. Recurrent GNAO1 mutations associated with developmental delay and a movement disorder. J. Child Neurol. 2016;31:1598–1601. doi: 10.1177/0883073816666474. - DOI - PubMed

Further readings

    1. Zhu X., Petrovski S., Xie P., et al. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet Med. 2015;17:774–781. doi: 10.1038/gim.2014.191. - DOI - PMC - PubMed
    1. Waak M., Mohammad S.S., Coman D., et al. GNAO1-related movement disorder with life-threatening exacerbations: movement phenomenology and response to DBS. J. Neurol. Neurosurg. Psychiatry. 2018;89:221–222. doi: 10.1136/jnnp-2017-315653. - DOI - PubMed
    1. Honey C.M., Malhotra A.K., Tarailo-Graovac M., van Karnebeek C.D.M., Horvath G., Sulistyanto A. GNAO1 mutation-induced pediatric dystonic storm rescue with pallidal deep brain stimulation. J. Child Neurol. 2018;33:413–416. doi: 10.1177/0883073818756134. - DOI - PubMed
    1. Ueda K., Serajee F., Huq A.M. Exome sequencing identifying dual mutations in calcium signaling genes GNAO1 and ATP2B3 in a patient with early infantile epileptic encephalopathy. J. Pediatr. Neurol. 2017;15:183–186. doi: 10.1055/s-0036-1597627. - DOI
    1. Benato A., Carecchio M., Burlina A., et al. Long-term effect of subthalamic and pallidal deep brain stimulation for status dystonicus in children with methylmalonic acidemia and GNAO1 mutation. J. Neural Transm. (Vienna) 2019;126:739–757. doi: 10.1007/s00702-019-02010-2. - DOI - PubMed

LinkOut - more resources