Dataset Information

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

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.

SUBMITTER: Al Masseri Z

PROVIDER: S-EPMC9248221 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundIn humans, Mammalian Target of Rapamycin (MTOR) encodes a 300 kDa serine/ threonine protein kinase that is ubiquitously expressed, particularly at high levels in brain. MTOR functions as an integrator of multiple cellular processes, and in so doing either directly or indirectly regulates the phosphorylation of at least 800 proteins. While somatic MTOR mutations have been recognized in tumors for many years, and more recently in hemimegalencephaly, germline MTOR mutations have rarely been described.Case presentationWe report the successful application of family-trio Diagnostic Exome Sequencing (DES) to identify the underlying molecular etiology in two brothers with multiple neurological and developmental lesions, and for whom previous testing was non-diagnostic. The affected brothers, who were 6 and 23 years of age at the time of DES, presented symptoms including but not limited to mild Autism Spectrum Disorder (ASD), megalencephaly, gross motor skill delay, cryptorchidism and bilateral iris coloboma. Importantly, we determined that each affected brother harbored the MTOR missense alteration p.E1799K (c.5395G>A). This exact variant has been previously identified in multiple independent human somatic cancer samples and has been shown to result in increased MTOR activation. Further, recent independent reports describe two unrelated families in whom p.E1799K co-segregated with megalencephaly and intellectual disability (ID); in both cases, p.E1799K was shown to have originated due to germline mosaicism. In the case of the family reported herein, the absence of p.E1799K in genomic DNA extracted from the blood of either parent suggests that this alteration most likely arose due to gonadal mosaicism. Further, the p.E1799K variant exerts its effect by a gain-of-function (GOF), autosomal dominant mechanism.ConclusionHerein, we describe the use of DES to uncover an activating MTOR missense alteration of gonadal mosaic origin that is likely to be the causative mutation in two brothers who present multiple neurological and developmental abnormalities. Our report brings the total number of families who harbor MTOR p.E1799K in association with megalencephaly and ID to three. In each case, evidence suggests that p.E1799K arose in the affected individuals due to gonadal mosaicism. Thus, MTOR p.E1799K can now be classified as a pathogenic GOF mutation that causes megalencephaly and cognitive impairment in humans.

Project description:Background: The approximate 5:1 male to female ratio in clinical detection of Autism Spectrum Disorder (ASD) prevents research from characterizing the female phenotype. Current open access repositories [such as those in the Autism Brain Imaging Data Exchange (ABIDE I-II)] contain large numbers of females to help begin providing a new characterization of females on the autistic spectrum. Here we introduce new methods to integrate data in a scale-free manner from continuous biophysical rhythms of the nervous systems and discrete (ordinal) observational scores. Methods: New data-types derived from image-based involuntary head motions and personalized statistical platform were combined with a data-driven approach to unveil sub-groups within the female cohort. Further, to help refine the clinical DSM-based ASD vs. Asperger's Syndrome (AS) criteria, distributional analyses of ordinal score data from Autism Diagnostic Observation Schedule (ADOS)-based criteria were used on both the female and male phenotypes. Results: Separate clusters were automatically uncovered in the female cohort corresponding to differential levels of severity. Specifically, the AS-subgroup emerged as the most severely affected with an excess level of noise and randomness in the involuntary head micro-movements. Extending the methods to characterize males of ABIDE revealed ASD-males to be more affected than AS-males. A thorough study of ADOS-2 and ADOS-G scores provided confounding results regarding the ASD vs. AS male comparison, whereby the ADOS-2 rendered the AS-phenotype worse off than the ASD-phenotype, while ADOS-G flipped the results. Females with AS scored higher on severity than ASD-females in all ADOS test versions and their scores provided evidence for significantly higher severity than males. However, the statistical landscapes underlying female and male scores appeared disparate. As such, further interpretation of the ADOS data seems problematic, rather suggesting the critical need to develop an entirely new metric to measure social behavior in females. Conclusions: According to the outcome of objective, data-driven analyses and subjective clinical observation, these results support the proposition that the female phenotype is different. Consequently the "social behavioral male ruler" will continue to mask the female autistic phenotype. It is our proposition that new observational behavioral tests ought to contain normative scales, be statistically sound and combined with objective data-driven approaches to better characterize the females across the human lifespan.