Reply to: “GNAO1 Haploinsufficiency Associated with a Mild Delayed‐Onset Dystonia Phenotype”

We read the letter written by Krenn et al. regarding our recent article on the mild dystonic phenotype associated with GNAO1 heterozygous variants. The authors report on two first-degree relatives (mother and daughter) with delayedonset dystonia and who carried a copy number variant (CNV) in GNAO1. The mother exhibited symptoms from the age of 40 years, focal cervical dystonia associated with head tremor, and then developed segmental dystonia with additional myoclonus. No encephalopathic features nor intellectual disability (ID) was reported. Her daughter showed nonprogressive focal cervical dystonia from the age of 16 years associated with learning difficulties in childhood and generalized tonic–clonic seizures. By reassessing the whole-exome sequencing (WES) data sets of a cohort of patients affected with dystonia, the authors identified a heterozygous interstitial deletion at 16q12.2 encompassing exons 4 to 8 of GNAO1 (NM_020988.3) in the mother–daughter pair. Interestingly, this finding was initially ranked as a variant of unknown signification (VUS) and then reclassified in light of our recent article. Together with our results, these new findings are highly relevant in clinical practice. They highlight the importance of GNAO1 CNV assessment facing patients presenting with autosomal dominantly inherited focal dystonia. Likewise, a very recent publication from Lasa-Aranzasti and colleagues identified a larger 16q deletion encompassing GNAO1 in a patient showing mild ID associated with generalized dystonia. GNAO1 CNV may thus be an important cause of prominent dystonic phenotypes, which should be carefully searched for in patients exhibiting such a clinical presentation. In addition, these new reports further support that delayed-onset dystonia with no or little additional neurodevelopmental and neurological symptoms can be an underrecognized phenotype of GNAO1-related disorder. As highlighted, autosomal dominantly inherited dystonia is not rare in movement disorder clinics. Our findings, taken together with those from Krenn and colleagues, suggest that a substantial number of those cases could potentially be related to GNAO1 likely pathogenic or pathogenic variants, which has important implications for genetic testing and counseling. GNAO1 variants should be consequently searched for when the phenotype is compatible with the newly described GNAO1related spectrum, which is reminding of THAP1-, GNAL-, or KMT2B-related dystonia. The report provides further indication of the relationship between GNAO1 haploinsufficiency and milder dystonic phenotypes without encephalopathic features. This question the current framework about genotype–phenotype correlations in GNAO1related disorders: the hypothesis of loss-of-function variants causing epileptic encephalopathy and gain-of-function variants causing a neurodevelopmental syndrome with prominent dystonia is probably oversimplistic. It also raises the question of the factors determining intrafamilial phenotypic variability and the differences in the clinical presentation between patients carrying loss-of-function variants. Further functional work assessing the specific impact of each mutation on the striatal cyclic adenosine monophosphate synthesis pathway, as well as neuroimaging studies of GNAO1 carriers, might lead to a better understanding of these genetic, epigenetic, and environmental factors and to the refinement of genotype–phenotype correlations.