GNAO1 Haploinsufficiency Associated with a Mild Delayed‐Onset Dystonia Phenotype

With great interest we read the manuscript recently published by Wirth and colleagues reporting 24 individuals with variants in GNAO1 related to delayed-onset, dystonia-predominant phenotypes without encephalopathic features.1 Based on the identification of two putative loss-of-function variants (including a nonsense alteration and a larger deletion containing GNAO1), the authors suggested that GNAO1 haploinsufficiency may be a possible mechanism underlying comparably mild dystonic presentations with an age of onset beyond childhood.1 By contrast, previous reports have associated GNAO1 variants, both missense and loss-of-function variants, mostly with severe, infantile-onset encephalopathic, and neurodevelopmental disorders (with or without hyperkinetic movements).2, 3 A causal relation between GNAO1 haploinsufficiency and dystonic conditions presenting to the adult neurology clinic remains to be confirmed. Motivated by the findings of Wirth and colleagues, we reassessed our in-house dystonia cohort with 1100 index-case whole-exome sequencing data sets4, 5 for the presence of rare GNAO1 variants. In addition to a set of four de novo missense changes causing previously published complex pediatric dystonia syndromes,4, 5 we observed a heterozygous interstitial deletion at 16q12.2 (61 kb) affecting the coding exons 4–8 of GNAO1 (NM_020988.3) in 2 first-degree relatives (mother and daughter) with unresolved disease (Fig. 1). This copy-number variation, one of the smallest GNAO1-disrupting 16q12.2 microdeletions reported to date,1, 6, 7 was initially considered to be of uncertain significance, as a relationship between heterozygous loss of GNAO1 and our patients' phenotypes had not been established. Individual I (mother) developed slowly progressive head tremor around the age of 40 years. There was no history of developmental delay or epileptic seizures. Neurological examination at age 53 revealed cervical dystonia with a marked phasic component and abnormal rotation toward the right side (45°). In addition, she showed dysarthria and dystonic posturing as well as myoclonic movements of shoulder-girdle muscles (left > right). Botulinum toxin injections were partially beneficial. Family history was positive for dystonia, with an affected father (unavailable for assessment) and an affected daughter. Individual II (daughter) first reported dystonic symptoms at age 16 . Although early neurodevelopment was normal, she had learning difficulties in elementary school, requiring special needs education. At age 17, she experienced a generalized tonic–clonic seizure. Brain magnetic resonance imaging was normal, whereas electroencephalogram showed generalized spike–wave activity. Subsequently, she remained seizure-free under medication with lamotrigine. Neurological examination at age 20 showed cervical dystonia with a 30° leftward rotation and a pronounced phasic component; she also exhibited latero- and retrocollis. Overall, our mother–daughter pair manifested familial nonprogressive dystonia with onset in late adulthood/adolescence and only minor neurological comorbidity, presentations that are frequently observed in daily outpatient care and often remain genetically undiagnosed. Our report substantiates the recent observation that GNAO1 loss-of-function variants can be associated with comparably mild dystonic phenotypes with or without comorbid epilepsy,1 which has important implications for genetic testing and counseling. Moreover, our findings highlight a notable degree of intrafamilial variability in dominant GNAO1-mutated pedigrees, especially regarding age at dystonia onset and accompanying epileptic manifestations. Open Access funding enabled and organized by Projekt DEAL. M.K. drafted the manuscript and was involved in clinical and genetic data interpretation. R.S. was responsible for clinical management of the patients. T.S. was involved in clinical and genetic diagnostic workup of the patients. M.Z. proposed and supervised the manuscript and performed genetic data analysis. MK: conception and design, data acquisition and analysis, drafting of the text. RS: data acquistion and analysis, revising of the text. TS: data acquisition and analysis, revising of the text. and MZ: conception and design, data acquisition and analysis, drafting and editing of the text. The data that support the findings of this study are available from the corresponding author upon reasonable request.