Confirmation of a Causal Role for <i>SHQ1</i> Variants in Early Infantile‐Onset Recessive Dystonia

Abstract

An overarching goal of genetics research in dystonia is the definition of converging molecular pathways, allowing grouping of patients according to disease biology rather than phenomenology.1 This may improve the development of stratification schemes and contribute to the transition from empiric selection of treatments to etiology-directed therapeutics. One downstream mechanistic effect shared by different mutant dystonia-associated gene products includes the perturbation of translational control.1 For example, abnormalities in eIF2α-signaling, induced by mutations in EIF2AK2 or PRKRA, are considered to result in aberrant protein synthesis via translation-initiation impairments.2 Most recently, Sleiman and colleagues have introduced a new player in translational defect-mediated dystonia, SHQ13; the gene encodes a component of the H/ACA–ribonucleoprotein complex, responsible for the modification of various RNA species, including those that regulate protein synthesis in the ribosome.4 Although two SHQ1-mutated families with dystonia have been described,3 the gene–phenotype relationship has not yet been firmly established.5 We have prioritized compound heterozygous SHQ1 variants, c.523G>T (p.Asp175Tyr) and c.828_831del (p.Asp277Serfs*27), in whole-exome sequencing data of a female study proband with infantile-onset dystonia (Table 1); these variants remained of uncertain significance during initial analysis (August 2021).6 Eventually, bioinformatics pipeline-based (re-) assessment of latest literature/ClinVar data revealed that our candidate SHQ1 variants were identical to mutations observed in one of the families reported by Sleiman and colleagues.3 These published carriers of c.523G>T/c.828_831del developed dystonia before the age 6 months, with diurnal fluctuations and partial response to levodopa.3 Similarly, our proband manifested dystonia in her first months of life, and the disorder was levodopa responsive. Her motor milestones were delayed. Over time, movement abnormalities evolved into a more complex pattern, and she experienced a generalized tonic–clonic seizure at age 14 years. On recent examination, she displayed a mixed hyperkinetic disorder characterized by dystonia, myoclonus, and chorea affecting the limbs, trunk, and facial region (Video S1). There was worsening of hyperkinesia in the evening, cognitive impairment, and truncal hypotonia, leading to an initially suspected diagnosis of ADCY5-related dyskinesia.1 All routine diagnostic studies were unrevealing except for an isolated moderate decrease in HVA levels in cerebrospinal fluid. SHQ1 variants RefSeq transcript: NM_018130.3 HVA: 277 nmol/L (normal: 300–1000 nmol/L) 5-HIAA: 239 nmol/l (normal: 200–600 nmol/l) HVA: 0.32 nmol/L (normal: 0.49–0.66 nmol/L) 5-HIAA: 0.26 nmol/L (normal: 0.19–0.30 nmol/L) HVA: 174 nmol/L (normal: 233–928 nmol/L) 5-HIAA: 105 nmol/L (normal: 74–345 nmol/L) HVA: 194 nmol/L (normal: 294–1115 nmol/L) 5-HIAA: 172 nmol/L (normal: 129–520 nmol/L) Recurrence of c.523G>T/c.828_831del in two separate dystonia-affected families provides strong evidence for pathogenicity of these variants. Moreover, c.828_831del has been detected in combination with another SHQ1 mutation in a third family3 (Table 1). Observing the same set of compound-heterozygous alleles in two nonrelated pedigrees is an uncommon finding and could be explained by the population frequency of the variants. Notably, both c.523G > T and c.828_831del are very rare but observed in an appreciable number of gnomAD controls (Table 1); c.523G>T is even found in 1 gnomAD individual in the homozygous state, indicating that it could represent a hypomorphic allele.3 We expect that SHQ1-associated dystonia is underdiagnosed and may have been ignored in some exome-sequenced cases analyzed using standard filter settings (often removing variants present in homozygous controls).7 Our report provides replication for the involvement of SHQ1 in autosomal recessive early-onset dystonia, which appears to be a more complex and progressive movement disorder. SHQ1 should be added to the compendium of dystonia-associated genes involved in translational control, expanding our understanding of common molecular themes in dystonia pathogenesis. We thank the patient and her family for their generous participation and permission to publish this case. We thank Philip Harrer, Institute of Neurogenomics (Helmholtz Zentrum München), for assistance with processing of video material. Open Access funding enabled and organized by Projekt DEAL. E.I.: acquisition of data, clinical examination, analysis and interpretation of data, and revision of manuscript for critical intellectual content. S.B.: study design and concept, acquisition of data, clinical examination, analysis and interpretation of data, and revision of manuscript for critical intellectual content. M.B.: acquisition of data, clinical examination, and revision of manuscript for critical intellectual content. B.P.: acquisition of data, clinical examination, and revision of manuscript for critical intellectual content. J.W.: study supervision and revision of manuscript for critical intellectual content. M.Z.: study design and concept, study supervision, analysis and interpretation of data, and wrote manuscript. Nothing to report. Full data set available from the corresponding author upon request. Video S1. Our patient with SHQ1 variants presented with a mixed hyperkinetic disorder comprising dystonic, choreatic, and myoclonic elements; note task-(gait)-specific dystonic mobile anterocollis (anterocapus). Rapid dystonic movements (right upper limb) and tics (mainly cervical) observed in the third segment of the video may be, in part, a consequence of levodopa chronic therapy. During infancy and early childhood, dystonia was the predominant movement disorder. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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