Compound heterozygous variants in SHQ1 are associated with a spectrum of neurological features, including early-onset dystonia

Abstract

SHQ1 is essential for biogenesis of H/ACA ribonucleoproteins, a class of molecules important for processing ribosomal RNAs, modifying spliceosomal small nuclear RNAs, and stabilizing telomerase. Components of the H/ACA ribonucleoprotein complex have been linked to neurological developmental defects. Here we report two sibling pairs from unrelated families with compound heterozygous variants in SHQ1. Exome sequencing was used to detect disease causing variants which were submitted to ‘matching’ platforms linked to MatchMaker Exchange. Phenotype comparisons supported these matches. The affected individuals present with early-onset dystonia, with individuals from one family displaying additional neurological phenotypes, including neurodegeneration. As a result of CSF studies suggesting possible abnormal dopamine metabolism, a trial of levodopa replacement therapy was started but no clear response was noted. We show that fibroblasts from affected individuals have dramatic loss of SHQ1 protein. Variants from both families were expressed in S. cerevisiae, resulting in a strong reduction in H/ACA snoRNA production and remarkable defects in rRNA processing and ribosome formation. Our study identifies SHQ1 as associated with neurological disease, including early-onset dystonia, and begins to delineate the molecular etiology of this novel condition.

Confirmation of a Causal Role for SHQ1 Variants in Early Infantile‐Onset Recessive Dystonia

“…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 family 3 (Table 1). Observing the same set of compoundheterozygous alleles in two nonrelated pedigrees is an uncommon finding and could be explained by the population frequency of the variants.…”

“…2 Most recently, Sleiman and colleagues have introduced a new player in translational defect-mediated dystonia, SHQ1 3 ; 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.…”

“…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.…”

“…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.…”