Objective: This study aims to delineate the genetic underpinnings of a case affected by dopa-responsive dystonia (DRD), characterized by novel compound heterozygous mutations within the tyrosine hydroxylase (TH) gene.

Background: DRD represents a subset of hereditary progressive dystonia notable for their marked diurnal fluctuations. Despite extensive searches for causative mutations within established DRD-associated genes (GCH1, TH, PTS, SPR, QDPR, PCBD), a significant proportion of patients remain molecularly undiagnosed. Recent advances in whole-genome sequencing (WGS) have unveiled a plethora of pathogenic deep-intronic mutations, propelling forward the investigation into these previously unexplained cases.

Method: In pursuit of a genetic diagnosis, comprehensive clinical information was collected from the proband and their family members. Following inconclusive results from a targeted dystonia genetic panel, the proband underwent WGS. Sanger sequencing was employed to verify segregation and phasing of identified mutations. Given the peripheral blood’s lack of TH gene expression, an in vitro minigene splicing assay was utilized to evaluate the functional impact of the TH gene mutations.

Results: Manifesting with progressive difficulty in hand control and a hypotonic trunk from the age of three, the proband demonstrated significant diurnal symptom fluctuation and responded positively to levodopa. Initial analysis identified a missense mutation (c.G605A;p.R202H;NM_000360.4). Subsequent WGS revealed a novel, deep-intronic mutation (c.487+118G>A;NM_000360.4) not previously reported in the Genome Aggregation Database. This deep-intronic mutation was predicted to disrupt splicing, confirmed by aberrant intron 3 retention in minigene splicing assay results. Sanger sequencing substantiated the familial segregation and phasing of these mutations. 

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Conclusion: This study uncovers compound heterozygous mutations in the TH gene, including a previously undocumented deep-intronic mutation, in a DRD patient. Notably, this represents the first identification of a deep-intronic mutation in a DRD patient with TH mutations, highlighting the indispensable role of WGS in the genetic elucidation of DRD, particularly for those with a singular heterozygous mutation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-compound-heterozygous-and-novel-deep-intronic-th-mutations-in-a-chinese-patient-with-dopa-responsive-dystonia/