High frequency of multiexonic deletion of the GCH1 gene in a Taiwanese cohort of dopa-response dystonia

• Published in: American journal of medical genetics. Part B, Neuropsychiatric genetics Neuropsychiatric genetics, 2010-06, Vol.153B (4), p.903-908
• Main Authors: Wu-Chou, Yah-Huei, Yeh, Tu-Hsueh, Wang, Chuan-Yu, Lin, Juei-Jueng, Huang, Chin-Chang, Chang, Hsiu-Chen, Lai, Szu-Chia, Chen, Rou-Shayn, Weng, Yi-Hsin, Huang, Chia-Ling, Lu, Chin-Song
• Format: Article
• Language: English
• Subjects: Adult; Asian Continental Ancestry Group - genetics; Biological and medical sciences; Case-Control Studies; Cohort Studies; Dihydroxyphenylalanine - genetics; Dystonia; Dystonia - genetics; Dystonic Disorders - genetics; Ethnic groups; Exons; Female; GCH1 deletion; Gene deletion; Heterozygote; Humans; Male; Medical genetics; Medical sciences; MLPA; Movement disorders; Mutation; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurodegenerative diseases; Neurology; Parkinson Disease - genetics; Parkinson's disease; Pathology, Molecular; Penetrance; Polymerase chain reaction; Probes; qPCR; Segawa's disease; Sequence Deletion - genetics; tremor
• ISSN: 1552-4841; 1552-485X; 1552-485X
• DOI: 10.1002/ajmg.b.31058

Large deletions in the GCH1 gene have been reported in a minority of cases of dopa‐responsive dystonia (DRD). In this study, we performed an extensive clinical and genetic investigation of 22 affected members in eight families. Sequence analysis revealed five different mutations in five families (n = 10); Ser81Pro (novel), Ser76X, Gly203Arg, 249del A, and IVS5 + 3insT. Applying multiple ligation‐dependent probe amplification analysis, we detected a large heterozygous deletion of exons 1–3 in the remaining three families (n = 12), which was verified by quantitative real‐time PCR analysis. Therefore, the large deletion accounted for 37.5% of the total families and 55% of our DRD population. The deletion appeared to have high penetrance and was associated with multifocal dystonia and adult onset in males. Adult‐onset patients were commonly presenting with resting tremor, rigidity, and bradykinesia, indistinguishable from those in Parkinson's disease. In conclusion, a high frequency of multiexonic deletion of GCH1 was identified in the Taiwanese DRD population. By dosage analysis, we were able to detect a mutation in all patients. Our study demonstrates that dosage analysis is necessary for molecular diagnostics in DRD patients of Han Chinese ethnicity. © 2010 Wiley‐Liss, Inc.