Clinical exome sequencing in early‐onset generalized dystonia and large‐scale resequencing follow‐up

Abstract

Our study identified whole-exome sequencing as an effective strategy for molecular diagnosis of early-onset generalized dystonia and offers insights into the heterogeneous genetic architecture of this condition. Furthermore, it provides confirmatory evidence for a dystonia-relevant role of ANO3 and ADCY5, both of which likely associate with a broader spectrum of dystonic expressions than previously thought. © 2016 International Parkinson and Movement Disorder Society.

ADCY5-related dyskinesia presenting as familial myoclonus-dystonia

“…Interestingly, this severely affected nonverbal and nonambulant patient received no therapeutic benefit from propranolol or from any other drug. However, the patients in this study did appear to benefit from deep-brain stimulation (DBS), as did another p.418W patient reported by Meijer et al [14]. Zech et al [15] identified seven early-onset generalised dystonia cases with novel ADCY5 mutations (c.2180G>A; p. R727K; c.1378A>T, p. I460F; c.1196C>T, p. P399L; c.1400A>G, p. N467S; c.3177_3182delTGA, p. D1060del; c.3625A>G, p. M1209V) [14].…”

“…However, the patients in this study did appear to benefit from deep-brain stimulation (DBS), as did another p.418W patient reported by Meijer et al [14]. Zech et al [15] identified seven early-onset generalised dystonia cases with novel ADCY5 mutations (c.2180G>A; p. R727K; c.1378A>T, p. I460F; c.1196C>T, p. P399L; c.1400A>G, p. N467S; c.3177_3182delTGA, p. D1060del; c.3625A>G, p. M1209V) [14]. Notably, the authors of this report highlight that the ADCY5 clinical spectrum may extend to isolated and focal dystonia presentations.…”

“…D1060del58 years++1 Sporadic1c.3625A>Gp. M1209 V53 years++Meijer et al [14]1 Sporadic1p. R418W<1 year++++++++Impaired vertical eye movementsDisturbed sleepWesten-berger et al [16]1 Sporadic1c.3045C>Ap.…”

KMT2B rare missense variants in generalized dystonia

“…To identify genetic variants responsible for the probands' phenotypes via a nontargeted approach, whole‐exome sequencing (WES) was conducted on genomic DNA from all probands using the SureSelect All Exon system (Agilent Technologies, Santa Clara, California) for exome capture and the HiSeq2500 platform (Illumina, San Diego, California) for sequencing. Sequence alignment, genotype calling, and variant annotation were performed as described earlier . In probands 1 and 2, parental DNA samples were included for trio‐based WES analysis, and de novo alterations were extracted using validated in‐house scripts .…”

“…Generalized dystonia has a strong, albeit considerably variable genetic basis . Despite the introduction of powerful sequencing techniques, a substantial proportion of cases remain genetically unsolved . Recently, we and an independent team delineated a novel autosomal‐dominant generalized dystonia syndrome, characterized molecularly by a monoallelic defect in the epigenetic regulator gene KMT2B (Mendelian Inheritance in Man (MIM): 606834).…”