Clinically relevant copy-number variants in exome sequencing data of patients with dystonia

A Recurrent EIF2AK2 Missense Variant Causes Autosomal‐Dominant Isolated Dystonia

“…3 In an attempt to replicate the association between the EIF2AK2 c.388G > A (p.Gly130Arg) variant and dystonic presentations, we re-analyzed whole-exome sequencing data from 953 patients with various forms of dystonia. 4,5 We identified EIF2AK2 c.388G > A (p.Gly130Arg) in 1 German kindred for which exome-sequences of 3 affected subjects had been generated, but no mutations in previously reported dystonia-related genes were found (Fig A -C). The EIF2AK2 mutation finding in the present family was not reported as part of the original paper by Kuipers et al 1 The index patient (III-1), a 10-year-old girl, manifested isolated dystonia, starting in the legs at the age of 2 years and progressing to generalized dystonia with involvement of all 4 extremities, the trunk, and larynx.…”

Biallelic AOPEP Loss‐of‐Function Variants Cause Progressive Dystonia with Prominent Limb Involvement

“…The study started with the detection of a homozygous candidate variant in a participant (proband 1, family I; Fig. 1A) of a whole‐exome sequencing study of unexplained dystonias 5,7 . Inclusion criteria, recruitment, and phenotyping strategies for this study have been reported in detail elsewhere 5,7 .…”

“…All probands were exome or genome sequenced (triobased whole-exome sequencing in families I and III; singleton whole-genome sequencing in family II; duo wholegenome sequencing in family IV). Target-enrichment, high-throughput sequencing and variant screenings were performed using established procedures 4,5,7,[9][10][11][12] (for details, see Supporting Information Methods). In brief, libraries were generated using SureSelect Human All Exon V6 (families I and III), KAPA HyperPrep (family II), or NEB-Next Ultra II (family IV) kits, and sequenced on Illumina platforms.…”

De Novo Missense Mutation of VPS16 in a Chinese Patient with Generalized Dystonia with Myoclonus

“…1 Further microscopy study of patientderived lymphocytes and fibroblasts observed endosomallysosomal dysfunction, which might contribute to the pathogenesis of dystonia. 1 Since then, a few studies reported several other loss-of-function variants and microdeletions of VPS16 in patients with generalized dystonia and multifocal dystonia from different ethnicities, where myoclonus was rarely described [3][4][5][6][7] (Table S4). A missense variant of uncertain significance in a Chinese patient with segmental dystonia (cranial-cervical dystonia) was also reported.…”