PurposeWe sought to determine the analytical sensitivity of several extended exome variation analysis approaches in terms of their contribution to diagnostic yield and their clinical feasibility.MethodsWe retrospectively analyzed the results of genetic testing in 1,059 distinct cases referred for exome sequencing to our institution. In these, we routinely employed extended exome analysis approaches in addition to basic variant analysis, including (i) copy-number variation (CNV) detection, (ii) nonconsensus splice defect detection, (ii) genomic breakpoint detection, (iv) homozygosity mapping, and (v) mitochondrial variant analysis.ResultsExtended exome analysis approaches assisted in identification of causative genetic variant in 44 cases, which represented a 4.2% increase in diagnostic yield. The greatest contribution was associated with CNV analysis (1.8%) and splice variant prediction (1.2%), and the remaining approaches contributed an additional 1.2%. Analysis of workload has shown that on average nine additional variants per case had to be interpreted in the extended analysis.ConclusionWe show that extended exome analysis approaches improve the diagnostic yield of heterogeneous genetic disorders and result in considerable increase of diagnostic yield of exome sequencing with a minor increase of interpretative workload.
impaired superior colliculus activation, by fMRI, in cervical dystonia and their relatives with abnormal TDTs response to looming visual stimuli. 10 We consider that further interrogation of the role of superior collicular processing in cervical dystonia is warranted. References1. Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord 2013;28:863-873. 2. Williams L, McGovern E, Kimmich O, et al. Epidemiological, clinical and genetic aspects of adult onset isolated focal dystonia in Ireland. Eur J Neurol 2017;24:73-81. 3. Ceballos-Baumann AO, Passingham RE, Warner T, Playford ED, Marsden CD, Brooks DJ. Overactive prefrontal and underactive motor cortical areas in idiopathic dystonia. Ann Neurol 1995;37:363-372. 4. Huang YZ, Rothwell JC, Lu CS, Wang J, Chen RS. Restoration of motor inhibition through an abnormal premotor-motor connection in dystonia. Mov Disord 2010;25:696-703. 5. Levy LM, Hallett M. Impaired brain GABA in focal dystonia. Ann Neurol 2002;51:93-101. 6. Tisch S, Limousin P, Rothwell JC, et al. Changes in blink reflex excitability after globus pallidus internus stimulation for dystonia. Mov Disord 2006;21:1650-1655. 7. Bradley D, Whelan R, Kimmich O, et al. Temporal discrimination thresholds in adult-onset primary torsion dystonia: an analysis by task type and by dystonia phenotype.
Several patients with rare genetic disorders remain undiagnosed following comprehensive diagnostic testing using whole-exome sequencing (WES). In these patients, pathogenic genetic variants may reside in intronic or regulatory regions or they may emerge through mutational mechanisms not detected by WES. For this reason, we implemented whole-genome sequencing (WGS) in routine clinical diagnostics of patients with undiagnosed genetic disorders and report on the outcome in 30 patients. Criteria for consideration included (1) negative WES, (2) a high likelihood of a genetic cause for the disorders, (3) positive family history, (4) detection of large blocks of homozygosity or (5) detection of a single pathogenic variant in a gene associated with recessive conditions. We successfully discovered a causative genetic variant in 6 cases, a retrotranspositional event in the APC gene, non-coding variants in the intronic region of the OTC gene and the promotor region of the UFM1 gene, repeat expansion in the RFC1 gene and a single exon duplication in the CNGB3 gene. We also discovered one coding variant, an indel, which was missed by variant caller during WES data analysis. Our study demonstrates the impact of WGS in the group of patients with undiagnosed genetic diseases after WES in the clinical setting and the diversity of mutational mechanisms discovered, which would remain undetected using other methods.
By converting physical forces into electrical signals or triggering intracellular cascades, stretch-activated ion channels (SACs) allow the cell to respond to osmotic and mechanical stress. Knowledge of the pathophysiological mechanisms underlying associations of SACs with human disease is limited. Here we describe 16 unrelated patients, with severe early onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment, associated with progressive neurodegenerative brain changes carrying ten distinct de novo variants of TMEM63B. Variants were missense, including the recurrent V44M in 7/16 patients, or in-frame, and affected highly conserved residues located in transmembrane regions of the protein. In 12 patients, haematological abnormalities co-occurred, such as macrocytosis and haemolysis, requiring blood transfusions in some. We modelled V44M, R443H, and T481N in transfected Neuro2a cells and demonstrated leak inward cation currents across the mutated channel even in isotonic conditions, while the response to hypo-osmotic challenge was impaired, as were the Ca2+ transients generated under hypo-osmotic stimulation. Ectopic expression of the V44M and G580C variants in Drosophila resulted in early death. TMEM63B-associated DEE represents a novel clinicopathological entity in which altered cation conductivity results in a severe neurological phenotype with progressive brain damage and early onset epilepsy, associated with haematological abnormalities in most patients.
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