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Table 1 Diagnostic variant observed following exome filtering and interpretative assessment after re-analysis

From: Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases

Case description and initial exome analysis
 Primary clinical features at referralSeizures; decreased white brain matter; neuropathyGlobal developmental delay; microcephaly; intellectual disabilityShort stature with deformities of lower extremities; muscle tone decreased throughout; spine with mild scoliosisHistory of depressive disorder and anxiety; seizures; sudden death
 Exome quality metricsAverage coverage: 83.7XAverage coverage: 101.3XAverage coverage: 78XAverage coverage: 118X
% of covered bases at ≥ 20x: 93.8%% of covered bases at ≥ 20x: 92.4%% of covered bases at ≥ 20x: 94%% of covered bases at ≥ 20x: 95.7%
 Initial exome interpretationNo clinically relevant variant (2015)No clinically relevant variant (2016)No clinically relevant variant (2017)No clinically relevant variant (2016)
Exome reanalysis
 Candidate variant (Hg19)chr1:154,560,601 G > Achr12:109,921,417 G > T; chr12:109,948,147 A > Gchr17:76,993,476 A > AG; chr17:76991236 C > Achr12:111,348,980 G > C
 HGVS NomenclatureNM_001111.5 (ADAR):c.3019  G > ANM_130466.4 (UBE3B):c.61 G > T; NM_130466.4 (UBE3B)c.1742-2 A > GNM_001159773.2 (CANT1):c.228dupC; NM_001159773.2 (CANT1)c.699 G > TNM_000432.3 (MYL2):c.403-1 G > C
 ACMG/AMP CriteriaPS1- strong; PS3-strong; PM2-moderatePVS1 (c.1742-2A>G; c.61G>T); PS1- strong (c.61G>T); PM2-moderate (c.1742-2A>G; c.61G>T)PVS1 (c.228dupC); PS3- strong (c.228dupC); PM2-moderate (c.228dupC; c.699 G > T); PP3-supporting (c.699  G > T); PP2-supporting (c.699  G > T)PVS1; PS3- strong; PM2-moderate
 Re-analysis assessmentPathogenic (DV)Pathogenic (DV; c.61G>T); likely pathogenic (DV; c.1742-2A>G)Pathogenic (DV; c.228dupC); possibly pathogenic (PDV; c.699 G > T)Pathogenic (DV)
 Diagnosis (OMIM)Aicardi-Goutieres Syndrome 6 (615010) [32]Kaufman Oculocerebrofacial Syndrome (244450) [33]Multiple epiphyseal dysplasia 7 (617719); Desbuquois dysplasia 1 (251450) [34]Familial hypertrophic cardiomyopathy 10 (608758) [35]
 PrognosisHeterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon. Death often occurs in early childhood.Unusually small head size (microcephaly), structural abnormalities of the brain. Affected individuals have weak muscle tone (hypotonia) and are delayed in developing motor skills such as walking. Intellectual disability is severe or profound.Mixture of the features observed in MED and DD. MED is a disorder of cartilage and bone development, primarily affecting the ends of the long bones in the arms and legs. DD is a more severe form of chondrodysplasia overall.Alteration of cardiac contraction which provoked changes in myofibrillar Ca2+ sensitivity, subsequently it could lead to diastolic dysfunction and sensitivity to dysrhythmias, which at times cause sudden death.