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

 Primary clinical features at referral

Seizures; decreased white brain matter; neuropathy

Global developmental delay; microcephaly; intellectual disability

Short stature with deformities of lower extremities; muscle tone decreased throughout; spine with mild scoliosis

History of depressive disorder and anxiety; seizures; sudden death

 Exome quality metrics

Average coverage: 83.7X

Average coverage: 101.3X

Average coverage: 78X

Average 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 interpretation

No clinically relevant variant (2015)

No clinically relevant variant (2016)

No clinically relevant variant (2017)

No clinically relevant variant (2016)

 Candidate variant (Hg19)

chr1:154,560,601 G > A

chr12:109,921,417 G > T; chr12:109,948,147 A > G

chr17:76,993,476 A > AG; chr17:76991236 C > A

chr12:111,348,980 G > C

 HGVS Nomenclature

NM_001111.5 (ADAR):c.3019  G > A

NM_130466.4 (UBE3B):c.61 G > T; NM_130466.4 (UBE3B)c.1742-2 A > G

NM_001159773.2 (CANT1):c.228dupC; NM_001159773.2 (CANT1)c.699 G > T

NM_000432.3 (MYL2):c.403-1 G > C

 ACMG/AMP Criteria

PS1- strong; PS3-strong; PM2-moderate

PVS1 (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 assessment

Pathogenic (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]

 Prognosis

Heterogeneous 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.