CaseJO: Female, 56 yrs onset

CasePresentingHPOs: HP:0002326, HP:0003236, HP:0001712, HP:0003458, HP:0012548, HP:0030197, HP:0003557, HP:0031237 (Transient ischemic attack, Elevated serum creatine kinase, Left ventricular hypertrophy, EMG: myopathic abnormalities, Fatty replacement of skeletal muscle, Fatigable weakness of skeletal muscles, Increased variability in muscle fiber diameter, Internally nucleated skeletal muscle fibers)

HPOsFreeText: N/A

CaseNotHPOs: HP:0030972, HP:0030177 (Abnormal systemic blood pressure, Abnormal nerve conduction study)

NotHPOsFreeText: N/A

CaseAddInfo: Proband is homozygous for this variant

CasePreviousTesting: No family history suggestive of neuromuscular or cardiac disorders

CaseGenotypingMethod: Leukocyte-derived DNA was examined via NGS sequencing with 265 genes and shown to carry a homozygous nonsense mutation in TRIM63. TRIM54 was examined and no variants were found.

Variant: NM_032588.3(TRIM63):c.739C>T (p.Gln247Ter)

ClinVar: 222849, https://www.ncbi.nlm.nih.gov/clinvar/variation/222849/

gnomAD: 0.008100, https://gnomad.broadinstitute.org/variant/1-26384973-G-A

Case: Male, 15 yrs onset

CasePresentingHPOs: HP:0002875, HP:0001639, HP:0009073, HP:0003551, HP:0001962, HP:0004749, HP:0003758, HP:0003306, HP:0003712, HP:0003691, HP:0003184, HP:0002515, HP:0001265, HP:0003236, HP:0003458, HP:0012548, HP:0031295, HP:0006699, HP:0002375, HP:0012664, HP:0001685, HP:0032341, HP:0003557 (Exertional dyspnea, Hypertrophic cardiomyopathy, Progressive proximal muscle weakness, Difficulty climbing stairs, Palpitations, Atrial flutter, Reduced subcutaneous adipose tissue, Spinal rigidity, Skeletal muscle hypertrophy, Scapular winging, Decreased hip abduction, Waddling gait, Hyporeflexia, Elevated serum creatine kinase, EMG: myopathic abnormalities, Fatty replacement of skeletal muscle, Left atrial enlargement, Premature atrial contractions, Hypokinesia, Reduced ejection fraction, Myocardial fibrosis, Reduced forced vital capacity, Increased variability in muscle fiber diameter)

HPOsFreeText: Difficulty lifting heavy objects, Unable to get up from the floor or stand up from a chair without support

CaseNotHPOs: HP:0000822, HP:0030319, HP:0007715 (Hypertension, Weakness of facial musculature, Weak extraocular muscles)

NotHPOsFreeText: N/A

CaseAddInfo: RT-PCR analysis indicated complete absence of TRIM63 transcripts in the proband indicating NMD, with TRIM54 expression found in muscle tissue and cultured cells

CasePreviousTesting: Treated with diltiazem 200 mg daily because he did not tolerate betablockers owing to asthenia; There were single or multiple well-circumscribed non-membrane-bound subsarcolemmal deposits in the majority of type I fibres, with partial colocalization to MyHC and MuRF3; Tested for mutations in MYH7 and gene panel involved in familial HCM (genes not provided)

CaseGenotypingMethod: Sanger sequencing was performed for the proband due to similarities found in MuRF1/MuRF3 null mice, with a homozygous nonsense variant in TRIM63 and heterozygous missense variant in TRIM54 being found. To exclude any other potential disease-causing variants, WES was performed and filtered down to nine genes with only these variants encoding muscle-specific proteins.

Variant: NM_032588.3(TRIM63):c.739C>T (p.Gln247Ter)

ClinVar: 222849, https://www.ncbi.nlm.nih.gov/clinvar/variation/222849/

gnomAD: 0.008100, https://gnomad.broadinstitute.org/variant/1-26384973-G-A?dataset=gnomad_r2_1