We describe a family with coexisting TIA1 and MYH7 variants. The proband is a 67-year-old woman with easy tripping since childhood and progressive asymmetric distal limb weakness, but no cardiac involvement.
CaseII.1: 67 year old female, proband
DiseaseAssertion: progressive asymmetric distal limb weakness - Welander distal myopathy
FamilyInfo: 66-year-old sister has a mild distal myopathy, supraventricular tachycardia and hypertrophic cardiomyopathy. Both sisters carry the only known pathogenic TIA1 mutation and a heterozygous MYH7 variant (c.5459G > A; p.Arg1820Gln). Another sibling with isolated distal myopathy carries only the TIA1 mutation.
CasePresentingHPOs: HP:0002460, HP:0003805
"distal limb weakness, rimmed vacuoles"
CaseHPOFreeText: congophilic inclusions
CaseNotHPOFreeText: cardiac involvement
CasePreviousTesting: Electromyography - showed myopathic changes in distal upper and lower limb muscles with fibrillation potentials and rare myotonic discharges. Neurological examination - asymmetric weakness limited to distal muscles.
ANO5, BAG3, CAV3, CRYAB, DES, DNAJB6, DYSF, FHL1, FLNC, GNE, LDB3, MATR3, MYH7, MYOT, TCAP, TIA1, TTN and VCP were tested, all coding regions plus 20 bp flanking non-coding regions were analyzed through a combination of targeted next generation sequencing and Sanger sequencing
MultipleGeneVariants:
(1) MYH7Variant: NM_000257.4:c.5459G>A
ClinVar: 419278
CAID: CA046848
gnomAD:https://gnomad.broadinstitute.org/variant/14-23884304-C-T
Allele Frequency: East Asian 0.00005437
(2) TIA1Variant: NM_022173.4:c.1150G>A
ClinVar: 41480
CAID: CA1697383
gnomAD: https://gnomad.broadinstitute.org/variant/2-70439862-C-T?dataset=gnomad_r2_1
Total Allele Frequency: Other 0.0001629
GenotypingMethod: Targeted next generation sequencing and Sanger sequencing