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Table 1 Confirmed diagnoses made by exome sequencing

From: Exome sequences versus sequential gene testing in the UK highly specialised Service for Limb Girdle Muscular Dystrophy

ID gene c.DNA change* Protein change Reported Segregation studies / Reverse phenotyping investigations
5 TTN c.107840 T > A p.(Ile35947Thr) reported Present in 3 affected family members / muscle MRI and MB re-analysis: findings consistent with titinopathy
9 COL6A1 c.957G > T p.(Lys319Asn) reported De novo / Repeated Sanger sequencing in DNA extracted from blood and from cultured fibroblasts demonstrates presence of mutation at low level consistent with mosaicism – see text and Fig. 3
13 PIEZO2 c.2136C > A p.(Met712Ile) novel Present in 4 affected family members / Phenotype consistent with Distal Arthrogryposis Type 5
18 TTN c.48312 + 2_48,312 + 15del ExSS novel De novo ExSS; maternally inherited nonsense / MB re-analysis consistent with titinopathy
c.1933G > T p.(Glu645a) novel
19 TTN c.107377 + 1G > A ESS reported Variants inherited in trans / MB re-analysis consistent with titinopathyb
c.97863G > A p.(Trp32621a) novel
23 TTN c.50170C > T p.(Arg16724a) novel novel Both variants present in two affected siblings, and confirmed in trans / MB re-analysis consistent with titinopathy
c.19091G > A p.(Cys6364Tyr)
25 GMPPB c.860G > A p.(Arg287Gln) p.(Cys113Tyr) reported novel Segregation not possible / MB consistent with dystroglycanopathy
c.338G > A
26 LAMA2 c.611C > T p.(Ser204Phe) novel novel Both variants present in 2 affected siblings, parental DNA not available / MRI brain demonstrated white matter changes, skin biopsy immunoanalysis demonstrated laminin α2 partial absence (previously reported [57])
c.4533delT p.(Gly1512Alafsa83)
  TTN c.107377 + 1G > A ESS reported novel Both variants present in 2 affected siblings and confirmed in trans / MB re-analysis consistent with titinopathyb
29
c.98603delT p.(Phe32868Serfsa11)
30 MYH7     Present in 2 affected family members and one with non-penetrance / MB reassessment
c.5533 N > T p.(Arg1845Trp) reported
32 LAMA2 c.6992 + 5G > A ExSS novel c.2049_2050delAG maternally inherited, paternal DNA not available / MRI brain demonstrated white matter changes, skin biopsy immunoanalysis demonstrated laminin α2 partial absence
c.2049_2050delAG p.(Arg683fs) novel
  MEGF10 c.2049_2050delAG p.(Arg683Serfsa21) reported Segregation in unaffected siblings consistent with AR inheritance in trans / MB re-analysis, muscle MRI
36 c.352 T > C p.Cys118Arg p.(Cys118Arg) novel
   c.1426 + 1G > T ESS novel Segregation in unaffected siblings consistent with AR inheritance / CAPN3 sequenced in prior testing: at that time c.1746-20C > G was classified as a benign polymorphism and c.759_761delGAA was not detected by Sanger sequencing
39 CAPN3 c.759_761delGAA c.1746-20C > G p.(Lys254del) reported
ExSS reported
47 COL6A1 c.362A > G p.(Lys121Arg) reported Present in 5 affected family members / muscle MRI consistent with COL6-RD
49 VCP c.329 N > A p.(Arg110His) reported Present in 4 affected family members / no additional investigations required
52 COL6A3 c.6265G > C p.(Gly2089Arg) novel Present in 2 affected family members / no additional investigations required
56 STIM1 c.242G > A p.(Gly81Asp) reported De novo / MB re-analysis, USS abdomen, biochemistry and haematology parameters assessment identified abnormalities consistent with STIM1 mutation (reported separately [58])
57 LMNA c.746G > A p.(Arg249Gln) reported De novo / no additional investigations required
59 DNM2 c.1684_1686delAAG p.(Lys562del) reported De novo / MB review
61 TTN c.107377 + 1G > A ESS reported Maternally inherited nonsense, paternal DNA not available / CT of lower limb muscles and phenotype reviewb
c.87529A > T p.(Lys29177a) novel
62 STIM1 c.262A > G p.(Ser88Gly) novel De novo / MB re-analysis, USS abdomen, biochemistry and haematology parameters assessment identified abnormalities consistent with STIM1 mutation (reported separately [58])
65 CAV3 c.136G > A p.(Ala46Thr) reported Present in two affected family members / Additional immunoanalysis of muscle biopsy demonstrated absence of caveolin 3
67 MTM1 c.1054-2_1054-1delinsTT ESS novel Segregation not possible / X-inactivation studies demonstrated skewed X-inactivation, muscle MRI and MB review consistent with MTM1 manifesting carrier phenotype
71 DYSF c.895 N > C p.(Gly299Arg) reported Consistent with AR inheritance in trans / MB review and repeat immunoanalysis
  c.2875C > T p.(Arg959Trp) reported
75 SGCG c.787G > A (Hom) p.(Glu263Lys) reported Homozygous in 2 affected siblings and heterozygous in parents and unaffected sibling / Variant was detected by prior testing but classified as of uncertain clinical significance. Muscle biopsy was of inadequate quality to perform immunoanalysis but phenotype in accordance with this diagnosis
  1. aAll reported variants are heterozygous except where indicated as Hom – homozygous
  2. bThree families with a shared phenotype and mutation in TTN have been reported separately [30]. ESS – essential splice site; ExSS – extended spice site; MB re-analysis –including additional relevant Immunoanalysis; MB review – no additional immunoanalysis performed. Reference sequences: CAPN3 ENST00000397163; CAV3 ENST00000343849; COL6A1 ENST00000361866; COL6A3 ENST00000295550; DNM2 ENST00000389253; DYSF ENST00000258104; GMPPB ENST00000308375; LAMA2 ENST00000421865; LMNA ENST00000368300; MEGF10 ENST00000508365; MTM1 ENST00000370396; MYH7 ENST00000355349; PIEZO2 ENST00000580640; SCN9A ENST00000409672; SLC2A1 ENST00000426263; STIM1 ENST00000300737; TTN ENST00000589042; VCP ENST00000417448
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Orphanet Journal of Rare Diseases

ISSN: 1750-1172