Table 1 Confirmed diagnoses made by exome sequencing

TTN

c.107840 T > A

p.(Ile35947Thr)

reported

Present in 3 affected family members / muscle MRI and MB re-analysis: findings consistent with titinopathy

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

PIEZO2

c.2136C > A

p.(Met712Ile)

novel

Present in 4 affected family members / Phenotype consistent with Distal Arthrogryposis Type 5

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.(Glu645^a)

novel

TTN

c.107377 + 1G > A

ESS

reported

Variants inherited in trans / MB re-analysis consistent with titinopathy^b

c.97863G > A

p.(Trp32621^a)

novel

TTN

c.50170C > T

p.(Arg16724^a)

novel novel

Both variants present in two affected siblings, and confirmed in trans / MB re-analysis consistent with titinopathy

c.19091G > A

p.(Cys6364Tyr)

GMPPB

c.860G > A

p.(Arg287Gln) p.(Cys113Tyr)

reported novel

Segregation not possible / MB consistent with dystroglycanopathy

c.338G > A

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.(Gly1512Alafs^a83)

TTN

c.107377 + 1G > A

ESS

reported novel

Both variants present in 2 affected siblings and confirmed in trans / MB re-analysis consistent with titinopathy^b

c.98603delT

p.(Phe32868Serfs^a11)

MYH7

Present in 2 affected family members and one with non-penetrance / MB reassessment

c.5533 N > T

p.(Arg1845Trp)

reported

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.(Arg683Serfs^a21)

reported

Segregation in unaffected siblings consistent with AR inheritance in trans / MB re-analysis, muscle MRI

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

CAPN3

c.759_761delGAA c.1746-20C > G

p.(Lys254del)

reported

ExSS

reported

COL6A1

c.362A > G

p.(Lys121Arg)

reported

Present in 5 affected family members / muscle MRI consistent with COL6-RD

VCP

c.329 N > A

p.(Arg110His)

reported

Present in 4 affected family members / no additional investigations required

COL6A3

c.6265G > C

p.(Gly2089Arg)

novel

Present in 2 affected family members / no additional investigations required

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])

LMNA

c.746G > A

p.(Arg249Gln)

reported

De novo / no additional investigations required

DNM2

c.1684_1686delAAG

p.(Lys562del)

reported

De novo / MB review

TTN

c.107377 + 1G > A

ESS

reported

Maternally inherited nonsense, paternal DNA not available / CT of lower limb muscles and phenotype review^b

c.87529A > T

p.(Lys29177^a)

novel

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])

CAV3

c.136G > A

p.(Ala46Thr)

reported

Present in two affected family members / Additional immunoanalysis of muscle biopsy demonstrated absence of caveolin 3

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

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

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