Fig. 1

Fig. 1 Pedigrees of the SRPK3/TTN myopathy families.

a, Segregation of the familial SRPK3 variants is shown. S indicates the SRPK3 variant and WT indicates the wild-type allele. Individuals presenting with skeletal muscle disease are indicated in black. Mild presentations are shown in gray (corresponding to YIII:4 and YIII:5, two female carriers with skewed X-inactivation, 80:20 and 65:35, in lymphocytes, respectively). b, Extended pedigree details of families M and Z. Individuals presenting with skeletal muscle disease are indicated in black. Cardiac involvement is indicated by gray/dotted symbols. Segregation of the familial SRPK3 (S) and TTN (T) variants is shown. S + T indicates cosegregating SRPK3/TTN variants; WT indicates both SRPK3 and TTN WT alleles. Individuals ZIV:1, ZIV:4, ZIV:6 and ZIV:7 carry the familial TTN variant (p.Arg16905*) previously reported in association with DCM (ref. ¹⁹) but are presymptomatic at ages 52, 44, 40 and 38 years old, respectively. Likewise, individual MIII:2 carries the familial TTN variant (p.Asp28805Metfs*6) but is also presymptomatic at age 46 years old. c, Cosegregation of the SRPK3 and TTN variants (S + T) with the myopathic phenotype (shown in black). All known genotypes are shown; WT, both SRPK3 and TTN WT alleles; empty symbols indicate that the sample was not available for testing (or failed testing). All affected individuals carry the SRPK3 and TTN variants (S + T), whereas their unaffected relatives carry one or the other, but never both. Two females carrying cosegregating SRPK3/TTN variants and showing a skewed X-inactivation pattern are mildly affected (YIII:4 and YIII:5), and those with random X-inactivation are unaffected (TI:2, UI:2, XII:2 and YII:2). A female carrying only the SRPK3 variant (but no TTN variant; ZII:5) and a complete X-inactivation pattern (3:97, in lymphocytes) is unaffected. Individual RI:2, with cosegregating SRPK3 and TTN variants whose fully inactivated chr X carries the SRPK3 deleterious variant, is also unaffected. Individuals RII:3 and SI:2 are noninformative for the CAG repeat analyzed in the X-inactivation assay.