PMC9842662_01
(A) Pedigree of a Malaysian family of Sri Lankan Tamil ethnicity with MC showing the segregation of the CLCN1 c.1667T>A (p.I556N) likely pathogenic variant. The variant is present in Patient 1 (IV:3), Patient 2 (IV:2), and their asymptomatic children. The variant was absent in Patient 2's wife (IV:1), all paternal (III:3, III:4, and III:8) and maternal (III:18 and III:19) siblings, and maternal great aunt of the proband (II:5). The arrow indicates the proband who underwent WES. Other family members were only genotyped for the specific variant. (B) Sanger sequencing electropherograms showing the wild-type (IV:1) and mutant sequence in Patient 1 (IV:3), Patient 2 (IV:2), and their respective children (V:1, V:2, and V:3). The asterisk denotes the heterozygous substitution of T to A. Individuals in each generation of the pedigree are numbered consecutively from left to right. Circles indicate females; squares indicate males. Solid symbols indicate the affected individual with MC, open symbols indicate family members showing a normal phenotype, black dots indicate asymptomatic carriers, and the arrow designates the proband.
fgene-13-972007-g001.jpg
PMC9842662_03_fgene-13-972007-g001.jpg
F1
MC symptoms were not reported in the remaining family members of patients 1 and 2, i.e., the deceased parents, the maternal and paternal siblings, and the maternal great aunt (Figure 1).
PMC9842662_02
(A) Pedigree of a Malaysian family of Sri Lankan Tamil ethnicity with MC showing the segregation of the CLCN1 c.1667T>A (p.I556N) likely pathogenic variant. The variant is present in Patient 1 (IV:3), Patient 2 (IV:2), and their asymptomatic children. The variant was absent in Patient 2's wife (IV:1), all paternal (III:3, III:4, and III:8) and maternal (III:18 and III:19) siblings, and maternal great aunt of the proband (II:5). The arrow indicates the proband who underwent WES. Other family members were only genotyped for the specific variant. (B) Sanger sequencing electropherograms showing the wild-type (IV:1) and mutant sequence in Patient 1 (IV:3), Patient 2 (IV:2), and their respective children (V:1, V:2, and V:3). The asterisk denotes the heterozygous substitution of T to A. Individuals in each generation of the pedigree are numbered consecutively from left to right. Circles indicate females; squares indicate males. Solid symbols indicate the affected individual with MC, open symbols indicate family members showing a normal phenotype, black dots indicate asymptomatic carriers, and the arrow designates the proband.
fgene-13-972007-g001.jpg
PMC9842662_03_fgene-13-972007-g001.jpg
F1
MC symptoms were not reported in the remaining family members of patients 1 and 2, i.e., the deceased parents, the maternal and paternal siblings, and the maternal great aunt (Figure 1).
Muscle hypertrophy on the right (A) and left (B) bilateral biceps and right (C) and left calves (D) in Patient 1 (IV:3).
fgene-13-972007-g002.jpg
PMC9842662_02_fgene-13-972007-g002.jpg
F2
Physical examination revealed muscle hypertrophy (athletic appearance) of the bilateral biceps and calves (Figure 2) with a mild myotonic reflex of the hands (percussion and handgrip).
Repeated short exercise test (SET) in MC patients with the c.1667T>A (p.I556N) variant on the CLCN1 gene. Changes in compound muscle action potential (CMAP) amplitude in the left ulnar nerve following three successive short exercises at room temperature in two heterozygous MC patients ( ) and three heterozygous asymptomatic carriers ( ). SET shows an initial decrement in CMAP, which subsequently improves (Fournier pattern II) in heterozygous MC patients. The amplitude of CMAP, expressed as a percentage of its value before the trials, is plotted against the time elapsed after the first exercise trials. Symbols and vertical bars represent mean +- SEM.
fgene-13-972007-g003.jpg
PMC9842662_03_fgene-13-972007-g003.jpg
F3
SET also showed Fournier pattern II (Figure 3) with no differences noted after cooling. Furthermore, the children's SET results did not show a reduction in CMAP post-exercise (Figure 3), and they all had normal creatine kinase levels (< 201 U/L).
PMC9842662_03
(A) Pedigree of a Malaysian family of Sri Lankan Tamil ethnicity with MC showing the segregation of the CLCN1 c.1667T>A (p.I556N) likely pathogenic variant. The variant is present in Patient 1 (IV:3), Patient 2 (IV:2), and their asymptomatic children. The variant was absent in Patient 2's wife (IV:1), all paternal (III:3, III:4, and III:8) and maternal (III:18 and III:19) siblings, and maternal great aunt of the proband (II:5). The arrow indicates the proband who underwent WES. Other family members were only genotyped for the specific variant. (B) Sanger sequencing electropherograms showing the wild-type (IV:1) and mutant sequence in Patient 1 (IV:3), Patient 2 (IV:2), and their respective children (V:1, V:2, and V:3). The asterisk denotes the heterozygous substitution of T to A. Individuals in each generation of the pedigree are numbered consecutively from left to right. Circles indicate females; squares indicate males. Solid symbols indicate the affected individual with MC, open symbols indicate family members showing a normal phenotype, black dots indicate asymptomatic carriers, and the arrow designates the proband.
fgene-13-972007-g001.jpg
PMC9842662_03_fgene-13-972007-g001.jpg
F1
MC symptoms were not reported in the remaining family members of patients 1 and 2, i.e., the deceased parents, the maternal and paternal siblings, and the maternal great aunt (Figure 1).
Repeated short exercise test (SET) in MC patients with the c.1667T>A (p.I556N) variant on the CLCN1 gene. Changes in compound muscle action potential (CMAP) amplitude in the left ulnar nerve following three successive short exercises at room temperature in two heterozygous MC patients ( ) and three heterozygous asymptomatic carriers ( ). SET shows an initial decrement in CMAP, which subsequently improves (Fournier pattern II) in heterozygous MC patients. The amplitude of CMAP, expressed as a percentage of its value before the trials, is plotted against the time elapsed after the first exercise trials. Symbols and vertical bars represent mean +- SEM.
fgene-13-972007-g003.jpg
PMC9842662_03_fgene-13-972007-g003.jpg
F3
SET also showed Fournier pattern II (Figure 3) with no differences noted after cooling. Furthermore, the children's SET results did not show a reduction in CMAP post-exercise (Figure 3), and they all had normal creatine kinase levels (< 201 U/L).