case_images: PMC11381389_01
case_images: Clinical manifestation of the proband I and molecular features of DSP. (A). The proband exhibited a homozygous variant of DSG2 (c.1592T>G p.F531C) and a heterozygous variant of DSP (c.7883T>C p.L2628P). (B) The variant of DSP c.7883T>C had been reported in 1000G and ExAC, it has predicted protein damaging by MutationTaster. (C) ECG of the proband. (D, D') Echocardiography demonstrated thrombus in apex of ventricles. (E, E') CMR demonstrated cardiac enlargement and delayed enhancement. (F) The protein structure of DSP has been built based on the 5dzz.1.A template. (G) Ramachandran plots indicated that amino acid positions were altered.
case_images: fgene-15-1428796-g001.jpg
case_images: PMC11381389_03_fgene-15-1428796-g001.jpg
case_images: F1
case_images: In proband I, we confirmed a heterozygous variant of DSP c.7883T>C (p.L2628P), which was paternally inherited (Figure 1A). Several allele carriers were retrieved from the 1000G (1 heterozygous record) and ExAC (16 heterozygous records) databases (Figure 1B). Moreover, the pathogenic effects of this mutation on the protein structure were validated using a crystal structure based on the 5dzz.1.A template between the wild-type and mutant DSP (p.L2628P) amino acid sequences (Figure 1F). Ramachandran plots demonstrated that the amino acid positions were altered in the mutant (Figure 1G).
case_images: PMC11381389_02
case_images: Clinical manifestation of the proband II and molecular features of SCN5a. (A) The proband exhibited a homozygous variant of DSG2 (c.1592T>G p.F531C) and a heterozygous variant of SCN5a c.3577C>T (p.R1193W). (B) The variant of SCN5a c.3577C>T had been reported in 1000G and ExAC, it has predicted protein damaging by MutationTaster. (C) ECG of the proband. (D, D') Echocardiography demonstrated thrombus in right ventricle and cardiac enlargement, marked dilation of the right atrium and right ventricle, along with inhomogeneous thinning of the ventricular wall with delayed enhancement in the left and right ventricular wall and septum. (E) The protein structure of SCN5a has been built based on the Q14524.1.A template. (F) Ramachandran plots indicated that amino acid positions were altered.
case_images: fgene-15-1428796-g002.jpg
case_images: PMC11381389_03_fgene-15-1428796-g002.jpg
case_images: F2
case_images: In proband II, we confirmed a heterozygous variant of SCN5a c.3577C>T (p.R1193W), which was maternally inherited (Figure 2A). Several allele carriers were retrieved from the 1000G (2 heterozygous records) and ExAC (9 heterozygous records) databases (Figure 2B). The pathogenic effects of this mutation on the protein structure were validated using a crystal structure based on the Q14524.1.A template between the wild-type and mutant (p.R1193W) amino acid sequences using AlphaFold2 (Figure 2E). Ramachandran plots demonstrated that the amino acid positions in the SCN5a (p.R1193W) mutant were altered (Figure 2F).
case_images: PMC11381389_03
case_images: Clinical manifestation of the proband I and molecular features of DSP. (A). The proband exhibited a homozygous variant of DSG2 (c.1592T>G p.F531C) and a heterozygous variant of DSP (c.7883T>C p.L2628P). (B) The variant of DSP c.7883T>C had been reported in 1000G and ExAC, it has predicted protein damaging by MutationTaster. (C) ECG of the proband. (D, D') Echocardiography demonstrated thrombus in apex of ventricles. (E, E') CMR demonstrated cardiac enlargement and delayed enhancement. (F) The protein structure of DSP has been built based on the 5dzz.1.A template. (G) Ramachandran plots indicated that amino acid positions were altered.
case_images: fgene-15-1428796-g001.jpg
case_images: PMC11381389_03_fgene-15-1428796-g001.jpg
case_images: F1
case_images: In proband I, we confirmed a heterozygous variant of DSP c.7883T>C (p.L2628P), which was paternally inherited (Figure 1A). Several allele carriers were retrieved from the 1000G (1 heterozygous record) and ExAC (16 heterozygous records) databases (Figure 1B). Moreover, the pathogenic effects of this mutation on the protein structure were validated using a crystal structure based on the 5dzz.1.A template between the wild-type and mutant DSP (p.L2628P) amino acid sequences (Figure 1F). Ramachandran plots demonstrated that the amino acid positions were altered in the mutant (Figure 1G).
case_images: Clinical manifestation of the proband II and molecular features of SCN5a. (A) The proband exhibited a homozygous variant of DSG2 (c.1592T>G p.F531C) and a heterozygous variant of SCN5a c.3577C>T (p.R1193W). (B) The variant of SCN5a c.3577C>T had been reported in 1000G and ExAC, it has predicted protein damaging by MutationTaster. (C) ECG of the proband. (D, D') Echocardiography demonstrated thrombus in right ventricle and cardiac enlargement, marked dilation of the right atrium and right ventricle, along with inhomogeneous thinning of the ventricular wall with delayed enhancement in the left and right ventricular wall and septum. (E) The protein structure of SCN5a has been built based on the Q14524.1.A template. (F) Ramachandran plots indicated that amino acid positions were altered.
case_images: fgene-15-1428796-g002.jpg
case_images: PMC11381389_03_fgene-15-1428796-g002.jpg
case_images: F2
case_images: In proband II, we confirmed a heterozygous variant of SCN5a c.3577C>T (p.R1193W), which was maternally inherited (Figure 2A). Several allele carriers were retrieved from the 1000G (2 heterozygous records) and ExAC (9 heterozygous records) databases (Figure 2B). The pathogenic effects of this mutation on the protein structure were validated using a crystal structure based on the Q14524.1.A template between the wild-type and mutant (p.R1193W) amino acid sequences using AlphaFold2 (Figure 2E). Ramachandran plots demonstrated that the amino acid positions in the SCN5a (p.R1193W) mutant were altered (Figure 2F).
case_images: Clinical manifestation of the proband III and molecular features of MYH7. (A) The proband exhibited a homozygous variant of DSG2 (c.1592T>G p.F531C) and a heterozygous variant of NYH7 c.427C>T (p.R143W). (B) The variant of MYH7 c.427C>T had been reported in 1000G and ExAC, it has predicted protein damaging by MutationTaster. (C) ECG of the proband. (D) Echocardiography demonstrated enlarged left ventricle. (E, E') CMR demonstrated demonstrated patchy abnormal signals in the apical left ventricular free wall, indicative of myocardial edema. (F) The protein structure of MYH7 has been built based on the 8g4l.1.A template. (G) Ramachandran plots indicated that amino acid positions were altered.
case_images: fgene-15-1428796-g003.jpg
case_images: PMC11381389_03_fgene-15-1428796-g003.jpg
case_images: F3
case_images: Proband III, a 6-year-old male, was admitted to the hospital with persistent abdominal pain for 5 days and chest pain for 2 days (Figure 3A). An immediate electrocardiogram demonstrated abnormal Q waves in leads I, II, aVF, V4, V5, and V6, and rightward deviation of the cardiac axis (Figure 3C). Echocardiography demonstrated mild enlargement of the left ventricle (42 mm) and a slight reduction in LVEF to 36% upon admission (Figure 3D). CMR demonstrated patchy abnormal signals in the apical left ventricular free wall, which indicated myocardial edema (Figures 3E, E'). In proband III, we confirmed a heterozygous variant of MYH7 c.427C>T (p.R143W), which was maternally inherited (Figure 3A). Several allele carriers were retrieved from the ExAC database (6 heterozygous records) (Figure 3B). Furthermore, the pathogenic effect of this mutation on the MYH7 (p.R143W) protein structure was confirmed by using a crystal structure based on the 8g4l.2.A template between wild-type and mutant (p.R143W) amino acid sequences with AlphaFold2 (Figure 3F). Ramachandran plots demonstrated that the amino acid positions were altered in the MYH7 (p.R143W) protein (Figure 3G).
case_images: PMC11381389_04