Variant assessment
Totally 6 rare heterozygous variants in 4 genes were detected in our
study (Table 1).
There is a heterozygous mutation in ABCC9 c.3589C>T
(p.Arg1197Cys) gene located on the 12: 21981972 chromosome in patient
R44 (Figure 2A). In East Asian the frequency of heterozygote was 0.13%,
which is more than caucasian (<0.1%). The sequence at this
locus is moderate conservative and computer-aided analysis predicts that
this variation is more likely to affect function. According to American
College of Medical Genetics and Genomics (ACMG) standard, this variation
should be categorized into “uncertain significance”. Both Brugada
(BrS) syndrome and short QT syndrome (SQTS) are ABCC9 gene
related diseases and autosomal dominant inheritance. The patient R47 was
affected by the heterozygous frameshift mutation c.8286_8289del
(p.Ile2763Leufs*15) in FBN1 gene located on the 15:48703514
chromosome (Figure 2B). According to ACMG standard, this variation
should be categorized into “pathogenic”. This is a novel mutation inFBN1 gene. All of patient R46, R42, and R51 have PKP2 gene
mutations. Patient R42 was affected by the heterozygous frameshift
mutation c.148_151del (p.Thr50Serfs*61) in PKP2 gene located on
the 12:33049515 chromosome (Figure 2C). According to ACMG standard, this
variation should be categorized into “pathogenic”. Patient R46 was
affected by the heterozygous nonsense mutation c.1237C>T
(p.Arg413Ter) in PKP2 gene located on the 12:33003841 chromosome
(Figure 2C). According to ACMG standard, this variation should be
categorized into “pathogenic”. Patient R51 was affected by the
heterozygous nonsense mutation c.2490-6T>C in PKP2gene located on the 12:32945671 chromosome (Figure 2C) and this mutation
leads to a splicing abnormality, thereby causing exon 13 extension.
According to ACMG standard, this variation should be categorized into
“likely pathogenic”. PKP2 is a susceptibility gene for familial
arrhythmogenic right ventricular dysplasia type 9 (ARVD9), which is an
autosomal dominant disease. Patient R52 was affected by missing codon
210 (lysine) due to the heterozygous mutation c.650_652delAGA
(p.Lys217del) in TNNT2 gene located on the 1:201331099 chromosome
(Figure 2D). According to ACMG standard, this variation should be
categorized into “pathogenic”. TNNT2 is a susceptibility gene
for dilated cardiomyopathy type 1D, which is an autosomal dominant
disease.