CASQ2 variants in Chinese children with catecholaminergic polymorphic ventricular tachycardia

Abstract

Background: Biallelic variants of the CASQ2 are known to cause the autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease that predisposes young individuals to syncope and sudden cardiac death. To date, only about 24 CASQ2 variants have been reported in association with CPVT pathogenesis; furthermore, studies in Asians, especially in the Chinese population, are relatively rare. The aim of this study was to detect CASQ2 variants in Chinese patients with CPVT.

Methods: We used targeted next-generation sequencing (NGS) to identify CASQ2 variants in Chinese patients with CPVT. A screening process was performed to prioritize rare variants of potential functional significance. Sanger sequencing was conducted to conform the candidate variants and determine the parental origin.

Results: We identified seven different CASQ2 variants, of which three (c.1074_1075delinsC, c.1175_1178delACAG, and c.838+1G>A) have not been previously reported. The variants exhibited autosomal recessive inheritance, and were detected in four unrelated Chinese families with CPVT. They included a nonsense variant c.97C>T (p.R33*) and a missense variant c.748C>T (p.R250C) in Family 1 with three CPVT patients; two heterozygous frameshift variants, c.1074_1075delinsC (p.G359Afs*12) and c.1175_1178delACAG (p.D392Vfs*84), in Family 2 with one CPVT patient; one pathogenic homozygous variant c.98G>A (p.R33Q) of CASQ2 in the CPVT patient of Family 3; and two heterozygous splicing variants, (c.532+1G>A) and (c.838+1G>A), in Family 4 with one CPVT patient.

Conclusion: To our knowledge, this is the first systematic study of Chinese children with CASQ2 variants. Our work further expands the genetic spectrum of CASQ2-associated CPVT.

Keywords: CASQ2 variants; autosomal recessive; catecholaminergic polymorphic ventricular tachycardia; targeted next-generation sequencing.

Figure 1

Electrocardiographic manifestations on exercise testing for patient 6. (A) normal 12‐lead baseline electrocardiogram before exercise; (B and C) bidirectional ventricular tachycardia and polymorphic ventricular tachycardia induced by exercise; (D) restoration of normal sinus rhythm after exercise

Figure 2

Pedigrees of the four CASQ2‐associated CPVT families and variant analysis. Black symbols indicated affected individuals. Half‐filled symbols indicated heterozygous individuals with a single variant. Blank symbols indicated healthy individuals. Black arrows indicated the family probands. Red arrows indicated variants in Sanger sequencing. CPVT, catecholaminergic polymorphic ventricular tachycardia

Figure 3

Location of the unreported and known variants in CASQ2. Lines indicate the sites of variants of CASQ2 on the exons or exon–intron junctions. Blue boxes indicate the 11 exons of CASQ2. The unreported and known CASQ2 variants identified in this study are indicated in red and blue, respectively. *this variant is reported previously in our team but not found in HGMD. HGMD, Human Genetics Mutations Database