ALPK3 gene mutation in a patient with congenital cardiomyopathy and dysmorphic features

Abstract

Primary cardiomyopathy is one of the most common inherited cardiac diseases and harbors significant phenotypic and genetic heterogeneity. Because of this, genetic testing has become standard in treatment of this disease group. Indeed, in recent years, next-generation DNA sequencing has found broad applications in medicine, both as a routine diagnostic tool for genetic disorders and as a high-throughput discovery tool for identifying novel disease-causing genes. We describe a male infant with primary dilated cardiomyopathy who was diagnosed using intrauterine echocardiography and found to progress to hypertrophic cardiomyopathy after birth. This proband was born to a nonconsanguineous family with a past history of a male fetus that died because of cardiac abnormalities at 30 wk of gestation. Using whole-exome sequencing, a novel homozygous frameshift mutation (c.2018delC; p.Gln675SerfsX30) in ALPK3 was identified and confirmed with Sanger sequencing. Heterozygous family members were normal with echocardiographic examination. To date, only two studies have reported homozygous pathogenic variants of ALPK3, with a total of seven affected individuals with cardiomyopathy from four unrelated consanguineous families. We include a discussion of the patient's phenotypic features and a review of relevant literature findings.

Keywords: hypertrophic cardiomyopathy.

Figure 1.

(A) Pedigree of the family demonstrating the affected siblings and, when available, their ALPK3 genotypes. (B) Transthoracic echocardiogram of apical four-chamber view (left) showing symmetrically thickened left ventricular wall and ventricular septum. Parasternal short-axis view (right) showed diffuse concentric left ventricular hypertrophy. RV, right ventricle; LV, left ventricle. (C) Sanger sequencing results. Chromatographs obtained via Sanger sequencing analysis of the index patient and his parents. Sanger sequencing of wild-type control DNA was also performed. Note that the mutation identified via whole-exome sequencing was confirmed as being homozygous versus heterozygous, in the index patient versus his parents, respectively. The bases outlined in red in the wild-type sequence indicate the mutated base pairs. (D) A schematic representation of ALPK3, showing the functional and conserved domains of ALPK3. The red arrowhead indicates the location of the identified variant in this study. Blue arrowheads indicate previously reported variants.