Novel ALPK3 mutation in a Tunisian patient with pediatric cardiomyopathy and facio-thoraco-skeletal features

Abstract

Pediatric cardiomyopathy is a complex disease with clinical and genetic heterogeneity. Recently, the ALPK3 gene was described as a new hereditary cardiomyopathy gene underlying pediatric cardiomyopathies. Only eight patients carrying mutations in ALPK3 have been reported to date. Here, we report a 3-year-old male patient with both hypertrophic and dilated cardiomyopathy. The patient presented dysmorphic features and skeletal deformities of hands and feet, pectus excavatum, and cleft palate. The genetic investigation was performed by whole-exome sequencing in the patient and his parents. We identified a novel homozygous mutation in ALPK3 (c.1531_1532delAA; p.Lys511Argfs*12). Our work extends the phenotypic spectrum of the ALPK3-associated cardiomyopathy by reporting additional clinical features. This is the first study of a Tunisian patient with mutation in the ALPK3 gene. In conclusion, ALPK3 should be included in the list of genes to be considered in genetic studies for patients affected with pediatric syndromic cardiomyopathy.

Two New Cases of Hypertrophic Cardiomyopathy and Skeletal Muscle Features Associated with ALPK3 Homozygous and Compound Heterozygous Variants

“…This further includes the variability of the skeletal and muscle system involvement in ALPK3 -associated cardiomyopathy. Musculoskeletal abnormalities were not reported in all patients with pathogenic ALPK3 variants, and examples of reported abnormalities included subtle signs of muscle weakness, dysmorphic features and skeletal abnormalities [ 8 , 9 ]. In the presented cases, both patients revealed decreased muscle tone, axial weakness and clinical signs of polyneuropathy, but no defined changes were detected in Patient 2 using neurography and electromyography.…”

“…Hitherto, 27 patients with hypertrophic cardiomyopathy, caused by 19 different mutations in ALPK3 , have been described [ 4 , 7 , 8 , 9 , 10 , 11 ] ( Table 1 ). All but two of the described patients presented before the age of 18 and, apart from HCM, often revealed musculoskeletal abnormalities.…”

“…All but two of the described patients presented before the age of 18 and, apart from HCM, often revealed musculoskeletal abnormalities. The latter included scoliosis, knee and shoulder contractures, camptodactyly/arthrogryposis, axial hypotonia, short neck, dysmorphic facial features (low-set ears, high-arched palate, cleft palate and broad forehead) and pectus excavatum [ 8 , 9 , 11 ]. The majority of the described patients came from consanguineous families with varying degrees of relatedness (first- to sixth-degree cousins).…”

Genome-Wide Association Study Reveals Candidate Genes for Litter Size Traits in Pelibuey Sheep

“…ALPK3 (alpha kinase 3) is implicated in a large variety of cellular processes such as protein translation, Mg 2+ homeostasis, intracellular transport, cell migration, adhesion, and proliferation [95]. A mutation in the ALPK3 gene in human is associated with cardiomyopathy [96]. The overexpression of ALPK3 enhances differentiation of murine embryonic carcinoma cells into cardiomyocytes [95].…”

A novel homozygous ALPK3 variant associated with cardiomyopathy and skeletal muscle involvement

“…The highest ALPK3 transcript expression profile in humans is observed in cardiac and skeletal muscle, and the GeneNetwork Assisted Diagnostic Optimization (GADO) method predicts "muscle contraction" and "myogenesis" as probable gene functions . [4][5][6][7][8][9][10][11] Nevertheless, clinically evident skeletal myopathy is not known to be associated with ALPK3 genetic variants. We present a patient showing both cardiac and skeletal muscle involvement linked to a novel homozygous ALPK3 variant.…”