ALPK3 Variants and Pediatric Cardiomyopathy: Missing Variations and Different Variants in ClinVar

Pediatric cardiomyopathy is both a clinical and genetic challenge due to its diverse manifestations and underlying mutations. The ALPK3 gene has been consistently linked to various cardiomyopathies, particularly in pediatric patients. In this article, we highlight five unique ALPK3 variants reported in patients with different cardiomyopathy presentations. Each variant, as of October 26, 2024, is either absent from ClinVar or recorded with an inconsistent identity, stressing the importance of resources like Adenine AI to thoroughly consolidate evidence for accurate variant interpretation.

1. Tunisian Pediatric Patient with Syndromic Cardiomyopathy ^#

• Mutation: ALPK3:c.1531_1532delAA (p.Lys511Argfs*12)

• PMID: 30046096

• Details: A 3-year-old male presenting with both hypertrophic and dilated cardiomyopathy, skeletal deformities, pectus excavatum, and a cleft palate. Whole-exome sequencing confirmed a homozygous ALPK3 mutation, marking the first reported case of this mutation in a Tunisian patient.

2. Hypertrophic Cardiomyopathy in a 14-Year-Old Girl

• Mutations: Compound heterozygous variants ALPK3:c.3907_3922del (p.Gly1303Leufs*28) and ALPK3:c.2200A>T (p.Arg734*)

• PMID: 37396576

• Clinical Course: The patient suffered sudden cardiac arrest, was resuscitated but remained comatose. Exome sequencing revealed compound heterozygous truncating mutations, which were identified as pathogenic. This severe case underscores the potential role of ALPK3 in sudden cardiac events in young patients.

3. Infant with Congenital Cardiomyopathy and Dysmorphic Features ^#

• Mutation: ALPK3:c.2018delC (p.Gln675SerfsX30)

• PMID: 28630369

• Presentation: A male infant with in utero diagnosis of dilated cardiomyopathy that progressed to hypertrophic cardiomyopathy post-birth. This mutation represents one of the rare cases of ALPK3-linked cardiomyopathy, highlighting the gene’s autosomal recessive inheritance pattern.

4. Severe Pediatric Cardiomyopathy in Consanguineous Families

• Mutations: ALPK3:c.4736-1G>A (p.Val1579Glyfs*30), ALPK3:c.3781C>T (p.Arg1261*), and ALPK3:c.5294G>A (p.Trp1765Ter)

• PMID: 26846950

• Findings: This study involved five children from consanguineous families with homozygous truncating mutations, manifesting as early-onset hypertrophic and/or dilated cardiomyopathy. The study emphasizes the severe cardiac impact of biallelic ALPK3 mutations, which can lead to significant remodeling at the cellular level. [While to stop-gain variants are present in ClinVar, the intronic variant is absent]

5. East Asian Cohort with Heterozygous ALPK3 Variants

• Mutations: ALPK3:c.350_352del (p.Leu117_Asp118delinsHis), ALPK3:c.1862_1879del (p.Arg621_Gly626del), ALPK3:c.256_267del (p.Arg86_Ser89del), ALPK3:c.5002_5003insTAGTCC (p.Thr1667_Arg1668insLeuVal)

• PMID: 35783621

• Study Summary: Heterozygous truncating and missense ALPK3 variants were observed in a cohort of East Asian patients with hypertrophic cardiomyopathy (HCM). Variants were associated with pronounced hypertrophy and greater cardiac wall thickness, highlighting the variable expressivity and impact of ALPK3 across populations.

Beyond ClinVar: The Importance of Consultation To Different Resources For Comprehensive Evidence Collection

The absence and/or inconsistency between article and ClinVar for ALPK3 variants emphasizes the need for additional evidence-gathering tools. Resources like Adenine AI ensures that clinicians and researchers have access to a complete genetic picture. This multi-resource approach supports more accurate variant interpretation, ultimately aiding in personalized care for patients with complex genetic diseases.

By expanding our knowledge of ALPK3 through curated resources, we move closer to understanding its full role in pediatric cardiomyopathies, underscoring the gene’s significance for both clinical research and patient management.