Routine use of next-generation sequencing has shown that most common phenotypes are genetically heterogeneous and that in many cases, mutations in the same gene may cause markedly different phenotypes. Furthermore, complex clinical presentations are often due to multiple coexisting genetic defects. Here, we describe a patient with a complex clinical phenotype: a childhood-onset neurodevelopmental disorder with progressive intellectual disability, and supraventricular tachyarrhythmias that led to cardiac arrest in early teens. The complex phenotype is paralleled by a complex genotype. The neurological manifestations were likely due to biallelic POLG variants. POLG encodes the catalytic subunit of mitochondrial polymerase gamma. Pathogenic POLG variants cause both autosomal and recessive diseases, with a wide variety of clinical presentations. This heterogeneity makes validating novel substitutions challenging. One of the patient's variants, p.(W113R), was novel, and to assess its pathogenicity, we employed a functional yeast-based assay. The cardiac phenotype was likely due to a de novo pathogenic variant in the RYR2 gene, which encodes a calcium release channel that plays an essential role in heart excitation-contraction coupling. The yeast assay was essential to establish the pathogenicity of the novel POLG variant and to correctly characterize this complex genotype.
Fumini et al. (2026) studied this question.