A novel AGK splicing mutation in a patient with Sengers syndrome and left ventricular non-compaction cardiomyopathy.

Background: Sengers syndrome characterized by hypertrophic cardiomyopathy is an extremely rare genetic disorder. Sengers syndrome associated with left ventricular non-compaction (LVNC) has not been described.

Methods: Genetic testing was used to identify candidate AGK variants in the proband. The predicted molecular structures were constructed by protein modeling. Exon skipping caused by the identified splicing mutations was verified by in silico analyses and in vitro assays. The genotypic and phenotypic features of patients with AGK splicing mutations were extracted by a systematic review.

Results: The proband was characterized by Sengers syndrome and LVNC and caused by a novel compound heterozygous AGK splicing mutation. This compound mutation simultaneously perturbed the protein sequences and spatial conformation of the acylglycerol kinase protein. In silico and in vitro analyses demonstrated skipping of exons 7 and 8 and premature truncation as a result of exon 8 skipping. The systematic review indicated that patients with an AGK splicing mutation may have milder phenotypes of Sengers syndrome.

Conclusions: The genotypic and phenotypic spectrums of Sengers syndrome have been expanded, which will provide essential information for genetic counseling. The molecular mechanism in AGK mutations can offer insights into the potential targets for treatment.

Impact: First description of a child with Sengers syndrome and left ventricular non-compaction cardiomyopathy. A novel pathogenic compound heterozygous splicing mutation in AGK for Sengers syndrome was identified. The identified mutations led to exons skipping by in silico analyses and in vitro assays.