Journal Article

Biallelic variants in RYR1 and STAC3 are predominant causes of King-Denborough Syndrome in an African cohort

Schoonen, Maryke, Human, Ronel, Vorster, Barend C., Smuts, Izelle, Taylor, Robert W., Patel, Krutik, Bisschoff, Michelle, Wilson, Lindsay A., Makwikwi, Tendai, Lubbe, Elsa, Vorster, Armand, Nonyane, Malebo, Vandrovcova, Jana, Hanna, Michael G., Fassad, Mahmoud, McFarland, Robert, van der Westhuizen, Francois H.

2025

Overview

King-Denborough Syndrome (KDS) is a congenital myopathy (CM) characterised by myopathy, dysmorphic features and susceptibility to malignant hyperthermia. The objective of this study was to investigate the genotype-phenotype correlation in Black African patients presenting with CM, specifically those with KDS-like phenotypes, who remained undiagnosed for over 25 years. A cohort of 67 Black African patients with CM was studied, of whom 44 were clinically evaluated and diagnosed with KDS. Whole-exome sequencing (WES) was performed as part of an international genomics study (ICGNMD) to identify potential pathogenic mutations. Genomic assessments focused on identifying relevant genes, including RYR1 and STAC3 , and establishing genotype-phenotype correlations. The study identified RYR1 and STAC3 mutations as the predominant genetic causes of KDS in this cohort, with mutations in both genes exhibiting autosomal recessive inheritance. While RYR1 has previously been linked to autosomal dominant mutations, STAC3 , which was formerly associated exclusively with Native American Myopathy/Bailey-Bloch Myopathy, congenital hypotonia, and susceptibility to malignant hyperthermia, is now newly associated with CM-KDS in this study. This establishes the first genotype-phenotype correlation for 44 Black African individuals with KDS. This study marks a significant milestone in research on understudied African populations with CM, emphasising the lengthy diagnostic journey these patients endured. The findings highlight the pressing need for improved access to genomic medicine in underserved regions and underscore the importance of expanding research and diagnostic capabilities in Africa. This work contributes to the advancement of genetic medicine in underrepresented populations, facilitating better diagnostic and therapeutic outcomes.

• Publisher: Springer International Publishing,Nature Publishing Group
• Subject: 45/22 / 45/23 / 45/77 / 692/308/2056 / 692/699/375/374 / Adolescent / Adult / Autosomal recessive inheritance / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Black People - genetics / Child / Child, Preschool / Cytogenetics / Female / Gene Expression / Genomics / Genotype & phenotype / Genotypes / Human Genetics / Humans / Hyperthermia / Male / Malignant hyperthermia / Malignant Hyperthermia - genetics / Malignant Hyperthermia - pathology / Minority & ethnic groups / Muscular Diseases - genetics / Mutation / Myopathy / Phenotype / Phenotypes / Population genetics / Ryanodine Receptor Calcium Release Channel - genetics / Ryanodine receptors / Whole genome sequencing