Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Apr;33(4):421-431.
doi: 10.1038/s41431-025-01795-z. Epub 2025 Feb 18.

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

Maryke Schoonen  1 , Mahmoud Fassad  2   3 , Krutik Patel  2 , Michelle Bisschoff  4 , Armand Vorster  4 , Tendai Makwikwi  4 , Ronel Human  5 , Elsa Lubbe  5 , Malebo Nonyane  5 , Barend C Vorster  6 , Jana Vandrovcova  7 , Michael G Hanna  7 , Robert W Taylor  2   8 , Robert McFarland  2   8 , Lindsay A Wilson  7 , Francois H van der Westhuizen #  4 , Izelle Smuts #  9
Affiliations

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

Maryke Schoonen et al. Eur J Hum Genet. 2025 Apr.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Ethical approval: Informed consent was obtained as part of the current ICGNMD studies, with ethical approval numbers 296/2019 (University of Pretoria) and NWU-00966-19-A1 (North-West University). Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Ethno-linguistic distribution in South Africa.
A Geographical distributions of first or home languages in South Africa, illustrating linguistic diversity in the northern provinces: Limpopo, Mpumalanga, Gauteng, and North-West Province. B Pie charts showing the distribution of the 67 study participants according to their primary language, broken down by referring province. C Language group distribution of 44 KDS-like participants (with RYR1 and STAC3 mutations), categorised by major language groups: Nguni-Tsonga or Sotho-Tswana.
Fig. 2
Fig. 2
Summary of the overall phenotypic and genetic findings for the original neuromuscular disease cohort of 67 participants.
Fig. 3
Fig. 3
Comparison of the most prominent clinical features, based on the three King-Denborough syndrome classifications, for the RYR1 and STAC3 genotypes in participants with KDS. All values are expressed as percentages.
Fig. 4
Fig. 4
Genotype analysis for a subset of 20 carriers of STAC3:c.851G>C.
See this image and copyright information in PMC

References

    1. King J, Denborough M. Anesthetic-induced malignant hyperpyrexia in children. J Pediatr. 1973;83:37–40. - PubMed
    1. Dowling JJ, Lillis S, Amburgey K, Zhou H, Al-Sarraj S, Buk SJ, et al. King–Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord. 2011;21:420–7. - PubMed
    1. Maggi L, Scoto M, Cirak S, Robb S, Klein A, Lillis S, et al. Congenital myopathies–clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom. Neuromuscul Disord. 2013;23:195–205. - PubMed
    1. Gonorazky HD, Dowling JJ, Volpatti JR, Vajsar J, editors. Signs and symptoms in congenital myopathies. Semin Pediatr Neurol. 2019;29:3–11. - PubMed
    1. Claeys KG. Congenital myopathies: an update. Dev Med Child Neurol. 2020;62:297–302. - PubMed

Substances

Supplementary concepts

LinkOut - more resources