Skeletal dysplasia

Gene: HMGCS1

Green List (high evidence)

Comment on list classification: There are four unrelated families reported with biallelic HMGCS1 variants and with congenital myopathy with rigid spine. All cases also had scoliosis. Hence, this gene can be promoted to green rating on this panel in the next GMS update.

Created: 28 May 2026, 2:39 p.m. | Last Modified: 28 May 2026, 2:39 p.m.

Panel Version: 9.13

PMID:39531736 (2025) reported biallelic variants in HMGCS1 gene identified via whole exome and genome sequencing in five patients from four unrelated families with rigid spine syndrome. The identified variants included 6 missense variants and one 2-basepair deletion resulting in a frameshift and early termination. All patients presented with spinal rigidity primarily affecting the cervical and dorsolumbar regions, scoliosis, and respiratory insufficiency. Creatine kinase levels were variably elevated and muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles.

Three of the four functionally analysed variants exhibited reduced thermal stability, and two of them showed subtle changes in enzymatic activity compared to the wildtype. Hmgcs1 mutant zebrafish displayed severe early defects and the four variants tested have reduced function compared to wild-type HMGCS1 in zebrafish rescue assays. In addition, potential for mevalonic acid supplementation to reduce phenotypic severity in mutant zebrafish was also demonstrated.

This gene has been associated with relevant phenotype in OMIM (MIM #62143) and the OMIM record was last accessed on 28 May 2026.
Sources: Literature

Created: 28 May 2026, 2:36 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Congenital myopathy 28 with rigid spine, OMIM:621433; congenital myopathy 28 with rigid spine, MONDO:0980756

Publications

• 39531736