A novel de novo variant in the RUNX2 gene causes cleidocranial dysplasia in a Malian girl

Key Clinical Message Cleidocranial dysplasia (CCD) is a rare genetic skeletal disorder with only few cases reported in Africa, mostly based on clinical and radiological findings. We report the first case in Mali, caused by a novel de novo variant in the RUNX2 gene. Abstract Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia characterized by an aplastic/hypoplastic clavicles, patent sutures and fontanels, dental abnormalities and a variety of other skeletal changes. We report a novel de novo variant in the RUNX2 gene causing a severe phenotype of CCD in a Malian girl

Expert Panel Curation of 31 Genes in Relation to Limb Girdle Muscular Dystrophy

Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD. The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene-disease relationships (GDR) using the ClinGen gene-disease clinical validity framework to evaluate 31 genes implicated in LGMD. The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as Definitive, 4 (11%) as Moderate and 1 (3%) as Limited. Two genes, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD. The expert-reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case-level data that help clarify disputed or novel LGMD associations