Project description:Background: Patients with neurodevelopmental and neuromuscular disorders often show overlapping clinical phenotypes. Pathogenic variants in KMT5B, a histone lysine methyltransferase, have been linked to neurodevelopmental disorders, yet their effects on human skeletal muscle remain unexplored. We report a patient with KMT5B-linked disease who presented to a neuromuscular specialty clinic with significant involvement of skeletal muscle, where a multi-omics approach established the genetic diagnosis and revealed neuromuscular findings relevant for diagnosis, care and rehabilitation. Methods: Whole-exome sequencing was performed from blood and data was analyzed using the RD-Connect Genome Phenome Analysis Platform. Histological analysis and proteomic profiling were performed on muscle tissue. Results: Whole-exome sequencing revealed a pathogenic heterozygous variant (c.554_557del, p.Tyr185Cysfs*27) in KMT5B. Histological examination revealed fiber-type grouping, angular fibers, increased fast-twitch fiber proportion, and lipid droplet accumulation, indicative of muscle denervation. Proteomic profiling identified 77 dysregulated proteins, including upregulation of sarcomeric proteins, mitochondrial and glycolytic enzymes, acute-phase and complement factors, and extracellular matrix components, reflecting structural remodeling, metabolic adaptation, and inflammatory activation. These findings align with phenotypes observed in Kmt5b mouse models, supporting a role of KMT5B in neuromuscular function.
Project description:Phosphoprotein phosphatases are the most abundant in the cell and regulate various cellular functions, such as cell survival, DNA damage response, tau dephosphorylation, and apoptosis. Some phosphoprotein phosphatase dysfunctions promote neurodevelopmental disorders. Exome or genome sequencing identified individuals with Marfan syndrome-like connective tissue disorders, mild neurodevelopmental disorders, and attention deficit in 11 individuals from 10 families due to a de novo in-frame deletion (NM_005436.5:c.415_417del p.Glu139del) in the CCDC6 gene. Zebrafish model analysis revealed loss of sociability and abnormal shapes in the skull, vertebra, and ribs. Proteome analyses using patient-derived lymphoblastoid cell line or mutant or wild-type CCDC6 overexpression in HeLa cells showed mutant CCDC6 strongly binds to phosphoprotein phosphatase and its regulators, causing phosphorylation regulation disorders. Interestingly, these patients showed partially overlapped findings of reported PP2A-related disorders. We demonstrate a new disorder, CLAMP syndrome, Craniofacial dysmorphisms, Language delay, Autistic features, Marfan syndrome-like findings, and Phosphoprotein phosphatase dysfunction.
Project description:Phosphoprotein phosphatases are the most abundant in the cell and regulate various cellular functions, such as cell survival, DNA damage response, tau dephosphorylation, and apoptosis. Some phosphoprotein phosphatase dysfunctions promote neurodevelopmental disorders. Exome or genome sequencing identified individuals with Marfan syndrome-like connective tissue disorders, mild neurodevelopmental disorders, and attention deficit in 11 individuals from 10 families due to a de novo in-frame deletion (NM_005436.5:c.415_417del p.Glu139del) in the CCDC6 gene. Zebrafish model analysis revealed loss of sociability and abnormal shapes in the skull, vertebra, and ribs. Proteome analyses using patient-derived lymphoblastoid cell line or mutant or wild-type CCDC6 overexpression in HeLa cells showed mutant CCDC6 strongly binds to phosphoprotein phosphatase and its regulators, causing phosphorylation regulation disorders. Interestingly, these patients showed partially overlapped findings of reported PP2A-related disorders. We demonstrate a new disorder, CLAMP syndrome, Craniofacial dysmorphisms, Language delay, Autistic features, Marfan syndrome-like findings, and Phosphoprotein phosphatase dysfunction.
Project description:Illumina human Omni5Exome arrays were used to investigate CNVs in SÑzary syndrome tumours as part of a larger study involving whole exome sequencing of the same samples and targeted resequencing of a further cohort. 16 Samples underwent SNP array including 10 tumour/gDNA matched samples that also underwent whole exome sequencing, public databases were used as further control data for calling CNVs.