![]() ![]() Rare pediatric disorders are typically with homozygous, compound heterozygous, or de novo pathogenic variants. These disorders make a major contribution to pediatric hospital admissions and mortality. One to two percent of all children are born with a developmental disorder, such as a heart defect, skeletal abnormality, or mental retardation as a result of errors in embryogenesis and early neurodevelopment. Our study provides molecular identity for the canine conditions and presents three novel physiologically relevant models of human rare diseases. Mutations in the SCARF2 and FAM20C genes have been associated with the human van den Ende-Gupta and Raine syndromes. SLC37A2 is a glucose-phosphate transporter in osteoclasts, and its defect suggests an impaired glucose homeostasis in developing bone, leading to hyperostosis. CMO is a clinical equivalent to an infantile cortical hyperostosis (Caffey disease) for which SLC37A2 is a new candidate gene. We have characterized the clinical features and genetic causes of three developmental syndromes in dogs, including craniomandibular osteopathy (CMO), a previously undescribed skeletal syndrome, and dental hypomineralization, for which we identified mutations in the canine SLC37A2, SCARF2 and FAM20C genes, respectively. ![]() Research can be facilitated by physiologically relevant models, such as dogs with corresponding disorders. There is a growing interest in the development of therapeutics for these conditions, but that requires understanding of the genetic cause and pathology. Rare developmental disorders make a major contribution to pediatric hospital admissions and mortality. ![]() Given the growing interest in the molecular characterization and treatment of human rare diseases, our study presents three novel physiologically relevant models for further research and therapy approaches, while providing the molecular identity for the canine conditions. Mutations in SCARF2 and FAM20C have been associated with the human van den Ende-Gupta and Raine syndromes that include numerous features similar to the affected dogs. osteoclasts, and suggests a disease mechanism, in which an impaired glucose homeostasis in osteoclasts compromises their function in the developing bone, leading to hyperostosis. ![]() It is expressed in many tissues, including cells of the macrophage lineage, e.g. SLC37A2 is a poorly characterized member of a glucose-phosphate transporter family without previous disease associations. CMO is a clinical equivalent to an infantile cortical hyperostosis (Caffey disease), for which SLC37A2 is a new candidate gene. combined genome-wide association and next generation sequencing, to investigate the clinico-pathological features and genetic causes of three developmental syndromes in dogs, including craniomandibular osteopathy (CMO), a previously undescribed skeletal syndrome, and dental hypomineralization, for which we identified pathogenic variants in the canine SLC37A2 (truncating splicing enhancer variant), SCARF2 (truncating 2-bp deletion) and FAM20C (missense variant) genes, respectively. Parallel developmental disorders in other species could provide complementary models for human rare diseases by uncovering new candidate genes, improving the understanding of the molecular mechanisms and opening possibilities for therapeutic trials. For many such syndromes, the molecular pathogenesis remains poorly characterized. One to two percent of all children are born with a developmental disorder requiring pediatric hospital admissions. ![]()
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