Abstract

One to two percent of all children are born with a developmental disorder requiring pediatric hospital admissions. For many such syndromes, the molecular pathogenesis remains poorly characterized. 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. We performed various experiments, e.g. 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. CMO is a clinical equivalent to an infantile cortical hyperostosis (Caffey disease), for which SLC37A2 is a new candidate gene. SLC37A2 is a poorly characterized member of a glucose-phosphate transporter family without previous disease associations. It is expressed in many tissues, including cells of the macrophage lineage, e.g. osteoclasts, and suggests a disease mechanism, in which an impaired glucose homeostasis in osteoclasts compromises their function in the developing bone, leading to hyperostosis. 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. 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.

Highlights

  • 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

  • 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

  • CMO is a clinical equivalent to an infantile cortical hyperostosis (Caffey disease) for which SLC37A2 is a new candidate gene

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Summary

Introduction

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. These disorders make a major contribution to pediatric hospital admissions and mortality [1]. There is a growing interest in the development of therapeutics for rare diseases, which requires the identification of the genetic defects, comprehensive understanding of the molecular pathology and access to physiologically relevant animal models. Developmental disorders are frequent in other species, including dogs, which as large animals bear very close physiologic and genetic resemblance with us. Online Mendelian Inheritance in Animals (OMIA), a catalogue of inherited disorders and associated genes in animals, reports more than 350 inherited diseases in dogs as potential models for human disease (http:// omia.angis.org.au/)

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