Abstract
Chiari malformation type 1 (CM1) is a congenital anomaly of cranio-cerebral junctions characterized by underdevelopment of the occipital bone and posterior fossa (PF) and consequent cerebellar tonsil herniation across the foramen magnum. This condition can impair the normal flow of cerebral spinal fluid (CSF) leading to syringomyelia. Patients display a high degree of clinical variability depending on the compression of the tissue, nerves and on the buildup of CSF pressure. CM1 is also associated with known syndromes, (e.g. craniosynostosis), and is often reported as clinical sign in more complex phenotypes, but the molecular mechanisms of isolated CM1 are not yet known. To understand the molecular basis and which factors could contribute to the high heterogeneity, we performed WES of 42 trios with sporadic and syndromic, without craniosynostosis, CM1. WES of syndromic cases provided a diagnosis of distinct genetic disorders, in which pathogenic variants were associated to bone dysplasia, growth retardation and resistance to gonadotropins. In sporadic cases, variants in genes involved in common molecular pathways have been identified; these are all associated with modeling and deposition of bone matrix and with regulatory processes, all requested in the same pathway. In 75% of trios we found variants in the same recurrent genes, shared both by isolated and syndromic CM1 cases; functional tests on bone biopsies of these patients are underway to demonstrate the pathogenicity of these genes. Our data remark complex interactions among several genes involved in different steps of the same pathways, underlying the high clinical-genetic heterogeneity of CM1.
