Genetic Analysis of the Chiari I Malformation

This study used whole exome sequencing (WES) on families affected with Chiari I Malformation (CM1). Individuals were recruited from the Republic of Tartarstan in the Russian Federation, where CM1 has a high prevalence (approximately 413 out of 100,000). At least one-third of these affected individuals have an affected relative. In collaboration with Dr. Enver Bogdanov of Kazan State Medical University, seven extended families affected with CM1 were identified. Eligible participants for this study were required to 1) have CM1 and a family member with syringomyelia or CM1, or 2) be a family member of a patient with CM1 and have at least two immediate family members diagnosed with CM1. Adults and minors were eligible for this study and recruitment was through self and physician referral. Patients were excluded if they had a contraindication to MRI scanning, were unable to understand the risks of testing, were under one year of age, or could not undergo MRI scanning without sedation. Study participants underwent SPGR (Spoiled Gradient Recalled) and T1-weighted MR-imaging of the brain and cervical spinal cord to assess the volume of the posterior fossa, as well as the presence of CM1. Individuals were defined as having CM1 if the inferior aspect of the cerebellar tonsils were lying ≥=2 mm caudal to the foramen magnum. Individuals were defined as having a small posterior fossa volume if the ratio of the posterior fossa volume to the supratentorial volume was < 0.15. Sixty-two patients (both cases and controls) from the seven extended families had DNA extracted from blood lymphocytes contained in 10 milliliters of stored blood. Whole exome sequencing (WES) was performed by the National Intramural Sequencing Center (NISC). These genotype data, as well as the case-control phenotype data on CM1 diagnosis and small posterior fossa diagnosis, were made available to dbGaP. ]]>
The data are in the public ftp site.
]]>Inclusion Criteria: To be eligible for this study required have CM1 and a family member with syringomyelia or CM1, OR be a family member of a patient with CM1 and have at least two immediate family members diagnosed with CM1. Adults and minors were eligible for this study. Exclusion Criteria: Patients were excluded if they had a contraindication to MRI scanning, were unable to understand the risks of testing, were under one year of age, or could not undergo MRI scanning without sedation.]]>
Final NIH IRB approval on February 14, 2000 First posted to ClinicalTrials.gov on February 28, 2000 Center for Inherited Disease Research (CIDR) application to perform a genome-wide scan and/or statistical analysis of DNA samples for this study was approved by CIDR's Board of Governors on October 10, 2003 Pedigrees for the first six families established in 2004 Final patient enrolled for whole exome sequencing analysis in July, 2016 Revised paper submitted to European Journal of Human Genetics in December, 2018 Revised paper conditionally accepted for publication in European Journal of Human Genetics on February 12, 2019]]>