Chiari malformation type I: what information from the genetics?
Chiari malformation type I (CMI), a rare disorder of the craniocerebral junction with an estimated incidence of 1 in 1280, is characterized by the downward herniation of the cerebellar tonsils of at least 5 mm through the foramen magnum, resulting in significant neurologic morbidity. Classical CMI is thought to be caused by an underdeveloped occipital bone, resulting in a posterior cranial fossa which is too small to accommodate the normal-sized cerebellum. In this review, we dissect the lines of evidence supporting a genetic contribution for this disorder.
We present the results of two types of approaches: animal models and human studies encompassing different study designs such as whole genome linkage analysis, case-control association studies, and expression studies. The update of the literature also includes the most recent findings emerged by whole exome sequencing strategy.
Despite evidence for a genetic component, no major genes have been identified and the genetics of CMI is still very much unknown. One major challenge is the variability of clinical presentation within CMI patient population that reflects an underlying genetic heterogeneity.
The identification of the genes that contribute to the etiology of CMI will provide an important step to the understanding of the underlying pathology. The finding of a predisposing gene may lead to the development of simple and accurate diagnostic tests for better prognosis, counseling, and clinical management of patients and their relatives.
KeywordsChiari type I malformation (CMI) Syringomyelia (SM) Hindbrain Tonsillar ectopia Posterior cranial fossa (PCF) Autosomal dominant/recessive inheritance Whole exome sequencing (WES)
This work was supported by Ricerca Corrente Ministero Salute-Italy 2016; M.I. is supported by Trust Volpati.
Compliance with ethical standards
Conflict of interest
The authors report no conflicts of interest.
- 24.Dietz HC, Sood S, Mcintosh J (1995) The phenotypic continuum associated with Fbn1 mutations includes the Shprintzen-Goldberg syndrome. Am J Hum Genet 57:1214Google Scholar
- 42.Lemay P, Knowler SP, Bouasker S, Nédélec Y, Platt S, Freeman C, Child G, Barreiro LB, Rouleau GA, Rusbridge C, Kibar Z (2014) Quantitative trait loci (QTL) study identifies novel genomic regions associated to Chiari-like malformation in Griffon Bruxellois dogs. PLoS One 9(4):e89816CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Ancot F, Lemay P, Knowler SP, Kennedy K, Griffiths S, Cherubini GB, Sykes J, Mandigers PJJ, Rouleau GA, Rusbridge C, Kibar Z (2018) A genome-wide association study identifies candidate loci associated to syringomyelia secondary to Chiari-like malformation in Cavalier King Charles Spaniels. BMC Genet 19(1):16CrossRefPubMedPubMedCentralGoogle Scholar
- 44.Solis-Moruno M, de Manuel M, Hernandez-Rodriguez J, Fontsere C, Gomara-Castaño A, Valsera-Naranjo C, Crailsheim D, Navarro A (2017) Potential damaging mutation in LRP5 from genome sequencing of the first reported chimpanzee with the Chiari malformation. Sci Rep 7(1):15224CrossRefPubMedPubMedCentralGoogle Scholar
- 45.Markunas CA, Soldano K, Dunlap K, Cope H, Assimwe E, Stajich J, Enterline D, Grant G, Fuchs H, Gregory SG, Ashley-Koch AE (2013) Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates. PLoS One 8:e615CrossRefGoogle Scholar
- 46.Boyles AL, Enterline DS, Hammock PH, Siegel DG, Slifer SH, Mehltretter L et al (2006) Phenotypic definition of Chiari type I malformation coupled with high-density SNP genome screen shows significant evidence for linkage to regions on chromosomes 9 and 15. Am J Med Genet A 140:2776–2785CrossRefPubMedGoogle Scholar
- 50.Merello E., Tattini L, Magi A, Accogli A, Piatelli GL, Pavanello M, Tortora D, Cama A, Kibar Z, Capra V, De Marco P (2017) Exome sequencing of two Italian pedigrees with non-isolated Chiari malformation type I reveals candidate genes for cranio-facial development. Eur J Hum Genet 25:952–958Google Scholar
- 51.Bamshad MJ, Ng SB, Shendure J (2011) Exome sequencing as a tool for Mendeleian disease gene discovery. Nature Review Genetics 12:745–755Google Scholar
- 52.Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, Shaffer T, Wong M, Bhattacharjee A, Elcher EE, Bamshad M, Nickerson DA, Shendure J (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461:272–276Google Scholar
- 53.Nilda A, Hiroko T, Kasai M, Furukawa Y, Nakamura Y, Suzuki Y, Sugano S, Akiyama (2004) DKK1, a negative regulator of Wnt signaling, is a target of the beta-catenin/TCF pathway. Oncogene 23:8520–8526Google Scholar
- 54.Mukhopadhyay M, Shtrom S, Rodriguez-Esteban C, Chen L, Tsukui T, Gomer L, et al (2001) Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Developmental Cell 1:423–434Google Scholar
- 55.Choi HY, Dieckmann M, Herz J, Niemeier A (2009) Lrp4, a novel receptor for Dickkopf 1 and Sclerostin, is expressed by osteoblasts and regulates bone growth and turnover in vivo. Plos ONE 4(11):e7930Google Scholar
- 56.Johnson EB, Hammer RE, Herz J (2005) Abnornal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice. Hum Mol Genet 14:3523–3538Google Scholar