Genetics of Chiari I malformation

Genetics of Chiari


Factors that influence the development of Chiari Malformation Type I (CMI) with or without syringomyelia are largely unknown, particularly in the absence of a known traumatic event.  However, there is evidence of familial aggregation among individuals with idiopathic (unknown causes) CMI, suggesting genetics may be important. In the early 1990’s, there were several reports of familial cases of CMI, including affected siblings1,  twins2,3, and identical triplets4.  Moreover, in a large study of over 300 CMI patients, 12% of those patients reported having at least one close relative with CMI and/or syringomyelia 5. Thus, genetic factors likely play a role in the development of CMI in at least a subset of CMI patients.

Importantly, CMI often co-occurs with other conditions that are known to be genetic. Many of these co-occurring genetic conditions affect cartilage and/or bone such as Ehlers Danlos syndrome6, achondroplasia7, Klippel Feil sequence5,8, Hadju-Cheney syndrome9, familial hypophosphatemia rickets10,11, and spondylo-epiphyseal dyplasia tarda12. CMI is also associated with syringohydromyelia, hydrocephalus, and several other disorders that cause malformations of the skull and cervical spine13-15. The connection to these other genetic conditions underscore that genetic factors can contribute to the occurrence of CMI, and also suggest that formation of bone and connective tissue are particularly relevant to the development of CMI.  To that end, one genomewide association study found that the evidence for several chromosomal regions increased significantly when limiting the analysis of families based on the presence or absence of connective tissue disorders16.  The results suggested that the genetic basis of CMI is likely caused by different genes in families with and without connective tissue disorders.  Within the subset of families without connective tissue disorders, two missense mutations in the GDF6 gene were identified.16  The GDF genes are involved in development, and mutations in GDF6 and GDF3 have been associated with Klippel Feil sequence 17-19.

Another approach to determining the genes involved in CMI has been to closely examine the shape of the bones and structures in the skull.  One study found that skull measurements from MRI were highly correlated among CMI family members, particularly the volume of the posterior fossa region20. This high degree of correlation within families suggests that the shape of the skull is inherited.  Perhaps surprisingly, the degree of cerebellar tonsil herniation was not heritable. These findings were confirmed and expanded in a subsequent study.21  Urbizu et al. identified four genetic variants (located in the genes ALDH1A2, CDX1 and FLT1) to be associated with adult classic CM-1, and found that two of the variants were also associated with the slope of the clivus22. Using a similar approach and defining two different “shapes” of the posterior fossa from MRI measures, Markunas et al. identified different levels of expression in genes related with dorso-ventral axis formation (ETS1, ETS2, NOTCH4), ribosome, spliceosome and proteasome in pediatric classic CM-1 patients23. These findings demonstrate the genetic complexity of the posterior fossa development, and provide more evidence that CM-1 is genetically heterogeneous, with many genes involved.

More recently, new genetic and genomic technologies have become available.  Next generation sequencing has given scientists the ability to deeply sequence the genomes of individuals in a timely and cost-effective manner.  This technology was used to identify three mutations in two Italian families with CMI24.  The genes involved were part of the WNT signaling pathway, which plays an important role in development.  This technology is currently being used by many scientists across the world to identify more genes involved in CMI.

In summary, the genetic etiology of CMI is complex and likely different genes contribute to CMI development in different families.  We are only beginning to identify the specific genes that are involved.  Based on the genes identified thus far, it appears that most of these genes are active during development, long before symptoms of CMI are present.


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