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Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation.

ABSTRACT: Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the base of the skull. Although cerebellar tonsillar herniation (CTH) is hypothesized to result from an underdeveloped posterior cranial fossa (PF), patients are frequently diagnosed by the extent of CTH without cranial morphometric assessment. We recently completed the largest CMI whole genome qualitative linkage screen to date. Despite an initial lack of statistical evidence, stratified analyses using clinical criteria to reduce heterogeneity resulted in a striking increase in evidence for linkage. The present study focused on the use of cranial base morphometrics to further dissect this heterogeneity and increase power to identify disease genes. We characterized the genetic contribution for a series of PF traits and evaluated the use of heritable, disease-relevant PF traits in ordered subset analysis (OSA). Consistent with a genetic hypothesis for CMI, much of the PF morphology was found to be heritable and multiple genomic regions were strongly implicated from OSA, including regions on Chromosomes 1 (LOD = 3.07, p = 3 × 10(-3) ) and 22 (LOD = 3.45, p = 6 × 10(-5) ) containing several candidates warranting further investigation. This study underscores the genetic heterogeneity of CMI and the utility of PF traits in CMI genetic studies.

SUBMITTER: Markunas CA

PROVIDER: S-EPMC4041368 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation.

Markunas Christina A CA Enterline David S DS Dunlap Kaitlyn K Soldano Karen K Cope Heidi H Stajich Jeffrey J Grant Gerald G Fuchs Herbert H Gregory Simon G SG Ashley-Koch Allison E AE

Annals of human genetics 20131006 1

Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the base of the skull. Although cerebellar tonsillar herniation (CTH) is hypothesized to result from an underdeveloped posterior cranial fossa (PF), patients are frequently diagnosed by the extent of CTH without cranial morphometric assessment. We recently completed the largest CMI whole genome qualitative linkage screen to date. Despite an initial lack of statistical evidence, stratified analyses u ...[more]

PMID: 24359474

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Project description:Chiari-like malformation (CM) and syringomyelia (SM) is a frequent diagnosis in predisposed brachycephalic toy breeds since increased availability of MRI. However, the relevance of that MRI diagnosis has been questioned as CM, defined as identification of a cerebellar herniation, is ubiquitous in some breeds and SM can be asymptomatic. This article reviews the current knowledge of neuroanatomical changes in symptomatic CM and SM and diagnostic imaging modalities used for the clinical diagnosis of CM-pain or myelopathy related to SM. Although often compared to Chiari type I malformation in humans, canine CM-pain and SM is more comparable to complex craniosynostosis syndromes (i.e., premature fusion of multiple skull sutures) characterized by a short skull (cranial) base, rostrotentorial crowding with rostral forebrain flattening, small, and ventrally orientated olfactory bulbs, displacement of the neural tissue to give increased height of the cranium and further reduction of the functional caudotentorial space with hindbrain herniation. MRI may further reveal changes suggesting raised intracranial pressure such as loss of sulci definition in conjunction with ventriculomegaly. In addition to these brachycephalic changes, dogs with SM are more likely to have craniocervical junction abnormalities including rostral displacement of the axis and atlas with increased odontoid angulation causing craniospinal junction deformation and medulla oblongata elevation. Symptomatic SM is diagnosed on the basis of signs of myelopathy and presence of a large syrinx that is consistent with the neuro-localization. The imaging protocol should establish the longitudinal and transverse extent of the spinal cord involvement by the syrinx. Phantom scratching and cervicotorticollis are associated with large mid-cervical syringes that extend to the superficial dorsal horn. If the cause of CSF channel disruption and syringomyelia is not revealed by anatomical MRI then other imaging modalities may be appropriate with radiography or CT for any associated vertebral abnormalities.

Dataset Information

Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation.

Publications

Genetic evaluation and application of posterior cranial fossa traits as endophenotypes for Chiari type I malformation.

Similar Datasets

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