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

Annals of Human Genetics
Christina A MarkunasAllison E Ashley-Koch

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....Continue Reading

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Citations

Mar 6, 2016·Neurology·Wendy J IntroneCamilo Toro
Feb 15, 2017·Neurology·Wendy J IntroneCamilo Toro
Dec 18, 2018·Fluids and Barriers of the CNS·Braden J LawrenceBryn A Martin
Aug 7, 2019·Child's Nervous System : ChNS : Official Journal of the International Society for Pediatric Neurosurgery·Valeria CapraPatrizia De Marco
Feb 6, 2017·Journal of Neurosurgery·Diana AbbottLisa A Cannon-Albright
Dec 23, 2020·American Journal of Human Genetics·Brooke SadlerGabe Haller
Mar 20, 2019·Morphologie : Bulletin De L'Association Des Anatomistes·Q SalardaineC Yardin
Jun 26, 2021·Child's Nervous System : ChNS : Official Journal of the International Society for Pediatric Neurosurgery·Federico BianchiLuca Massimi
Jul 14, 2021·Neurosurgical Review·William H ShumanRaj K Shrivastava

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