Small posterior fossa in Chiari I malformation affected families is significantly linked to 1q43-44 and 12q23-24.11 using whole exome sequencing

Abstract

The posterior fossa of the cranium contains the cerebellum and brainstem. Processes that reduce the volume of the posterior fossa squeeze the cerebellum and brainstem caudally, resulting in Chiari I malformation (CM1). CM1 causes neck pain, balance issues, decreased motor skills and headaches in those affected. We have posterior fossa measurements and whole exome sequence data on individuals from 7 extended families from Russia that have a family history of CM1. We performed parametric linkage analyses using an autosomal dominant inheritance model with a disease allele frequency of 0.01 and a penetrance of 0.8 for carriers and 0.0 for non-carriers. Variant-based two-point linkage analysis and gene-based linkage analysis was performed. Our results found a genome-wide significant signal on chromosome 1q43-44 (max HLOD = 3.3) in the variant-based analysis and 12q23 (max HLOD = 4.2) in the gene-based analysis. In both cases, the signal was driven by a single (different) family that contained a long, linked haplotype across the region in question. Using functional annotation, we were able to identify several rare nonsynonymous variants that were enriched in each family. The best candidate genes were rs765865412:G>A in MYBPC1 for the 12q haplotype and rs61749963:A>G in COX20 for the 1q haplotype. Good candidate variants in the 1q haplotype were also identified in CEP170 and AKT. Further laboratory work is planned to verify the causality of these genes.

Fig. 1

CM1 and small posterior fossa phenotyping. a CM1 phenotyping midsagittal T1-weighted MR-image showing the cerebellar tonsils (white arrow) extending ≥5 mm below the foramen magnum in a patient with CM1. b Small posterior fossa diagram of the measurements taken in the midsagittal plane, adapted from an earlier, non-copyrighted publication: Heiss JD, Suffredini G, Bakhtian KD, Sarntinoranont M, Oldfield EH. Normalization of hindbrain morphology after decompression of Chiari malformation Type I. J Neurosurg. 2012;117(5):942-6. Measurements (mm) to assess for the small bone phenotype included: supraocciput length (so, internal occipital protuberance to opisthion); clivus length (cl, apex of dorsum sellae to basion); and basiocciput length (bo, the portion of the clivus below the sphenoocipital synchondrosis). Cerebellar tonsillar ectopia (T, maximum extension of the cerebellar tonsils caudal to the foramen magnum) was not used to assess for the small bone phenotype

Fig. 2

Genome-wide HLOD Scores for Small Posterior Fossa. The genome-wide HLOD scores combined across all 7 families for the variant-based (a) and the gene-based (b) linkage analyses. The lines at 3.3 and 1.9 represent the significant and suggestive thresholds as recommended by Lander and Kruglyak

Fig. 3

LOD scores for Family 4. This figure shows the genome-wide LOD scores for family 4 for the variant based linkage analysis (a) as well as zoomed plots of the chromosome 1 LOD scores for family 4 for the variant-based (b) and gene-based (c) linkage analyses. The line at 1.9 represents the suggestive threshold as recommended by Lander and Kruglyak

Fig. 4

LOD scores for Family 22. This figure shows the genome-wide LOD scores for family 22 for the variant based linkage analysis (a) as well as zoomed plots of the chromosome 12 LOD scores for family 4 for the variant-based (b) and gene-based (c) linkage analyses. The line at 1.9 represents the suggestive threshold as recommended by Lander and Kruglyak