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

Anthony M. Musolf, Winson S.C. Ho, Kyle A. Long, Zhengping Zhuang, Davis P. Argersinger, Haiming Sun, Bilal A. Moiz, Claire Simpson, Elena G. Mendelevich, Enver I. Bogdanov, Joan E. Bailey-Wilson, John D. Heiss

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalEuropean Journal of Human Genetics
DOIs
StatePublished - Jan 1 2019

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Exome
Haplotypes
Cerebellum
Genes
Brain Stem
Motor Skills
Penetrance
Neck Pain
Russia
Gene Frequency
Skull
Causality
Headache
Chromosomes
Genome

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Small posterior fossa in Chiari I malformation affected families is significantly linked to 1q43-44 and 12q23-24.11 using whole exome sequencing. / Musolf, Anthony M.; Ho, Winson S.C.; Long, Kyle A.; Zhuang, Zhengping; Argersinger, Davis P.; Sun, Haiming; Moiz, Bilal A.; Simpson, Claire; Mendelevich, Elena G.; Bogdanov, Enver I.; Bailey-Wilson, Joan E.; Heiss, John D.

In: European Journal of Human Genetics, 01.01.2019.

Research output: Contribution to journalArticle

Musolf, Anthony M. ; Ho, Winson S.C. ; Long, Kyle A. ; Zhuang, Zhengping ; Argersinger, Davis P. ; Sun, Haiming ; Moiz, Bilal A. ; Simpson, Claire ; Mendelevich, Elena G. ; Bogdanov, Enver I. ; Bailey-Wilson, Joan E. ; Heiss, John D. / Small posterior fossa in Chiari I malformation affected families is significantly linked to 1q43-44 and 12q23-24.11 using whole exome sequencing. In: European Journal of Human Genetics. 2019.
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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.",
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AU - Musolf, Anthony M.

AU - Ho, Winson S.C.

AU - Long, Kyle A.

AU - Zhuang, Zhengping

AU - Argersinger, Davis P.

AU - Sun, Haiming

AU - Moiz, Bilal A.

AU - Simpson, Claire

AU - Mendelevich, Elena G.

AU - Bogdanov, Enver I.

AU - Bailey-Wilson, Joan E.

AU - Heiss, John D.

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AB - 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.

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