The Genomics of Arthrogryposis, a Complex Trait

Candidate Genes and Further Evidence for Oligogenic Inheritance

Baylor-Hopkins Center for Mendelian Genomics

Research output: Contribution to journalArticle

Abstract

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.

Original languageEnglish
Pages (from-to)132-150
Number of pages19
JournalAmerican Journal of Human Genetics
Volume105
Issue number1
DOIs
Publication statusPublished - 03-07-2019

Fingerprint

Arthrogryposis
Multifactorial Inheritance
Genomics
Genes
Exome
Ryanodine Receptor Calcium Release Channel
Mosaicism
Comparative Genomic Hybridization
Genetic Heterogeneity
Polymerase Chain Reaction
Mutation

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

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title = "The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance",
abstract = "Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2{\%} (58/89) of families. Eleven out of 58 families (19.0{\%}) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.",
author = "{Baylor-Hopkins Center for Mendelian Genomics} and Davut Pehlivan and Yavuz Bayram and Nilay Gunes and {Coban Akdemir}, Zeynep and Anju Shukla and Tatjana Bierhals and Burcu Tabakci and Yavuz Sahin and Alper Gezdirici and Fatih, {Jawid M.} and Gulec, {Elif Yilmaz} and Gozde Yesil and Jaya Punetha and Zeynep Ocak and Grochowski, {Christopher M.} and Ender Karaca and Albayrak, {Hatice Mutlu} and Periyasamy Radhakrishnan and Erdem, {Haktan Bagis} and Ibrahim Sahin and Timur Yildirim and Bayhan, {Ilhan A.} and Aysegul Bursali and Muhsin Elmas and Zafer Yuksel and Ozturk Ozdemir and Fatma Silan and Onur Yildiz and Osman Yesilbas and Sedat Isikay and Burhan Balta and Shen Gu and Jhangiani, {Shalini N.} and Harsha Doddapaneni and Jianhong Hu and Muzny, {Donna M.} and Eric Boerwinkle and Gibbs, {Richard A.} and Konstantinos Tsiakas and Maja Hempel and Girisha, {Katta Mohan} and Davut Gul and Posey, {Jennifer E.} and Elcioglu, {Nursel H.} and Beyhan Tuysuz and Lupski, {James R.}",
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The Genomics of Arthrogryposis, a Complex Trait : Candidate Genes and Further Evidence for Oligogenic Inheritance. / Baylor-Hopkins Center for Mendelian Genomics.

In: American Journal of Human Genetics, Vol. 105, No. 1, 03.07.2019, p. 132-150.

Research output: Contribution to journalArticle

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T2 - Candidate Genes and Further Evidence for Oligogenic Inheritance

AU - Baylor-Hopkins Center for Mendelian Genomics

AU - Pehlivan, Davut

AU - Bayram, Yavuz

AU - Gunes, Nilay

AU - Coban Akdemir, Zeynep

AU - Shukla, Anju

AU - Bierhals, Tatjana

AU - Tabakci, Burcu

AU - Sahin, Yavuz

AU - Gezdirici, Alper

AU - Fatih, Jawid M.

AU - Gulec, Elif Yilmaz

AU - Yesil, Gozde

AU - Punetha, Jaya

AU - Ocak, Zeynep

AU - Grochowski, Christopher M.

AU - Karaca, Ender

AU - Albayrak, Hatice Mutlu

AU - Radhakrishnan, Periyasamy

AU - Erdem, Haktan Bagis

AU - Sahin, Ibrahim

AU - Yildirim, Timur

AU - Bayhan, Ilhan A.

AU - Bursali, Aysegul

AU - Elmas, Muhsin

AU - Yuksel, Zafer

AU - Ozdemir, Ozturk

AU - Silan, Fatma

AU - Yildiz, Onur

AU - Yesilbas, Osman

AU - Isikay, Sedat

AU - Balta, Burhan

AU - Gu, Shen

AU - Jhangiani, Shalini N.

AU - Doddapaneni, Harsha

AU - Hu, Jianhong

AU - Muzny, Donna M.

AU - Boerwinkle, Eric

AU - Gibbs, Richard A.

AU - Tsiakas, Konstantinos

AU - Hempel, Maja

AU - Girisha, Katta Mohan

AU - Gul, Davut

AU - Posey, Jennifer E.

AU - Elcioglu, Nursel H.

AU - Tuysuz, Beyhan

AU - Lupski, James R.

PY - 2019/7/3

Y1 - 2019/7/3

N2 - Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.

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