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Am J Hum Genet. 2019 Jul 3;105(1):132-150. doi: 10.1016/j.ajhg.2019.05.015. Epub 2019 Jun 20.

The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3
Department of Pediatric Genetics, Istanbul University-Cerrahpasa Medical Faculty, Istanbul 34096, Turkey.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
5
Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, India.
6
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg 20246, Germany.
7
Department of Pediatric Genetics, Marmara University Medical School, Istanbul 34854, Turkey.
8
Department of Medical Genetics, Necip Fazıl City Hospital, Kahramanmaras 46050, Turkey.
9
Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul 34303, Turkey.
10
Department of Medical Genetics, Bezmi Alem Vakif University Faculty of Medicine, Istanbul 34093, Turkey.
11
Department of Pediatrics, Division of Pediatric Genetics, Faculty of Medicine, Ondokuz Mayıs University, Samsun 55270, Turkey.
12
Department of Medical Genetics, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara 06110, Turkey.
13
Department of Medical Genetics, University of Erzurum, School of Medicine, Erzurum 25240, Turkey.
14
Department of Orthopedics and Traumatology, Baltalimani Bone Diseases Training and Research Hospital, Istanbul 34470, Turkey.
15
Department of Medical Genetics, Afyon Kocatepe University, School of Medicine, Afyon 03218, Turkey.
16
Medical Genetics Clinic, Mersin Women and Children Hospital, Mersin 33330, Turkey.
17
Department of Medical Genetics, Faculty of Medicine, Onsekiz Mart University, Canakkale 17000, Turkey.
18
Division of Critical Care Medicine, Department of Pediatrics, University of Health Sciences, Van Training and Research Hospital, Van 65130, Turkey.
19
Department of Physiotherapy and Rehabilitation, Hasan Kalyoncu University, School of Health Sciences, Gaziantep 27000, Turkey.
20
Department of Medical Genetics, Kayseri Training and Research Hospital, Kayseri 38080, Turkey.
21
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
22
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genetics Center, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
23
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
24
Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany.
25
Department of Medical Genetics, Gulhane Military Medical School, Ankara 06010, Turkey.
26
Department of Pediatric Genetics, Marmara University Medical School, Istanbul 34854, Turkey; Eastern Mediterranean University School of Medicine, Cyprus, Mersin 10, Turkey.
27
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.

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.

KEYWORDS:

ES reanalysis; absence of heterozygosity; arthrogryposis; identity-by-descent; joint contracture; multilocus pathogenic variation; neuromuscular disease; trio-exome

PMID:
31230720
PMCID:
PMC6612529
[Available on 2020-01-03]
DOI:
10.1016/j.ajhg.2019.05.015

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