title: Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations.
abstract: The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: seemal@bcm.edu.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Lalani
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital Center for Human Immuno-Biology, Houston, TX 77030, USA.
authors.forename: Levi B
authors.initials: LB
authors.lastname: Watkin
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Theodore
authors.initials: T
authors.lastname: Chiang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
authors.forename: Magalie S
authors.initials: MS
authors.lastname: Leduc
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
authors.forename: Wenmiao
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Pan
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vetrini
authors.affiliation: Department of Pediatric Cardiology, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Christina Y
authors.initials: CY
authors.lastname: Miyake
authors.affiliation: Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Marwan
authors.initials: M
authors.lastname: Shinawi
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Eldomery
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zeynep Hande Coban
authors.initials: ZH
authors.lastname: Akdemir
authors.affiliation: Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Emrick
authors.affiliation: Division of Medical Genetics, Stanford School of Medicine, Stanford, CA 94304, USA.
authors.forename: Yael
authors.initials: Y
authors.lastname: Wilnai
authors.affiliation: Division of Medical Genetics, Stanford School of Medicine, Stanford, CA 94304, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Schelley
authors.affiliation: Division of Child & Adolescent Neurology, Department of Pediatrics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Koenig
authors.affiliation: Division of Cardiology, DCH Regional Medical Center, Tuscaloosa, AL 35401, USA.
authors.forename: Nada
authors.initials: N
authors.lastname: Memon
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Farach
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Coe
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mahshid
authors.initials: M
authors.lastname: Azamian
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Hernandez
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Gladys
authors.initials: G
authors.lastname: Zapata
authors.affiliation: 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.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: 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.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Lotze
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Clark
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Angus
authors.initials: A
authors.lastname: Wilfong
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Hope
authors.initials: H
authors.lastname: Northrup
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Adekunle
authors.initials: A
authors.lastname: Adesina
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bacino
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Scaglia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Penelope E
authors.initials: PE
authors.lastname: Bonnen
authors.affiliation: Division of Pediatric Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Crosson
authors.affiliation: Mckusick-Nathans Inst. of Genetic Medicine & Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Duis
authors.affiliation: Mckusick-Nathans Inst. of Genetic Medicine & Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pediatrics, Division of Genetics & Metabolism, University of Florida, Gainsville, FL 32610, USA.
authors.forename: Gustavo H B
authors.initials: GH
authors.lastname: Maegawa
authors.affiliation: Department of Metabolic Medicine, Lady Cilento Children's Hospital, South Brisbane, QLD 4101, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Coman
authors.affiliation: Department of Metabolic Medicine, Lady Cilento Children's Hospital, South Brisbane, QLD 4101, Australia.
authors.forename: Anita
authors.initials: A
authors.lastname: Inwood
authors.affiliation: Department of Metabolic Medicine, Lady Cilento Children's Hospital, South Brisbane, QLD 4101, Australia.
authors.forename: Jim
authors.initials: J
authors.lastname: McGill
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genetics Center, School of Public Health, University of Houston Health Science Center, Houston, TX 77030, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Graham
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Art
authors.initials: A
authors.lastname: Beaudet
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hanchard
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital Center for Human Immuno-Biology, Houston, TX 77030, USA.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA. Electronic address: yapingy@bcm.edu.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000483:Alleles; D018912:Arabs / Q000235:genetics; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D059472:Exome; D005091:Exons; D005260:Female; D017353:Gene Deletion; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D006630:Hispanic or Latino / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D018908:Muscle Weakness / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D012206:Rhabdomyolysis / Q000175:diagnosis / Q000235:genetics*; D044465:White People / Q000235:genetics