2. Academic Validation
  3. Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders

Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders

  • Am J Hum Genet. 2019 Nov 7;105(5):1005-1015. doi: 10.1016/j.ajhg.2019.09.017.
Tadahiro Mitani 1,  Jaya Punetha 2,  Ibrahim Akalin 3,  Davut Pehlivan 4,  Mateusz Dawidziuk 5,  Zeynep Coban Akdemir 6,  Sarenur Yilmaz 3,  Ezgi Aslan 7,  Jill V Hunter 8,  Hadia Hijazi 6,  Christopher M Grochowski 6,  Shalini N Jhangiani 9,  Ender Karaca 10,  Jawid M Fatih 6,  Piotr Iwanowski 11,  Tomasz Gambin 12,  Pawel Wlasienko 5,  Alicja Goszczanska-Ciuchta 13,  Monika Bekiesinska-Figatowska 14,  Masoumeh Hosseini 15,  Sanaz Arzhangi 15,  Hossein Najmabadi 15,  Jill A Rosenfeld 6,  Haowei Du 6,  Dana Marafi 16,  Susan Blaser 17,  Ronni Teitelbaum 18,  Rachel Silver 18,  Baylor-Hopkins Center for Mendelian Genomics,  Jennifer E Posey 6,  Hans-Hilger Ropers 19,  Richard A Gibbs 20,  Wojciech Wiszniewski 21,  James R Lupski 22,  David Chitayat 23,  Kimia Kahrizi 15,  Pawel Gawlinski 24
Affiliations

Affiliations

  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: tadahiro.mitani@bcm.edu.
  • 2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Present address: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 3 Department of Medical Genetics, Istanbul Medeniyet University, Faculty of Medicine, Istanbul, 34720, Turkey.
  • 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Section of Neurology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5 Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
  • 6 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 7 Istanbul Medeniyet University, Faculty of Medicine, Istanbul, 34720, Turkey.
  • 8 Department of Radiology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 9 Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, 77030, USA.
  • 10 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Present address: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024, USA.
  • 11 Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, 04-730, Poland.
  • 12 Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland; Institute of Computer Science, Warsaw University of Technology, Warsaw, 00-661, -SA'>04-730, Poland.
  • 13 Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, 01-211, Poland.
  • 14 Department of Diagnostic Imaging, Institute of Mother and Child, Warsaw, 01-211, Poland.
  • 15 Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, 19857, Iran.
  • 16 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110 Safat, Kuwait.
  • 17 Department of Diagnostic Imaging, Division of Pediatric Neuroradiology, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
  • 18 The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1Z5, Canada.
  • 19 Institute for Human Genetics, University Medicine Mainz, Mainz, 55131, Germany.
  • 20 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, 77030, USA.
  • 21 Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland; Department of Molecular and Medical Genetics, Oregon Health and Sciences University, Portland, OR 97239, USA.
  • 22 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 23 The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1Z5, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
  • 24 Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland. Electronic address: pawel.gawlinski@imid.med.pl.
PMID: 31630790 DOI: 10.1016/j.ajhg.2019.09.017
Abstract

Lissencephaly comprises a spectrum of malformations of cortical development. This spectrum includes agyria, pachygyria, and subcortical band heterotopia; each represents anatomical malformations of brain cortical development caused by neuronal migration defects. The molecular etiologies of neuronal migration anomalies are highly enriched for genes encoding microtubules and microtubule-associated proteins, and this enrichment highlights the critical role for these genes in cortical growth and gyrification. Using exome Sequencing and family based rare variant analyses, we identified a homozygous variant (c.997C>T [p.Arg333Cys]) in TUBGCP2, encoding gamma-tubulin complex protein 2 (GCP2), in two individuals from a consanguineous family; both individuals presented with microcephaly and developmental delay. GCP2 forms the multiprotein γ-tubulin ring complex (γ-TuRC) together with γ-tubulin and Other GCPs to regulate the assembly of microtubules. By querying clinical exome Sequencing cases and through GeneMatcher-facilitated collaborations, we found three additional families with bi-allelic variation and similarly affected phenotypes including a homozygous variant (c.1843G>C [p.Ala615Pro]) in two families and compound heterozygous variants consisting of one missense variant (c.889C>T [p.Arg297Cys]) and one splice variant (c.2025-2A>G) in another family. Brain imaging from all five affected individuals revealed varying degrees of cortical malformations including pachygyria and subcortical band heterotopia, presumably caused by disruption of neuronal migration. Our data demonstrate that pathogenic variants in TUBGCP2 cause an autosomal recessive neurodevelopmental trait consisting of a neuronal migration disorder, and our data implicate GCP2 as a core component of γ-TuRC in neuronal migrating cells.

Keywords

GCP2; Lissencephaly; TUBGCP2; cortical malformation; multilocus pathogenic variation; γ-TuRC.

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