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

TitleBi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders.
Publication TypeJournal Article
Year of Publication2019
AuthorsMitani, T, Punetha, J, Akalin, I, Pehlivan, D, Dawidziuk, M, Akdemir, ZCoban, Yilmaz, S, Aslan, E, Hunter, JV, Hijazi, H, Grochowski, CM, Jhangiani, SN, Karaca, E, Fatih, JM, Iwanowski, P, Gambin, T, Wlasienko, P, Goszczanska-Ciuchta, A, Bekiesinska-Figatowska, M, Hosseini, M, Arzhangi, S, Najmabadi, H, Rosenfeld, JA, Du, H, Marafi, D, Blaser, S, Teitelbaum, R, Silver, R, Posey, JE, Ropers, H-H, Gibbs, RA, Wiszniewski, W, Lupski, JR, Chitayat, D, Kahrizi, K, Gawlinski, P
Corporate AuthorsBaylor-Hopkins Center for Mendelian Genomics
JournalAm J Hum Genet
Volume105
Issue5
Pagination1005-1015
Date Published2019 11 07
ISSN1537-6605
KeywordsAlleles, Brain, Cell Movement, Child, Exome, Female, Genetic Variation, Homozygote, Humans, Lissencephaly, Male, Microcephaly, Microtubule-Associated Proteins, Microtubules, Nervous System Malformations, Neurons, Phenotype, Tubulin
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.

DOI10.1016/j.ajhg.2019.09.017
Alternate JournalAm J Hum Genet
PubMed ID31630790
PubMed Central IDPMC6848995
Grant ListT32 GM007526 / GM / NIGMS NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
T32 NS043124 / NS / NINDS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States