TY - JOUR
T1 - Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders
AU - Baylor-Hopkins Center for Mendelian Genomics
AU - Mitani, Tadahiro
AU - Punetha, Jaya
AU - Akalin, Ibrahim
AU - Pehlivan, Davut
AU - Dawidziuk, Mateusz
AU - Coban Akdemir, Zeynep
AU - Yilmaz, Sarenur
AU - Aslan, Ezgi
AU - Hunter, Jill V.
AU - Hijazi, Hadia
AU - Grochowski, Christopher M.
AU - Jhangiani, Shalini N.
AU - Karaca, Ender
AU - Fatih, Jawid M.
AU - Iwanowski, Piotr
AU - Gambin, Tomasz
AU - Wlasienko, Pawel
AU - Goszczanska-Ciuchta, Alicja
AU - Bekiesinska-Figatowska, Monika
AU - Hosseini, Masoumeh
AU - Arzhangi, Sanaz
AU - Najmabadi, Hossein
AU - Rosenfeld, Jill A.
AU - Du, Haowei
AU - Marafi, Dana
AU - Blaser, Susan
AU - Teitelbaum, Ronni
AU - Silver, Rachel
AU - Posey, Jennifer E.
AU - Ropers, Hans Hilger
AU - Gibbs, Richard A.
AU - Wiszniewski, Wojciech
AU - Lupski, James R.
AU - Chitayat, David
AU - Kahrizi, Kimia
AU - Gawlinski, Pawel
N1 - Publisher Copyright:
© 2019 American Society of Human Genetics
PY - 2019/11/7
Y1 - 2019/11/7
N2 - 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.
AB - 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.
KW - GCP2
KW - Lissencephaly
KW - TUBGCP2
KW - cortical malformation
KW - multilocus pathogenic variation
KW - γ-TuRC
UR - http://www.scopus.com/inward/record.url?scp=85074300997&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074300997&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2019.09.017
DO - 10.1016/j.ajhg.2019.09.017
M3 - Article
C2 - 31630790
AN - SCOPUS:85074300997
SN - 0002-9297
VL - 105
SP - 1005
EP - 1015
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -