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.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Mitani T,Punetha J,Akalin I,Pehlivan D,Dawidziuk M,Coban Akdemir Z,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-Fidoi
10.1016/j.ajhg.2019.09.017subject
Has Abstractpub_date
2019-11-07 00:00:00pages
1005-1015issue
5eissn
0002-9297issn
1537-6605pii
S0002-9297(19)30357-Xjournal_volume
105pub_type
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