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Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders
- Source :
- Am J Hum Genet
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
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.
- Subjects :
- Male
0301 basic medicine
Microcephaly
Lissencephaly
Biology
Nervous System Malformations
Compound heterozygosity
Microtubules
03 medical and health sciences
0302 clinical medicine
Cell Movement
Tubulin
Report
Genetics
medicine
Humans
Missense mutation
Exome
Child
Gyrification
Alleles
Genetics (clinical)
Exome sequencing
Neurons
Pachygyria
Homozygote
Brain
Genetic Variation
medicine.disease
Phenotype
030104 developmental biology
Neuronal migration disorder
Female
Microtubule-Associated Proteins
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 00029297
- Volume :
- 105
- Database :
- OpenAIRE
- Journal :
- The American Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....d9518ca339fa6b2bb841d7f812e8cbf9