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

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Lissencephaly encompasses a range of cortical malformations, including agyria, pachygyria, and subcortical band heterotopia, stemming from neuronal migration defects.
• Genes involved in microtubule function and associated proteins are frequently implicated in the molecular causes of neuronal migration anomalies, underscoring their importance in brain development.

Purpose of the Study:

• To identify the genetic basis of autosomal recessive neurodevelopmental disorders characterized by cortical malformations and neuronal migration defects.
• To investigate the role of gamma-tubulin complex protein 2 (GCP2) in human brain development and neurodevelopmental disorders.

Main Methods:

• Exome sequencing and family-based rare variant analysis were employed to identify causative genetic variants.
• Clinical exome sequencing data and GeneMatcher collaborations were utilized to find additional affected families.
• Brain imaging (MRI) was performed to assess cortical malformations in affected individuals.

Main Results:

• Bi-allelic variants in TUBGCP2, encoding GCP2, were identified in five families with affected individuals presenting with microcephaly, developmental delay, and cortical malformations (pachygyria, subcortical band heterotopia).
• Identified variants include homozygous (c.997C>T [p.Arg333Cys], c.1843G>C [p.Ala615Pro]) and compound heterozygous (c.889C>T [p.Arg297Cys] and c.2025-2A>G) mutations in TUBGCP2.
• The identified phenotypes are consistent with disrupted neuronal migration, implicating GCP2 in this process.

Conclusions:

• Pathogenic variants in TUBGCP2 cause an autosomal recessive neurodevelopmental disorder characterized by a neuronal migration defect.
• GCP2 is essential for proper neuronal migration and cortical development, functioning as a core component of the gamma-tubulin ring complex (γ-TuRC).
• This study expands the genetic spectrum of lissencephaly and related disorders, highlighting TUBGCP2 as a novel disease gene.