Cerebral organoids containing an AUTS2 missense variant model microcephaly.

Scientists studied a gene called AUTS2 that, when altered, causes intellectual disability and smaller head size. They grew mini-brains in the lab using cells from a child with this genetic change. These mini-brains were smaller and had problems with brain cell growth compared to normal ones. When researchers fixed the genetic problem, the mini-brains grew better. This helps us understand how this gene affects brain development and could lead to better treatments.

This study investigated AUTS2 gene variants associated with intellectual disability and microcephaly using human cerebral organoids. Researchers created brain organoids from a patient with an AUTS2 missense variant who had primary microcephaly and profound intellectual disability. The patient-derived organoids showed reduced growth, impaired neural progenitor cell proliferation, and disrupted cell organization compared to controls. When researchers corrected the genetic variant using CRISPR gene editing, the organoid defects were rescued.

Single-cell analysis revealed the variant affected genes controlling cell division and WNT signaling pathways. This research demonstrates how AUTS2 variants disrupt early brain development and validates cerebral organoids as a model for studying AUTS2 syndrome mechanisms.

This research advances understanding of AUTS2 syndrome mechanisms and validates cerebral organoids for studying genetic causes of intellectual disability. The identification of specific cellular and molecular pathways affected by AUTS2 variants may inform future therapeutic approaches targeting cell proliferation and WNT signaling.

Study examined only one patient with a specific AUTS2 variant. Cerebral organoids, while valuable models, may not fully recapitulate all aspects of human brain development. Sample size and statistical power details not reported in the abstract.

Variants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain malformations. Here, we use a human cerebral organoid model to investigate the pathophysiology of a heterozygous de novo missense AUTS2 variant identified in a patient with multiple neurological impairments including primary microcephaly and profound intellectual disability. Proband cerebral organoids exhibit reduced growth, deficits in neural progenitor cell (NPC) proliferation and disrupted NPC polarity within ventricular zone-like regions compared to control cerebral organoids. We used CRISPR-Cas9-mediated gene editing to correct this variant and demonstrate rescue of impaired organoid growth and NPC proliferative deficits.

Single-cell RNA sequencing revealed a marked reduction of G1/S transition gene expression and alterations in WNT-β-catenin signalling within proband NPCs, uncovering a novel role for AUTS2 in NPCs during human cortical development. Collectively, these results underscore the value of cerebral organoids to investigate molecular mechanisms underlying AUTS2 syndrome.