02582nas a2200541   4500000000100000000000100001008004100002260001500043653001900058653002200077653001600099653002600115653001100141653002800152653001700180653002200197653001400219653002600233653002300259653001700282653003200299100001900331700001900350700002200369700001600391700001500407700002000422700002300442700001900465700002400484700002800508700002000536700002700556700001900583700001700602700001600619700001600635700001600651700002200667700002300689700002200712700001900734245007900753300001200832490000800844520117400852022001402026       2023                            d  c2023-01-0510aAUTS2 syndrome10aAutistic Disorder10aCRISPR-Cas910aCytoskeletal Proteins10aHumans10aIntellectual Disability10aMicrocephaly10aNeural Stem Cells10aorganoids10aTranscription Factors10acerebral organoids10aMicrocephaly10aneurodevelopmental disorder1 aSummer R. Fair1 aWesley Schwind1 aDominic L. Julian1 aAlecia Biel1 aGongbo Guo1 aRyan Rutherford1 aSwetha Ramadesikan1 aJesse Westfall1 aKatherine E. Miller1 aMeisam Naeimi Kararoudi1 aScott E. Hickey1 aTheresa Mihalic Mosher1 aKim L. McBride1 aReid Neinast1 aJames Fitch1 aDean A. Lee1 aPeter White1 aRichard K. Wilson1 aTracy A. Bedrosian1 aDaniel C. Koboldt1 aMark E. Hester00aCerebral organoids containing an AUTS2 missense variant model microcephaly  a387-4040 v1463 aVariants 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.  a1460-2156