# Neurodevelopmental mechanisms in 17q12 CNV disorders and autism > **NIH NIH R01** · BROWN UNIVERSITY · 2024 · $789,482 ## Abstract PROJECT SUMMARY Copy number variants (CNVs) are contiguous gene deletions or duplications that confer susceptibility to neuro- psychiatric and neurodevelopmental disorders (NDDs). Thereby, CNVs offer a powerful opportunity to investi- gate multigenic mechanisms in complex brain disease. Recent studies demonstrate that the 17q12 Deletion (17qDel) is among the strongest CNV risk factors for autism; however, the mechanisms of circuit dysgenesis caused by 17q12Dels remain poorly understood. The objective of this research is to define defective neurode- velopmental mechanisms caused by 17q12 CNVs, particularly 17q12Dels, which represent a high-penetrant, high-confidence risk factor for autism and related neurodevelopmental disorders (NDDs). To meet this objec- tive, we have generated unique experimental resources, including: a 17q12Del mouse; and human 17q12 CNV induced pluripotent stem cells (iPSCs) (with robust controls), from patients with 17q12Dels, as well as from pa- tients with reciprocal 17q12 duplications. Our central hypothesis is that the combinatorial haploinsufficiency of the genes within the interval, including the transcription factor Lhx1, a known regulator of Wnt signaling, dis- rupts multiple steps in brain and circuit development. Notably, we have discovered that 17q12Del mice exhibit a spectrum of anterior brain and craniofacial abnormalities. These phenotypes vary depending on the mouse genetic background, and are akin to, but milder than, the Lhx1-null mouse. The 17q12Del on the inbred C57BL/6N background displays greater phenotypic severity, including neonatal lethality, compared to 17q12Del mice on the outbred CD-1 background, that survive into adulthood with milder cortical and hippo- campal abnormalities. We will pursue the following Aims: 1) Define defective transcriptional mechanisms and molecular pathways in embryonic brain development in 17q12Del mice; 2) Define defective molecular path- ways and rescue strategies in patient-derived 17q12 CNV neurons; and 3) Define postnatal neurodevelopmen- tal and behavioral abnormalities in 17q12Del mice on diverse background genetics using MRI morphometry, molecular and behavioral studies. This research will have a sustained impact on the field given the high level of significance and innovation: 1) 17q12Dels represent an understudied, high-confidence autism locus; 2) the study of Wnt signaling will permit convergence of the 17q12Del mutation with other high-confidence autism genes; 3) we are testing proof-of-concept Wnt-related therapeutics; 4) methodologically, study of an autism- associated mutation on diverse, mouse genetic backgrounds provides an important, experimental paradigm for investigating phenotypic heterogeneity; and 5) we use an integrated translational approach, that involves a multidisciplinary team coordinating cross-species experiments, including in vivo rodent and in vitro human iPSC models, with clinical studies in patients. This research will permit bench-to-beds... ## Key facts - **NIH application ID:** 10942686 - **Project number:** 1R01MH137004-01 - **Recipient organization:** BROWN UNIVERSITY - **Principal Investigator:** Eric M Morrow - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $789,482 - **Award type:** 1 - **Project period:** 2024-09-01 → 2029-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10942686 ## Citation > US National Institutes of Health, RePORTER application 10942686, Neurodevelopmental mechanisms in 17q12 CNV disorders and autism (1R01MH137004-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10942686. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*