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<p>3q29 deletion (3q29Del) syndrome is caused by a 1.6&#xa0;Mb copy number variant (CNV) located near the telomeric end of the long arm of the third human chromosome. Hemizygosity of this set of 22 protein-coding genes significantly increases risk for schizophrenia and autism spectrum disorders among other neurodevelopmental conditions, but it is not known which genes in this CNV interval are responsible for these phenotypes. We have evaluated existing literature and public genomic resources for this set of genes, categorizing them based on known cellular functions and assessed their potential as phenotypic drivers. We provide a comprehensive, synthetic review of the essential known functions of 3q29 deleted genes, and how multiple 3q29-encoded proteins may functionally interact. Our analysis reveals that ubiquitination/SUMOylation stands out among processes potentially compromised due to compound haploinsufficiency of four 3q29Del genes (<i>UBXN7</i>, <i>FBXO45</i>, <i>RNF168</i>, <i>SENP5</i>). The available genomic evidence indicates that no single gene in the 3q29 locus is solely responsible for the neurodevelopmental phenotypes of 3q29Del syndrome. Overall, we propose that functional, expression, and gene constraint evidence supports six genes (<i>TFRC</i>,<i> UBXN7</i>,<i> FBXO45</i>,<i> PAK2</i>,<i> NCBP2</i>,<i> DLG1</i>) as the most likely phenotypic drivers in 3q29Del syndrome. Haploinsufficiency of these proteins would likely disrupt metabolic, synaptic, and signaling mechanisms in developing and mature neurons, which collectively may impair neural circuit differentiation and function.</p>

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Driver or passenger? A new assessment of genes in the schizophrenia-associated 3q29 deletion locus for contribution to neurodevelopmental disorders

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月21日

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  • Allyson R. Herriges,
  • Ryan H. Purcell

摘要

3q29 deletion (3q29Del) syndrome is caused by a 1.6 Mb copy number variant (CNV) located near the telomeric end of the long arm of the third human chromosome. Hemizygosity of this set of 22 protein-coding genes significantly increases risk for schizophrenia and autism spectrum disorders among other neurodevelopmental conditions, but it is not known which genes in this CNV interval are responsible for these phenotypes. We have evaluated existing literature and public genomic resources for this set of genes, categorizing them based on known cellular functions and assessed their potential as phenotypic drivers. We provide a comprehensive, synthetic review of the essential known functions of 3q29 deleted genes, and how multiple 3q29-encoded proteins may functionally interact. Our analysis reveals that ubiquitination/SUMOylation stands out among processes potentially compromised due to compound haploinsufficiency of four 3q29Del genes (UBXN7, FBXO45, RNF168, SENP5). The available genomic evidence indicates that no single gene in the 3q29 locus is solely responsible for the neurodevelopmental phenotypes of 3q29Del syndrome. Overall, we propose that functional, expression, and gene constraint evidence supports six genes (TFRC, UBXN7, FBXO45, PAK2, NCBP2, DLG1) as the most likely phenotypic drivers in 3q29Del syndrome. Haploinsufficiency of these proteins would likely disrupt metabolic, synaptic, and signaling mechanisms in developing and mature neurons, which collectively may impair neural circuit differentiation and function.