Implication of m>LRRC4Cm> and m>DPP6m> in neurodevelopmental disorders

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• 作者：Gilles Maussion ; Cristiana Cruceanu ; Jill A. Rosenfeld ; Scott C. Bell ; Fabrice Jollant ; Jin Szatkiewicz ; Ryan L. Collins ; Carrie Hanscom ; Ilaria Kolobova ; Nicolas Menjot de Champfleur ; Ian Blumenthal ; Colby Chiang ; Vanessa Ota ; Christina Hultman ; Colm O'Dushlaine ; Steve McCarroll ; Martin Alda ; Sebastien Jacquemont ; Zehra Ordulu ; Christian R. Marshall ; Melissa T. Carter ; Lisa G. Shaffer ; Pamela Sklar ; Santhosh Girirajan ; Cynthia C. Morton ; James F. Gusella ; Gustavo Turecki ; Dimitri J. Stavropoulos ; Patrick F. Sullivan ; Stephen W. Scherer ; Michael E. Talkowski and Carl Ernst
• 刊名：American Journal of Medical Genetics Part A
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：173
• 期：2
• 页码：395-406
• 全文大小：1844K
• ISSN：1552-4833

文摘

We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted m>LRRC4Cm>, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted m>DPP6m>, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in m>LRRC4Cm> had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11.2, 1q44, and 2q33.1 CN syndromes, suggesting m>LRRC4Cm> deletion variants may be modifiers of neurodevelopmental disorders. In vitro, functional assessments modeling patient deletions in m>LRRC4Cm> suggest a negative regulatory role of these exons found in the untranslated region of m>LRRC4Cm>, which has a single, terminal coding exon. These data suggest that the proband's autism may be due to the inheritance of disruptions in both m>DPP6m> and m>LRRC4Cm>, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders.