Implication of LRRC4C and DPP6 in neurodevelopmental disorders

• Published in: American journal of medical genetics. Part A Vol. 173; no. 2; pp. 395 - 406
• Main Authors: Maussion, Gilles, Cruceanu, Cristiana, Rosenfeld, Jill A., Bell, Scott C., Jollant, Fabrice, Szatkiewicz, Jin, Collins, Ryan L., Hanscom, Carrie, Kolobova, Ilaria, de Champfleur, Nicolas Menjot, Blumenthal, Ian, Chiang, Colby, Ota, Vanessa, Hultman, Christina, O'Dushlaine, Colm, McCarroll, Steve, Alda, Martin, Jacquemont, Sebastien, Ordulu, Zehra, Marshall, Christian R., Carter, Melissa T., Shaffer, Lisa G., Sklar, Pamela, Girirajan, Santhosh, Morton, Cynthia C., Gusella, James F., Turecki, Gustavo, Stavropoulos, Dimitri J., Sullivan, Patrick F., Scherer, Stephen W., Talkowski, Michael E., Ernst, Carl
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.02.2017; Wiley
• Subjects: 5' Untranslated Regions; Adolescent; Adult; Apraxias - diagnosis; Apraxias - genetics; Autism; Autistic Disorder - diagnosis; Autistic Disorder - genetics; Axon guidance; Child; Child, Preschool; Chromosome Breakpoints; Chromosome Inversion; Chromosome rearrangements; Cognitive ability; Comparative Genomic Hybridization; Copy number; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - genetics; DNA Copy Number Variations; DPP6; Exons; Female; Gene Expression; Gene Expression Profiling; Genetic Association Studies; Genetics; Genomes; Heredity; High-Throughput Nucleotide Sequencing; Human genetics; Human health and pathology; Humans; Information processing; Karyotype; Life Sciences; LRRC4C; Male; Middle Aged; Multigene Family; Nerve Tissue Proteins - genetics; Netrin G; Neural coding; Neurodevelopmental disorders; Neurodevelopmental Disorders - diagnosis; Neurodevelopmental Disorders - genetics; Pedigree; Phenotype; Phenotypes; Potassium; Potassium Channels - genetics; Receptors, Cell Surface - genetics; Sensory integration; sensory processing; Translocation, Genetic; Young Adult; DPP6; sensory processing; Netrin G; LRRC4C; autism
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.38021

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 LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, 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 LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11.2, 1q44, and 2q33.1 CN syndromes, suggesting LRRC4C deletion variants may be modifiers of neurodevelopmental disorders. In vitro, functional assessments modeling patient deletions in LRRC4C suggest a negative regulatory role of these exons found in the untranslated region of LRRC4C, 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 DPP6 and LRRC4C, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders. © 2016 Wiley Periodicals, Inc.