title: Implication of LRRC4C and DPP6 in neurodevelopmental disorders.
abstract: 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.
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, and Douglas Mental Health University Institute, Montreal, Canada.
authors.forename: Gilles
authors.initials: G
authors.lastname: Maussion
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, and Douglas Mental Health University Institute, Montreal, Canada.|Department of Human Genetics, McGill University, Montreal, Canada.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Cruceanu
authors.affiliation: Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, Washington.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, and Douglas Mental Health University Institute, Montreal, Canada.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Bell
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, and Douglas Mental Health University Institute, Montreal, Canada.|Nîmes Academic Hospital (CHU), Nîmes, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jollant
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Jin
authors.initials: J
authors.lastname: Szatkiewicz
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Collins
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Carrie
authors.initials: C
authors.lastname: Hanscom
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, and Douglas Mental Health University Institute, Montreal, Canada.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Kolobova
authors.affiliation: Department of Neuroradiology, University Hospital Center of Montpellier, Montpellier, France.
authors.forename: Nicolas Menjot
authors.initials: NM
authors.lastname: de Champfleur
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Ian
authors.initials: I
authors.lastname: Blumenthal
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.|McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Colby
authors.initials: C
authors.lastname: Chiang
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, and Douglas Mental Health University Institute, Montreal, Canada.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ota
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Christina
authors.initials: C
authors.lastname: Hultman
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Colm
authors.initials: C
authors.lastname: O'Dushlaine
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.|Department of Genetics, Harvard Medical School, Boston, Massachusetts.
authors.forename: Steve
authors.initials: S
authors.lastname: McCarroll
authors.affiliation: Department of Psychiatry Halifax, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Alda
authors.affiliation: Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Montreal, Canada.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Jacquemont
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Zehra
authors.initials: Z
authors.lastname: Ordulu
authors.affiliation: The Centre for Applied Genomics and Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: Regional Genetics Program, The Children's Hospital of Eastern Ontario, Ottawa, Canada.
authors.forename: Melissa T
authors.initials: MT
authors.lastname: Carter
authors.affiliation: Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, Washington.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.affiliation: Departments of Neuroscience, Psychiatry and Genetics and Genome Sciences, Mount Sinai Hospital, New York, New York.
authors.forename: Pamela
authors.initials: P
authors.lastname: Sklar
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Girirajan
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.|Departments of Obstetrics, Gynecology, and Reproductive Biology and of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.|Manchester Academic Health Science Center, University of Manchester, Manchester, United Kingdom.
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Morton
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.|Department of Genetics, Harvard Medical School, Boston, Massachusetts.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, and Douglas Mental Health University Institute, Montreal, Canada.|Department of Human Genetics, McGill University, Montreal, Canada.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
authors.affiliation: Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Dimitri J
authors.initials: DJ
authors.lastname: Stavropoulos
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
authors.affiliation: The Centre for Applied Genomics and Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.|Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.|Department of Neurology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
authors.affiliation: Department of Psychiatry, McGill Group for Suicide Studies, and Douglas Mental Health University Institute, Montreal, Canada.|Department of Human Genetics, McGill University, Montreal, Canada.
authors.forename: Carl
authors.initials: C
authors.lastname: Ernst
mesh_terms: D020121:5' Untranslated Regions; D000293:Adolescent; D000328:Adult; D001072:Apraxias / Q000175:diagnosis / Q000235:genetics; D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D056905:Chromosome Breakpoints; D007446:Chromosome Inversion; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D059785:Karyotype; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics*; D065886:Neurodevelopmental Disorders / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: D020121:5' Untranslated Regions; C480698:LRRC4C protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D011956:Receptors, Cell Surface; C503535:DPP6 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
keywords: DPP6; LRRC4C; Netrin G; autism; sensory processing