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Am J Med Genet A. 2017 Feb;173(2):395-406. doi: 10.1002/ajmg.a.38021. Epub 2016 Oct 19.

Implication of LRRC4C and DPP6 in neurodevelopmental disorders.

Author information

1
Department of Psychiatry, McGill Group for Suicide Studies, and Douglas Mental Health University Institute, Montreal, Canada.
2
Department of Human Genetics, McGill University, Montreal, Canada.
3
Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, Washington.
4
Nîmes Academic Hospital (CHU), Nîmes, France.
5
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.
6
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.
7
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
8
Department of Neuroradiology, University Hospital Center of Montpellier, Montpellier, France.
9
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
10
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
11
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
12
Department of Genetics, Harvard Medical School, Boston, Massachusetts.
13
Department of Psychiatry Halifax, Dalhousie University, Halifax, Nova Scotia, Canada.
14
Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Montreal, Canada.
15
Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts.
16
Harvard Medical School, Boston, Massachusetts.
17
The Centre for Applied Genomics and Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
18
Regional Genetics Program, The Children's Hospital of Eastern Ontario, Ottawa, Canada.
19
Departments of Neuroscience, Psychiatry and Genetics and Genome Sciences, Mount Sinai Hospital, New York, New York.
20
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania.
21
Departments of Obstetrics, Gynecology, and Reproductive Biology and of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
22
Manchester Academic Health Science Center, University of Manchester, Manchester, United Kingdom.
23
Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
24
Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Canada.
25
Department of Neurology, Harvard Medical School, Boston, Massachusetts.

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.

KEYWORDS:

DPP6; LRRC4C; Netrin G; autism; sensory processing

PMID:
27759917
PMCID:
PMC5833302
DOI:
10.1002/ajmg.a.38021
[Indexed for MEDLINE]
Free PMC Article

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