title: Incomplete penetrance of NRXN1 deletions in families with schizophrenia.
abstract: Neurexin 1 (NRXN1) is a presynaptic neuronal adhesion molecule that interacts with postsynaptic neuroligins in both glutamatergic and GABAergic synapses and is important in synaptic formation and function. NRXN1 deletions increase the risk of schizophrenia, so our aims were to explore this in our family sample, to distinguish de novo from inherited mutations, to examine transmission to affected and unaffected siblings and to estimate penetrance. We performed copy number analyses in NRXN1 using data from Illumina BeadArrays from 635 subjects with schizophrenia (276 in genotyped families), 487 of their unaffected parents and 309 unaffected siblings as well as 635 normal controls, all from the CBDB/NIMH Genetic Study of Schizophrenia. Deletions called by software were confirmed by quantitative PCR and comparative genome hybridization. There were deletions in 15 individuals in 11 families, including de novo exonic deletions in one case and one unaffected sibling. We observed no deletions in controls, 7 deletions in cases (1.10%), and an unexpectedly high deletion frequency in parents (n=5, 1.02%) and siblings (n=3, 0.97%). Three families showed inheritance from an unaffected parent, and in two families an unaffected parent did not transmit to the affected offspring. Thus we have added to the evidence that NRXN1 deletions are more frequent in patients with schizophrenia than in healthy individuals. However, the presence of de novo deletions in unaffected relatives and transmission from and to unaffected family members demonstrated that while the deletions may well have been necessary for some carriers to develop schizophrenia, they were not always sufficient.
authors.affiliation: Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Todarello
authors.affiliation: Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, Intramural Research Program, NIMH, NIH, Bethesda, MD 20892, United States.
authors.forename: Ningping
authors.initials: N
authors.lastname: Feng
authors.affiliation: Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, Intramural Research Program, NIMH, NIH, Bethesda, MD 20892, United States.
authors.forename: Bhaskar S
authors.initials: BS
authors.lastname: Kolachana
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, 855 North Wolfe St, Suite 300, Baltimore, MD 21205, United States.
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.affiliation: Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, Intramural Research Program, NIMH, NIH, Bethesda, MD 20892, United States.
authors.forename: Radhakrishna
authors.initials: R
authors.lastname: Vakkalanka
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, Bari, Italy; Pharma Research and Early Development, Neuroscience DTA, Hoffman-La Roche, Ltd., Basel, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
authors.affiliation: Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, Intramural Research Program, NIMH, NIH, Bethesda, MD 20892, United States; Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, 855 North Wolfe St, Suite 300, Baltimore, MD 21205, United States; Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD 21230, United States; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21230, United States; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21230, United States; Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21230, United States.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, 855 North Wolfe St, Suite 300, Baltimore, MD 21205, United States. Electronic address: richard.straub@libd.org.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Straub
mesh_terms: D000293:Adolescent; D000328:Adult; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019006:Neural Cell Adhesion Molecules; D019683:Penetrance; D012559:Schizophrenia / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*; D055815:Young Adult
chemical_list: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules
keywords: CNV; Copy number variation; Deletion; NRXN1; Neurexin; Schizophrenia