Sequence analysis of 17 NRXN1 deletions

Louise Kristine Enggaard Hoeffding, Thomas Hansen, Andrés Ingason, Linh Doung, Johan H Thygesen, Rikke S Møller, Niels Tommerup, George Kirov, Dan Rujescu, Lars A Larsen, Thomas Werge

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

BACKGROUND: Genome instability plays fundamental roles in human evolution and phenotypic variation within our population. This instability leads to genomic rearrangements that are involved in a wide variety of human disorders, including congenital and neurodevelopmental disorders, and cancers. Insight into the molecular mechanisms governing such genomic rearrangements may increase our understanding of disease pathology and evolutionary processes. Here we analyse 17 carriers of non-recurrent deletions in the NRXN1 gene, which have been associated with neurodevelopmental disorders, e.g. schizophrenia, autism and epilepsies.

METHODS: 17 non-recurrent NRXN1 deletions identified by GWA were sequenced to map the breakpoints of each. Meme … etc. was used to identify shared patterns between the deletions and compare these were previously studies on non-recurrent deletions.

RESULTS: We discovered two novel sequence motifs shared between all 17 NRXN1 deletions and a significantly higher AT nucleotide content at the breakpoints, compared to the overall nucleotide content on chromosome 2. We found different alteration of sequence at the breakpoint; small insertions and duplications giving rise to short microhomology sequences.

CONCLUSIONS: No single mechanism seems to be implicated in the deletion events, but the results suggest that NHEJ, FoSTeS or MMBIR is implicated. The two novel sequence motifs together with a high AT content in all in NRXN1 deletions may lead to increased instability leading to a increase susceptibility to a single stranded structures. This favours potentially repaired by NHEJ mechanism of double strand breaks or may leading to replication errors. © 2013 Wiley Periodicals, Inc.

OriginalsprogEngelsk
TidsskriftAmerican Journal of Medical Genetics. Part B: Neuropsychiatric Genetics
Vol/bind165
Udgave nummer1
Sider (fra-til)52-61
ISSN1552-4841
DOI
StatusUdgivet - jan. 2014

Fingeraftryk

Sequence Analysis
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Chromosomes, Human, Pair 2
Pathology
Population
Neoplasms

Citer dette

Enggaard Hoeffding, L. K., Hansen, T., Ingason, A., Doung, L., Thygesen, J. H., Møller, R. S., ... Werge, T. (2014). Sequence analysis of 17 NRXN1 deletions. American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics, 165(1), 52-61. https://doi.org/10.1002/ajmg.b.32204
Enggaard Hoeffding, Louise Kristine ; Hansen, Thomas ; Ingason, Andrés ; Doung, Linh ; Thygesen, Johan H ; Møller, Rikke S ; Tommerup, Niels ; Kirov, George ; Rujescu, Dan ; Larsen, Lars A ; Werge, Thomas. / Sequence analysis of 17 NRXN1 deletions. I: American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics. 2014 ; Bind 165, Nr. 1. s. 52-61.
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title = "Sequence analysis of 17 NRXN1 deletions",
abstract = "BACKGROUND: Genome instability plays fundamental roles in human evolution and phenotypic variation within our population. This instability leads to genomic rearrangements that are involved in a wide variety of human disorders, including congenital and neurodevelopmental disorders, and cancers. Insight into the molecular mechanisms governing such genomic rearrangements may increase our understanding of disease pathology and evolutionary processes. Here we analyse 17 carriers of non-recurrent deletions in the NRXN1 gene, which have been associated with neurodevelopmental disorders, e.g. schizophrenia, autism and epilepsies.METHODS: 17 non-recurrent NRXN1 deletions identified by GWA were sequenced to map the breakpoints of each. Meme … etc. was used to identify shared patterns between the deletions and compare these were previously studies on non-recurrent deletions.RESULTS: We discovered two novel sequence motifs shared between all 17 NRXN1 deletions and a significantly higher AT nucleotide content at the breakpoints, compared to the overall nucleotide content on chromosome 2. We found different alteration of sequence at the breakpoint; small insertions and duplications giving rise to short microhomology sequences.CONCLUSIONS: No single mechanism seems to be implicated in the deletion events, but the results suggest that NHEJ, FoSTeS or MMBIR is implicated. The two novel sequence motifs together with a high AT content in all in NRXN1 deletions may lead to increased instability leading to a increase susceptibility to a single stranded structures. This favours potentially repaired by NHEJ mechanism of double strand breaks or may leading to replication errors. {\circledC} 2013 Wiley Periodicals, Inc.",
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Enggaard Hoeffding, LK, Hansen, T, Ingason, A, Doung, L, Thygesen, JH, Møller, RS, Tommerup, N, Kirov, G, Rujescu, D, Larsen, LA & Werge, T 2014, 'Sequence analysis of 17 NRXN1 deletions', American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics, bind 165, nr. 1, s. 52-61. https://doi.org/10.1002/ajmg.b.32204

Sequence analysis of 17 NRXN1 deletions. / Enggaard Hoeffding, Louise Kristine; Hansen, Thomas; Ingason, Andrés; Doung, Linh; Thygesen, Johan H; Møller, Rikke S; Tommerup, Niels; Kirov, George; Rujescu, Dan; Larsen, Lars A; Werge, Thomas.

I: American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics, Bind 165, Nr. 1, 01.2014, s. 52-61.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Sequence analysis of 17 NRXN1 deletions

AU - Enggaard Hoeffding, Louise Kristine

AU - Hansen, Thomas

AU - Ingason, Andrés

AU - Doung, Linh

AU - Thygesen, Johan H

AU - Møller, Rikke S

AU - Tommerup, Niels

AU - Kirov, George

AU - Rujescu, Dan

AU - Larsen, Lars A

AU - Werge, Thomas

N1 - © 2013 Wiley Periodicals, Inc.

PY - 2014/1

Y1 - 2014/1

N2 - BACKGROUND: Genome instability plays fundamental roles in human evolution and phenotypic variation within our population. This instability leads to genomic rearrangements that are involved in a wide variety of human disorders, including congenital and neurodevelopmental disorders, and cancers. Insight into the molecular mechanisms governing such genomic rearrangements may increase our understanding of disease pathology and evolutionary processes. Here we analyse 17 carriers of non-recurrent deletions in the NRXN1 gene, which have been associated with neurodevelopmental disorders, e.g. schizophrenia, autism and epilepsies.METHODS: 17 non-recurrent NRXN1 deletions identified by GWA were sequenced to map the breakpoints of each. Meme … etc. was used to identify shared patterns between the deletions and compare these were previously studies on non-recurrent deletions.RESULTS: We discovered two novel sequence motifs shared between all 17 NRXN1 deletions and a significantly higher AT nucleotide content at the breakpoints, compared to the overall nucleotide content on chromosome 2. We found different alteration of sequence at the breakpoint; small insertions and duplications giving rise to short microhomology sequences.CONCLUSIONS: No single mechanism seems to be implicated in the deletion events, but the results suggest that NHEJ, FoSTeS or MMBIR is implicated. The two novel sequence motifs together with a high AT content in all in NRXN1 deletions may lead to increased instability leading to a increase susceptibility to a single stranded structures. This favours potentially repaired by NHEJ mechanism of double strand breaks or may leading to replication errors. © 2013 Wiley Periodicals, Inc.

AB - BACKGROUND: Genome instability plays fundamental roles in human evolution and phenotypic variation within our population. This instability leads to genomic rearrangements that are involved in a wide variety of human disorders, including congenital and neurodevelopmental disorders, and cancers. Insight into the molecular mechanisms governing such genomic rearrangements may increase our understanding of disease pathology and evolutionary processes. Here we analyse 17 carriers of non-recurrent deletions in the NRXN1 gene, which have been associated with neurodevelopmental disorders, e.g. schizophrenia, autism and epilepsies.METHODS: 17 non-recurrent NRXN1 deletions identified by GWA were sequenced to map the breakpoints of each. Meme … etc. was used to identify shared patterns between the deletions and compare these were previously studies on non-recurrent deletions.RESULTS: We discovered two novel sequence motifs shared between all 17 NRXN1 deletions and a significantly higher AT nucleotide content at the breakpoints, compared to the overall nucleotide content on chromosome 2. We found different alteration of sequence at the breakpoint; small insertions and duplications giving rise to short microhomology sequences.CONCLUSIONS: No single mechanism seems to be implicated in the deletion events, but the results suggest that NHEJ, FoSTeS or MMBIR is implicated. The two novel sequence motifs together with a high AT content in all in NRXN1 deletions may lead to increased instability leading to a increase susceptibility to a single stranded structures. This favours potentially repaired by NHEJ mechanism of double strand breaks or may leading to replication errors. © 2013 Wiley Periodicals, Inc.

KW - Autistic Disorder

KW - Base Composition

KW - Base Sequence

KW - Cell Adhesion Molecules, Neuronal

KW - DNA Copy Number Variations

KW - DNA End-Joining Repair

KW - Epilepsy

KW - Gene Deletion

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Genomic Instability

KW - Humans

KW - Nerve Tissue Proteins

KW - Schizophrenia

KW - Sequence Analysis, DNA

KW - Breakpoints

KW - Neurexin 1

KW - Deletion

U2 - 10.1002/ajmg.b.32204

DO - 10.1002/ajmg.b.32204

M3 - Journal article

C2 - 24339137

VL - 165

SP - 52

EP - 61

JO - American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics

JF - American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics

SN - 1552-4841

IS - 1

ER -