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One CNV Discordance in NRXN1 Observed Upon Genome-wide Screening in 38 Pairs of Adult Healthy Monozygotic Twins

  • Patrik K. E. Magnusson (a1), Donghwan Lee (a2), Xu Chen (a1), Jin Szatkiewicz (a3), Setia Pramana (a4), Shumei Teo (a1), Patrick F. Sullivan (a1) (a3), Lars Feuk (a5) and Yudi Pawitan (a1)...
Abstract

Monozygotic (MZ) twins stem from the same single fertilized egg and therefore share all their inherited genetic variation. This is one of the unequivocal facts on which genetic epidemiology and twin studies are based. To what extent this also implies that MZ twins share genotypes in adult tissues is not precisely established, but a common pragmatic assumption is that MZ twins are 100% genetically identical also in adult tissues. During the past decade, this view has been challenged by several reports, with observations of differences in post-zygotic copy number variations (CNVs) between members of the same MZ pair. In this study, we performed a systematic search for differences of CNVs within 38 adult MZ pairs who had been misclassified as dizygotic (DZ) twins by questionnaire-based assessment. Initial scoring by PennCNV suggested a total of 967 CNV discordances. The within-pair correlation in number of CNVs detected was strongly dependent on confidence score filtering and reached a plateau of r = 0.8 when restricting to CNVs detected with confidence score larger than 50. The top-ranked discordances were subsequently selected for validation by quantitative polymerase chain reaction (qPCR), from which one single ~120kb deletion in NRXN1 on chromosome 2 (bp 51017111–51136802) was validated. Despite involving an exon, no sign of cognitive/mental consequences was apparent in the affected twin pair, potentially reflecting limited or lack of expression of the transcripts containing this exon in nerve/brain.

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      One CNV Discordance in NRXN1 Observed Upon Genome-wide Screening in 38 Pairs of Adult Healthy Monozygotic Twins
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      One CNV Discordance in NRXN1 Observed Upon Genome-wide Screening in 38 Pairs of Adult Healthy Monozygotic Twins
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      One CNV Discordance in NRXN1 Observed Upon Genome-wide Screening in 38 Pairs of Adult Healthy Monozygotic Twins
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Copyright
Corresponding author
address for correspondence: Patrik K. E. Magnusson, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, 17177, Stockholm, Sweden. E-mail: patrik.magnusson@ki.se
References
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Abdellaoui, A., Ehli, E. A., Hottenga, J. J., Weber, Z., Mbarek, H., Willemsen, G., . . . Boomsma, D. I. (2015). CNV concordance in 1,097 MZ twin pairs. Twin Research and Human Genetics, 18, 112.
Bassett, A. S., Scherer, S. W., & Brzustowicz, L. M. (2010). Copy number variations in schizophrenia: Critical review and new perspectives on concepts of genetics and disease. American Journal of Psychiatry, 167, 899914.
Bruder, C. E., Piotrowski, A., Gijsbers, A. A., Andersson, R., Erickson, S., Diaz de Stahl, T., . . . Dumanski, J. P. (2008). Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. American Journal of Human Genetics, 82, 763771.
Ching, M. S., Shen, Y., Tan, W. H., Jeste, S. S., Morrow, E. M., Chen, X., . . . Children's Hospital Boston Genotype Phenotype Study Group. (2010). Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 153B, 937947.
Chung, B. H., Tao, V. Q., & Tso, W. W. (2014). Copy number variation and autism: New insights and clinical implications. Journal of the Formosan Medical Association, 113, 400408.
Curran, S., Ahn, J. W., Grayton, H., Collier, D. A., & Ogilvie, C. M. (2013). NRXN1 deletions identified by array comparative genome hybridisation in a clinical case series — Further understanding of the relevance of NRXN1 to neurodevelopmental disorders. Journal of Molecular Psychiatry, 1, 4.
Forsberg, L. A., Rasi, C., Razzaghian, H. R., Pakalapati, G., Waite, L., Thilbeault, K. S., . . . Dumanski, J. P. (2012). Age-related somatic structural changes in the nuclear genome of human blood cells. American Journal of Human Genetics, 90, 217228.
Imitola, J., Walleigh, D., Anderson, C. E., Jethva, R., Carvalho, K. S., Legido, A., & Khurana, D. S. (2014). Fraternal twins with autism, severe cognitive deficit, and epilepsy: Diagnostic role of chromosomal microarray analysis. Seminars in Pediatric Neurology, 21, 167171.
Kirov, G. (2015). CNVs in neuropsychiatric disorders. Human Molecular Genetics, 24, R45–49.
Kirov, G., Rujescu, D., Ingason, A., Collier, D. A., O'Donovan, M. C., & Owen, M. J. (2009). Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophrenia Bulletin, 35, 851854.
Ludvigsson, J. F., Andersson, E., Ekbom, A., Feychting, M., Kim, J. L., Reuterwall, C., . . . Olausson, P. O. (2011). External review and validation of the Swedish national inpatient register. BMC Public Health, 11, 450.
Luo, X., Huang, L., Han, L., Luo, Z., Hu, F., Tieu, R., & Gan, L. (2014). Systematic prioritization and integrative analysis of copy number variations in schizophrenia reveal key schizophrenia susceptibility genes. Schizophrenia Bulletin, 40, 12851299.
Magnusson, P. K., Almqvist, C., Rahman, I., Ganna, A., Viktorin, A., Walum, H., . . . Lichtenstein, P. (2013). The Swedish Twin Registry: Establishment of a biobank and other recent developments. Twin Research and Human Genetics, 16, 317329.
Marenne, G., Rodriguez-Santiago, B., Closas, M. G., Perez-Jurado, L., Rothman, N., Rico, D., . . . Malats, N. (2011). Assessment of copy number variation using the Illumina Infinium 1M SNP-array: A comparison of methodological approaches in the Spanish Bladder Cancer/EPICURO study. Human Mutation, 32, 240248.
McCarroll, S. A., & Altshuler, D. M. (2007). Copy-number variation and association studies of human disease. Nature Genetics, 39 (Suppl.), S37S42.
McRae, A. F., Visscher, P. M., Montgomery, G. W., & Martin, N. G. (2015). Large autosomal copy-number differences within unselected monozygotic twin pairs are rare. Twin Research and Human Genetics, 18, 1318.
Neale, M. C., & Cardon, L. R. (1992). Methodology for genetic studies of twins and families. Dordrecht: Kluwer Academic.
Szatkiewicz, J. P., O'Dushlaine, C., Chen, G., Chambert, K., Moran, J. L., Neale, B. M., . . . Sullivan, P. F. (2014). Copy number variation in schizophrenia in Sweden. Molecular Psychiatry, 19, 762773.
Teo, S. M., Pawitan, Y., Ku, C. S., Chia, K. S., & Salim, A. (2012). Statistical challenges associated with detecting copy number variations with next-generation sequencing. Bioinformatics, 28, 27112718.
Todarello, G., Feng, N., Kolachana, B. S., Li, C., Vakkalanka, R., Bertolino, A., . . . Straub, R. E. (2014). Incomplete penetrance of NRXN1 deletions in families with schizophrenia. Schizophrenia Research, 155, 17.
Wang, K., Li, M., Hadley, D., Liu, R., Glessner, J., Grant, S. F., . . . Bucan, M. (2007). PennCNV: An integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Research, 17, 16651674.
Zheng, X., Shaffer, J. R., McHugh, C. P., Laurie, C. C., Feenstra, B., Melbye, M., . . . Feingold, E. (2012). Using family data as a verification standard to evaluate copy number variation calling strategies for genetic association studies. Genetic Epidemiology, 36, 253262.
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