De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes

Nirmal Vadgama, Alan Pittman, Michael Simpson, Niranjanan Nirmalananthan, Robin Murray, Takeo Yoshikawa, Peter De Rijk, Elliott Rees, George Kirov, Deborah Hughes, Tomas Fitzgerald, Mark Kristiansen, Kerra Pearce, Eliza Cerveira, Qihui Zhu, Chengsheng Zhang, Charles Lee, John Hardy, Jamal Nasir

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Recent studies have demonstrated genetic differences between monozygotic (MZ) twins. To test the hypothesis that early post-twinning mutational events associate with phenotypic discordance, we investigated a cohort of 13 twin pairs (n = 26) discordant for various clinical phenotypes using whole-exome sequencing and screened for copy number variation (CNV). We identified a de novo variant in PLCB1, a gene involved in the hydrolysis of lipid phosphorus in milk from dairy cows, associated with lactase non-persistence, and a variant in the mitochondrial complex I gene MT-ND5 associated with amyotrophic lateral sclerosis (ALS). We also found somatic variants in multiple genes (TMEM225B, KBTBD3, TUBGCP4, TFIP11) in another MZ twin pair discordant for ALS. Based on the assumption that discordance between twins could be explained by a common variant with variable penetrance or expressivity, we screened the twin samples for known pathogenic variants that are shared and identified a rare deletion overlapping ARHGAP11B, in the twin pair manifesting with either schizotypal personality disorder or schizophrenia. Parent-offspring trio analysis was implemented for two twin pairs to assess potential association of variants of parental origin with susceptibility to disease. We identified a de novo variant in RASD2 shared by 8-year-old male twins with a suspected diagnosis of autism spectrum disorder (ASD) manifesting as different traits. A de novo CNV duplication was also identified in these twins overlapping CD38, a gene previously implicated in ASD. In twins discordant for Tourette's syndrome, a paternally inherited stop loss variant was detected in AADAC, a known candidate gene for the disorder.

    Original languageEnglish
    Pages (from-to)1121-1133
    Number of pages13
    JournalEuropean journal of human genetics : EJHG
    Volume27
    Early online date18 Mar 2019
    DOIs
    Publication statusPublished - 18 Mar 2019

    Fingerprint

    Monozygotic Twins
    Nucleotides
    Genes
    Amyotrophic Lateral Sclerosis
    Schizotypal Personality Disorder
    Exome
    Lactase
    Tourette Syndrome
    Penetrance
    Disease Susceptibility
    Phosphorus
    Schizophrenia
    Milk
    Hydrolysis
    Phenotype
    Lipids

    Cite this

    Vadgama, Nirmal ; Pittman, Alan ; Simpson, Michael ; Nirmalananthan, Niranjanan ; Murray, Robin ; Yoshikawa, Takeo ; De Rijk, Peter ; Rees, Elliott ; Kirov, George ; Hughes, Deborah ; Fitzgerald, Tomas ; Kristiansen, Mark ; Pearce, Kerra ; Cerveira, Eliza ; Zhu, Qihui ; Zhang, Chengsheng ; Lee, Charles ; Hardy, John ; Nasir, Jamal. / De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes. In: European journal of human genetics : EJHG. 2019 ; Vol. 27. pp. 1121-1133.
    @article{fbb412c9de4140e4bb3cf1cecf485505,
    title = "De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes",
    abstract = "Recent studies have demonstrated genetic differences between monozygotic (MZ) twins. To test the hypothesis that early post-twinning mutational events associate with phenotypic discordance, we investigated a cohort of 13 twin pairs (n = 26) discordant for various clinical phenotypes using whole-exome sequencing and screened for copy number variation (CNV). We identified a de novo variant in PLCB1, a gene involved in the hydrolysis of lipid phosphorus in milk from dairy cows, associated with lactase non-persistence, and a variant in the mitochondrial complex I gene MT-ND5 associated with amyotrophic lateral sclerosis (ALS). We also found somatic variants in multiple genes (TMEM225B, KBTBD3, TUBGCP4, TFIP11) in another MZ twin pair discordant for ALS. Based on the assumption that discordance between twins could be explained by a common variant with variable penetrance or expressivity, we screened the twin samples for known pathogenic variants that are shared and identified a rare deletion overlapping ARHGAP11B, in the twin pair manifesting with either schizotypal personality disorder or schizophrenia. Parent-offspring trio analysis was implemented for two twin pairs to assess potential association of variants of parental origin with susceptibility to disease. We identified a de novo variant in RASD2 shared by 8-year-old male twins with a suspected diagnosis of autism spectrum disorder (ASD) manifesting as different traits. A de novo CNV duplication was also identified in these twins overlapping CD38, a gene previously implicated in ASD. In twins discordant for Tourette's syndrome, a paternally inherited stop loss variant was detected in AADAC, a known candidate gene for the disorder.",
    author = "Nirmal Vadgama and Alan Pittman and Michael Simpson and Niranjanan Nirmalananthan and Robin Murray and Takeo Yoshikawa and {De Rijk}, Peter and Elliott Rees and George Kirov and Deborah Hughes and Tomas Fitzgerald and Mark Kristiansen and Kerra Pearce and Eliza Cerveira and Qihui Zhu and Chengsheng Zhang and Charles Lee and John Hardy and Jamal Nasir",
    year = "2019",
    month = "3",
    day = "18",
    doi = "10.1038/s41431-019-0376-7",
    language = "English",
    volume = "27",
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    Vadgama, N, Pittman, A, Simpson, M, Nirmalananthan, N, Murray, R, Yoshikawa, T, De Rijk, P, Rees, E, Kirov, G, Hughes, D, Fitzgerald, T, Kristiansen, M, Pearce, K, Cerveira, E, Zhu, Q, Zhang, C, Lee, C, Hardy, J & Nasir, J 2019, 'De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes', European journal of human genetics : EJHG, vol. 27, pp. 1121-1133. https://doi.org/10.1038/s41431-019-0376-7

    De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes. / Vadgama, Nirmal; Pittman, Alan; Simpson, Michael; Nirmalananthan, Niranjanan; Murray, Robin; Yoshikawa, Takeo; De Rijk, Peter; Rees, Elliott; Kirov, George; Hughes, Deborah; Fitzgerald, Tomas; Kristiansen, Mark; Pearce, Kerra; Cerveira, Eliza; Zhu, Qihui; Zhang, Chengsheng; Lee, Charles; Hardy, John; Nasir, Jamal.

    In: European journal of human genetics : EJHG, Vol. 27, 18.03.2019, p. 1121-1133.

    Research output: Contribution to journalArticleResearchpeer-review

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    T1 - De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes

    AU - Vadgama, Nirmal

    AU - Pittman, Alan

    AU - Simpson, Michael

    AU - Nirmalananthan, Niranjanan

    AU - Murray, Robin

    AU - Yoshikawa, Takeo

    AU - De Rijk, Peter

    AU - Rees, Elliott

    AU - Kirov, George

    AU - Hughes, Deborah

    AU - Fitzgerald, Tomas

    AU - Kristiansen, Mark

    AU - Pearce, Kerra

    AU - Cerveira, Eliza

    AU - Zhu, Qihui

    AU - Zhang, Chengsheng

    AU - Lee, Charles

    AU - Hardy, John

    AU - Nasir, Jamal

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    AB - Recent studies have demonstrated genetic differences between monozygotic (MZ) twins. To test the hypothesis that early post-twinning mutational events associate with phenotypic discordance, we investigated a cohort of 13 twin pairs (n = 26) discordant for various clinical phenotypes using whole-exome sequencing and screened for copy number variation (CNV). We identified a de novo variant in PLCB1, a gene involved in the hydrolysis of lipid phosphorus in milk from dairy cows, associated with lactase non-persistence, and a variant in the mitochondrial complex I gene MT-ND5 associated with amyotrophic lateral sclerosis (ALS). We also found somatic variants in multiple genes (TMEM225B, KBTBD3, TUBGCP4, TFIP11) in another MZ twin pair discordant for ALS. Based on the assumption that discordance between twins could be explained by a common variant with variable penetrance or expressivity, we screened the twin samples for known pathogenic variants that are shared and identified a rare deletion overlapping ARHGAP11B, in the twin pair manifesting with either schizotypal personality disorder or schizophrenia. Parent-offspring trio analysis was implemented for two twin pairs to assess potential association of variants of parental origin with susceptibility to disease. We identified a de novo variant in RASD2 shared by 8-year-old male twins with a suspected diagnosis of autism spectrum disorder (ASD) manifesting as different traits. A de novo CNV duplication was also identified in these twins overlapping CD38, a gene previously implicated in ASD. In twins discordant for Tourette's syndrome, a paternally inherited stop loss variant was detected in AADAC, a known candidate gene for the disorder.

    UR - http://www.nature.com/articles/s41431-019-0376-7

    UR - http://www.mendeley.com/research/novo-singlenucleotide-copy-number-variation-discordant-monozygotic-twins-reveals-diseaserelated-gene

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