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 JournalArticle

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.
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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 JournalArticle

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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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