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Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence

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Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence. / Dunlop, Elaine A.; Dodd, Kayleigh M.; Land, Stephen C.; Davies, Peter A.; Martins, Nicole; Stuart, Helen; McKee, Shane; Kingswood, Chris; Saggar, Anand; Corderio, Isabel; Medeira, Ana Maria Duarte; Kingston, Helen; Sampson, Julian R.; Davies, David Mark; Tee, Andrew R.

In: European Journal of Human Genetics, Vol. 19, No. 7, 2011, p. 789-795.

Research output: Contribution to journalArticle

Harvard

Dunlop, EA, Dodd, KM, Land, SC, Davies, PA, Martins, N, Stuart, H, McKee, S, Kingswood, C, Saggar, A, Corderio, I, Medeira, AMD, Kingston, H, Sampson, JR, Davies, DM & Tee, AR 2011, 'Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence' European Journal of Human Genetics, vol 19, no. 7, pp. 789-795.

APA

Dunlop, E. A., Dodd, K. M., Land, S. C., Davies, P. A., Martins, N., Stuart, H., McKee, S., Kingswood, C., Saggar, A., Corderio, I., Medeira, A. M. D., Kingston, H., Sampson, J. R., Davies, D. M., & Tee, A. R. (2011). Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence. European Journal of Human Genetics, 19(7), 789-795doi: 10.1038/ejhg.2011.38

Vancouver

Dunlop EA, Dodd KM, Land SC, Davies PA, Martins N, Stuart H et al. Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence. European Journal of Human Genetics. 2011;19(7):789-795.

Author

Dunlop, Elaine A.; Dodd, Kayleigh M.; Land, Stephen C.; Davies, Peter A.; Martins, Nicole; Stuart, Helen; McKee, Shane; Kingswood, Chris; Saggar, Anand; Corderio, Isabel; Medeira, Ana Maria Duarte; Kingston, Helen; Sampson, Julian R.; Davies, David Mark; Tee, Andrew R. / Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence.

In: European Journal of Human Genetics, Vol. 19, No. 7, 2011, p. 789-795.

Research output: Contribution to journalArticle

Bibtex - Download

@article{a3e932ce0e614e8480daf2a05ef7075c,
title = "Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence",
author = "Dunlop, {Elaine A.} and Dodd, {Kayleigh M.} and Land, {Stephen C.} and Davies, {Peter A.} and Nicole Martins and Helen Stuart and Shane McKee and Chris Kingswood and Anand Saggar and Isabel Corderio and Medeira, {Ana Maria Duarte} and Helen Kingston and Sampson, {Julian R.} and Davies, {David Mark} and Tee, {Andrew R.}",
year = "2011",
volume = "19",
number = "7",
pages = "789--795",
journal = "European Journal of Human Genetics",
issn = "1018-4813",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence

A1 - Dunlop,Elaine A.

A1 - Dodd,Kayleigh M.

A1 - Land,Stephen C.

A1 - Davies,Peter A.

A1 - Martins,Nicole

A1 - Stuart,Helen

A1 - McKee,Shane

A1 - Kingswood,Chris

A1 - Saggar,Anand

A1 - Corderio,Isabel

A1 - Medeira,Ana Maria Duarte

A1 - Kingston,Helen

A1 - Sampson,Julian R.

A1 - Davies,David Mark

A1 - Tee,Andrew R.

AU - Dunlop,Elaine A.

AU - Dodd,Kayleigh M.

AU - Land,Stephen C.

AU - Davies,Peter A.

AU - Martins,Nicole

AU - Stuart,Helen

AU - McKee,Shane

AU - Kingswood,Chris

AU - Saggar,Anand

AU - Corderio,Isabel

AU - Medeira,Ana Maria Duarte

AU - Kingston,Helen

AU - Sampson,Julian R.

AU - Davies,David Mark

AU - Tee,Andrew R.

PY - 2011

Y1 - 2011

N2 - <p>Tuberous sclerosis complex (TSC) is a genetic condition characterized by the growth of benign tumours in multiple organs, including the brain and kidneys, alongside intellectual disability and seizures. Identification of a causative mutation in TSC1 or TSC2 is important for accurate genetic counselling in affected families, but it is not always clear from genetic data whether a sequence variant is pathogenic or not. In vitro functional analysis could provide support for determining whether an unclassified TSC1 or TSC2 variant is disease-causing. We have performed a detailed functional analysis of four patient-derived TSC2 mutations, E92V, R505Q, H597R and L1624P. One mutant, E92V, functioned similarly to wild-type TSC2, whereas H597R and L1624P had abnormal function in all assays, consistent with available clinical and segregation information. One TSC2 mutation, R505Q, was identified in a patient with intellectual disability, seizures and autistic spectrum disorder but who did not fulfil the diagnostic criteria for TSC. The R505Q mutation was also found in two relatives, one with mild learning difficulties and one without apparent phenotypic abnormality. R505Q TSC2 exhibited partially disrupted function in our assays. These data highlight the difficulties of assessing pathogenicity of a mutation and suggest that multiple lines of evidence, both genetic and functional, are required to assess the pathogenicity of some mutations. European Journal of Human Genetics (2011) 19, 789-795; doi:10.1038/ejhg.2011.38; published online 16 March 2011</p>

AB - <p>Tuberous sclerosis complex (TSC) is a genetic condition characterized by the growth of benign tumours in multiple organs, including the brain and kidneys, alongside intellectual disability and seizures. Identification of a causative mutation in TSC1 or TSC2 is important for accurate genetic counselling in affected families, but it is not always clear from genetic data whether a sequence variant is pathogenic or not. In vitro functional analysis could provide support for determining whether an unclassified TSC1 or TSC2 variant is disease-causing. We have performed a detailed functional analysis of four patient-derived TSC2 mutations, E92V, R505Q, H597R and L1624P. One mutant, E92V, functioned similarly to wild-type TSC2, whereas H597R and L1624P had abnormal function in all assays, consistent with available clinical and segregation information. One TSC2 mutation, R505Q, was identified in a patient with intellectual disability, seizures and autistic spectrum disorder but who did not fulfil the diagnostic criteria for TSC. The R505Q mutation was also found in two relatives, one with mild learning difficulties and one without apparent phenotypic abnormality. R505Q TSC2 exhibited partially disrupted function in our assays. These data highlight the difficulties of assessing pathogenicity of a mutation and suggest that multiple lines of evidence, both genetic and functional, are required to assess the pathogenicity of some mutations. European Journal of Human Genetics (2011) 19, 789-795; doi:10.1038/ejhg.2011.38; published online 16 March 2011</p>

KW - TSC

KW - mutation

KW - function

KW - pathogenicity

KW - TUBEROUS SCLEROSIS COMPLEX

KW - MISSENSE MUTATIONS

KW - MAMMALIAN TARGET

KW - GENE-PRODUCTS

KW - IDENTIFICATION

KW - MTOR

KW - RHEB

KW - MOTIF

KW - PHOSPHORYLATION

KW - GTPASE

U2 - 10.1038/ejhg.2011.38

DO - 10.1038/ejhg.2011.38

M1 - Article

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

IS - 7

VL - 19

SP - 789

EP - 795

ER -

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