Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions

Maria Tropeano; Deirdre Howley; Matthew J Gazzellone; C Ellie Wilson; Joo Wook Ahn; Dimitri J Stavropoulos; Clodagh Murphy; Peggy S Eis; Eli Hatchwell; Richard J B Dobson; Dene Robertson; Muriel Holder; Melita Irving; Dragana Josifova; Annelise Nehammer; Mina Ryten; Debbie Spain; Mark Pitts; Jessica Bramham; Philip Asherson; Sarah Curran; Evangelos Vassos; Gerome Breen; Frances Flinter; Caroline Mackie Ogilvie; David A Collier; Stephen W Scherer; Grainne M Mcalonan; Declan G Murphy

doi:10.1136/jmedgenet-2015-103621

Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions

Maria Tropeano, Deirdre Howley, Matthew J Gazzellone, C Ellie Wilson, Joo Wook Ahn, Dimitri J Stavropoulos, Clodagh Murphy, Peggy S Eis, Eli Hatchwell, Richard J B Dobson, Dene Robertson, Muriel Holder, Melita Irving, Dragana Josifova, Annelise Nehammer, Mina Ryten, Debbie Spain, Mark Pitts, Jessica Bramham, Philip AshersonSarah Curran, Evangelos Vassos, Gerome Breen, Frances Flinter, Caroline Mackie Ogilvie, David A Collier, Stephen W Scherer, Grainne M Mcalonan, Declan G Murphy

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Abstract

Background The pseudoautosomal short stature homeobox-containing (SHOX) gene encodes a homeodomain transcription factor involved in cell-cycle and growth regulation. SHOX/SHOX enhancers deletions cause short stature and skeletal abnormalities in a female-dominant fashion; duplications appear to be rare. Neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASDs), are complex disorders with high heritability and skewed sex ratio; several rare (<1% frequency) CNVs have been implicated in risk.

Methods We analysed data from a discovery series of 90 adult ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation (CGH). Twenty-seven individuals harboured CNV abnormalities, including two unrelated females with microduplications affecting SHOX. To determine the prevalence of SHOX duplications and delineate their associated phenotypic spectrum, we subsequently examined array-CGH data from a follow-up sample of 26 574 patients, including 18 857 with NDD (3541 with ASD).

Results We found a significant enrichment of SHOX microduplications in the NDD cases (p=0.00036; OR 2.21) and, particularly, in those with ASD (p=9.18×10⁻⁷; OR 3.63) compared with 12 594 population-based controls. SHOX duplications affecting the upstream or downstream enhancers were enriched only in females with NDD (p=0.0043; OR 2.69/p=0.00020; OR 7.20), but not in males (p=0.404; OR 1.38/p=0.096; OR 2.21).

Conclusions Microduplications at the SHOX locus are a low penetrance risk factor for ASD/NDD, with increased risk in both sexes. However, a concomitant duplication of SHOX enhancers may be required to trigger a NDD in females. Since specific SHOX isoforms are exclusively expressed in the developing foetal brain, this may reflect the pathogenic effect of altered SHOX protein dosage on neurodevelopment.

Original language	English
Journal	Journal of Medical Genetics
Early online date	12 Apr 2016
DOIs	https://doi.org/10.1136/jmedgenet-2015-103621 https://doi.org/10.1136/jmedgenet-2015-103621
Publication status	Published - 2016

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Tropeano, M., Howley, D., Gazzellone, M. J., Wilson, C. E., Ahn, J. W., Stavropoulos, D. J., Murphy, C., Eis, P. S., Hatchwell, E., Dobson, R. J. B., Robertson, D., Holder, M., Irving, M., Josifova, D., Nehammer, A., Ryten, M., Spain, D., Pitts, M., Bramham, J., ... Murphy, D. G. (2016). Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions. Journal of Medical Genetics. https://doi.org/10.1136/jmedgenet-2015-103621, https://doi.org/10.1136/jmedgenet-2015-103621

@article{9e6df64bfb3544d596693f7deaac21d4,

title = "Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions",

abstract = "Background The pseudoautosomal short stature homeobox-containing (SHOX) gene encodes a homeodomain transcription factor involved in cell-cycle and growth regulation. SHOX/SHOX enhancers deletions cause short stature and skeletal abnormalities in a female-dominant fashion; duplications appear to be rare. Neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASDs), are complex disorders with high heritability and skewed sex ratio; several rare (<1% frequency) CNVs have been implicated in risk. Methods We analysed data from a discovery series of 90 adult ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation (CGH). Twenty-seven individuals harboured CNV abnormalities, including two unrelated females with microduplications affecting SHOX. To determine the prevalence of SHOX duplications and delineate their associated phenotypic spectrum, we subsequently examined array-CGH data from a follow-up sample of 26 574 patients, including 18 857 with NDD (3541 with ASD). Results We found a significant enrichment of SHOX microduplications in the NDD cases (p=0.00036; OR 2.21) and, particularly, in those with ASD (p=9.18×10−7; OR 3.63) compared with 12 594 population-based controls. SHOX duplications affecting the upstream or downstream enhancers were enriched only in females with NDD (p=0.0043; OR 2.69/p=0.00020; OR 7.20), but not in males (p=0.404; OR 1.38/p=0.096; OR 2.21). Conclusions Microduplications at the SHOX locus are a low penetrance risk factor for ASD/NDD, with increased risk in both sexes. However, a concomitant duplication of SHOX enhancers may be required to trigger a NDD in females. Since specific SHOX isoforms are exclusively expressed in the developing foetal brain, this may reflect the pathogenic effect of altered SHOX protein dosage on neurodevelopment. ",

author = "Maria Tropeano and Deirdre Howley and Gazzellone, {Matthew J} and Wilson, {C Ellie} and Ahn, {Joo Wook} and Stavropoulos, {Dimitri J} and Clodagh Murphy and Eis, {Peggy S} and Eli Hatchwell and Dobson, {Richard J B} and Dene Robertson and Muriel Holder and Melita Irving and Dragana Josifova and Annelise Nehammer and Mina Ryten and Debbie Spain and Mark Pitts and Jessica Bramham and Philip Asherson and Sarah Curran and Evangelos Vassos and Gerome Breen and Frances Flinter and Ogilvie, {Caroline Mackie} and Collier, {David A} and Scherer, {Stephen W} and Mcalonan, {Grainne M} and Murphy, {Declan G}",

year = "2016",

doi = "10.1136/jmedgenet-2015-103621",

language = "English",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "B M J PUBLISHING GROUP",

}

Tropeano, M, Howley, D, Gazzellone, MJ, Wilson, CE, Ahn, JW, Stavropoulos, DJ, Murphy, C, Eis, PS, Hatchwell, E, Dobson, RJB , Robertson, D, Holder, M, Irving, M , Josifova, D, Nehammer, A, Ryten, M, Spain, D, Pitts, M, Bramham, J , Asherson, P , Curran, S , Vassos, E , Breen, G , Flinter, F, Ogilvie, CM, Collier, DA, Scherer, SW, Mcalonan, GM & Murphy, DG 2016, 'Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions', Journal of Medical Genetics. https://doi.org/10.1136/jmedgenet-2015-103621, https://doi.org/10.1136/jmedgenet-2015-103621

TY - JOUR

T1 - Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions

AU - Tropeano, Maria

AU - Howley, Deirdre

AU - Gazzellone, Matthew J

AU - Wilson, C Ellie

AU - Ahn, Joo Wook

AU - Stavropoulos, Dimitri J

AU - Murphy, Clodagh

AU - Eis, Peggy S

AU - Hatchwell, Eli

AU - Dobson, Richard J B

AU - Robertson, Dene

AU - Holder, Muriel

AU - Irving, Melita

AU - Josifova, Dragana

AU - Nehammer, Annelise

AU - Ryten, Mina

AU - Spain, Debbie

AU - Pitts, Mark

AU - Bramham, Jessica

AU - Asherson, Philip

AU - Curran, Sarah

AU - Vassos, Evangelos

AU - Breen, Gerome

AU - Flinter, Frances

AU - Ogilvie, Caroline Mackie

AU - Collier, David A

AU - Scherer, Stephen W

AU - Mcalonan, Grainne M

AU - Murphy, Declan G

PY - 2016

Y1 - 2016

N2 - Background The pseudoautosomal short stature homeobox-containing (SHOX) gene encodes a homeodomain transcription factor involved in cell-cycle and growth regulation. SHOX/SHOX enhancers deletions cause short stature and skeletal abnormalities in a female-dominant fashion; duplications appear to be rare. Neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASDs), are complex disorders with high heritability and skewed sex ratio; several rare (<1% frequency) CNVs have been implicated in risk. Methods We analysed data from a discovery series of 90 adult ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation (CGH). Twenty-seven individuals harboured CNV abnormalities, including two unrelated females with microduplications affecting SHOX. To determine the prevalence of SHOX duplications and delineate their associated phenotypic spectrum, we subsequently examined array-CGH data from a follow-up sample of 26 574 patients, including 18 857 with NDD (3541 with ASD). Results We found a significant enrichment of SHOX microduplications in the NDD cases (p=0.00036; OR 2.21) and, particularly, in those with ASD (p=9.18×10−7; OR 3.63) compared with 12 594 population-based controls. SHOX duplications affecting the upstream or downstream enhancers were enriched only in females with NDD (p=0.0043; OR 2.69/p=0.00020; OR 7.20), but not in males (p=0.404; OR 1.38/p=0.096; OR 2.21). Conclusions Microduplications at the SHOX locus are a low penetrance risk factor for ASD/NDD, with increased risk in both sexes. However, a concomitant duplication of SHOX enhancers may be required to trigger a NDD in females. Since specific SHOX isoforms are exclusively expressed in the developing foetal brain, this may reflect the pathogenic effect of altered SHOX protein dosage on neurodevelopment.

AB - Background The pseudoautosomal short stature homeobox-containing (SHOX) gene encodes a homeodomain transcription factor involved in cell-cycle and growth regulation. SHOX/SHOX enhancers deletions cause short stature and skeletal abnormalities in a female-dominant fashion; duplications appear to be rare. Neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASDs), are complex disorders with high heritability and skewed sex ratio; several rare (<1% frequency) CNVs have been implicated in risk. Methods We analysed data from a discovery series of 90 adult ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation (CGH). Twenty-seven individuals harboured CNV abnormalities, including two unrelated females with microduplications affecting SHOX. To determine the prevalence of SHOX duplications and delineate their associated phenotypic spectrum, we subsequently examined array-CGH data from a follow-up sample of 26 574 patients, including 18 857 with NDD (3541 with ASD). Results We found a significant enrichment of SHOX microduplications in the NDD cases (p=0.00036; OR 2.21) and, particularly, in those with ASD (p=9.18×10−7; OR 3.63) compared with 12 594 population-based controls. SHOX duplications affecting the upstream or downstream enhancers were enriched only in females with NDD (p=0.0043; OR 2.69/p=0.00020; OR 7.20), but not in males (p=0.404; OR 1.38/p=0.096; OR 2.21). Conclusions Microduplications at the SHOX locus are a low penetrance risk factor for ASD/NDD, with increased risk in both sexes. However, a concomitant duplication of SHOX enhancers may be required to trigger a NDD in females. Since specific SHOX isoforms are exclusively expressed in the developing foetal brain, this may reflect the pathogenic effect of altered SHOX protein dosage on neurodevelopment.

U2 - 10.1136/jmedgenet-2015-103621

DO - 10.1136/jmedgenet-2015-103621

M3 - Article

SN - 0022-2593

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

ER -

Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions

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