Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation

Laura Addis; Joo Wook Ahn; Richard Dobson; Abhishek Dixit; Caroline M Ogilvie; Dalila Pinto; Andrea K Vaags; Hilary Coon; Pauline Chaste; Scott Wilson; Jeremy R Parr; Joris Andrieux; Bruno Lenne; Zeynep Tumer; Vincenzo Leuzzi; Kristina Aubell; Hannele Koillinen; Sarah Curran; Christian R Marshall; Stephen W Scherer; Lisa J Strug; David A Collier; Deb K Pal

doi:10.1002/humu.22816

Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation

Laura Addis, Joo Wook Ahn, Richard Dobson, Abhishek Dixit, Caroline M Ogilvie, Dalila Pinto, Andrea K Vaags, Hilary Coon, Pauline Chaste, Scott Wilson, Jeremy R Parr, Joris Andrieux, Bruno Lenne, Zeynep Tumer, Vincenzo Leuzzi, Kristina Aubell, Hannele Koillinen, Sarah Curran, Christian R Marshall, Stephen W SchererLisa J Strug, David A Collier, Deb K Pal

Institut for Klinisk Medicin

20 Citationer (Scopus)

Abstract

Copy-number variations (CNVs) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4,092 UK individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridization, with WTCCC controls (n = 4,783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3,143) compared with six additional control groups (n = 6,469). In the clinical discovery series, we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism, and epilepsy. Six further cases with a primary diagnosis of autism spectrum disorder (ASD) and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11,252 controls. We found a significant excess of CNVs in discovery cases compared with controls, P = 7.5 × 10^-3, as well as for autism, P = 2.7 × 10^-3. Our results suggest that ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy. We have identified a significant excess (p = 7.5 × 10^-3) of small deletions (shown as red lines on the figure) at the PAX6-ELP4 locus, 11p13, in three cohorts of patients with neurodevelopmental disorders. The deletions predispose to a range of phenotypes including autism spectrum disorder, language impairment, mental retardation and epilepsy, and likely disrupt the functions of the Elongator protein complex and/or the transcription factor PAX6.

Originalsprog	Engelsk
Tidsskrift	Human Mutation
Vol/bind	36
Udgave nummer	9
Sider (fra-til)	842-50
Antal sider	9
ISSN	1059-7794
DOI	https://doi.org/10.1002/humu.22816
Status	Udgivet - 1 sep. 2015

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10.1002/humu.22816

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Addis, L., Ahn, J. W., Dobson, R., Dixit, A., Ogilvie, C. M., Pinto, D., Vaags, A. K., Coon, H., Chaste, P., Wilson, S., Parr, J. R., Andrieux, J., Lenne, B., Tumer, Z., Leuzzi, V., Aubell, K., Koillinen, H., Curran, S., Marshall, C. R., ... Pal, D. K. (2015). Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation. Human Mutation, 36(9), 842-50. https://doi.org/10.1002/humu.22816

Addis, L, Ahn, JW, Dobson, R, Dixit, A, Ogilvie, CM, Pinto, D, Vaags, AK, Coon, H, Chaste, P, Wilson, S, Parr, JR, Andrieux, J, Lenne, B, Tumer, Z, Leuzzi, V, Aubell, K, Koillinen, H, Curran, S, Marshall, CR, Scherer, SW, Strug, LJ, Collier, DA & Pal, DK 2015, 'Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation', Human Mutation, bind 36, nr. 9, s. 842-50. https://doi.org/10.1002/humu.22816

@article{ced5809e5cdf41a0a3e758c71057030a,

title = "Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation",

abstract = "Copy-number variations (CNVs) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4,092 UK individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridization, with WTCCC controls (n = 4,783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3,143) compared with six additional control groups (n = 6,469). In the clinical discovery series, we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism, and epilepsy. Six further cases with a primary diagnosis of autism spectrum disorder (ASD) and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11,252 controls. We found a significant excess of CNVs in discovery cases compared with controls, P = 7.5 × 10-3, as well as for autism, P = 2.7 × 10-3. Our results suggest that ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy. We have identified a significant excess (p = 7.5 × 10-3) of small deletions (shown as red lines on the figure) at the PAX6-ELP4 locus, 11p13, in three cohorts of patients with neurodevelopmental disorders. The deletions predispose to a range of phenotypes including autism spectrum disorder, language impairment, mental retardation and epilepsy, and likely disrupt the functions of the Elongator protein complex and/or the transcription factor PAX6.",

keywords = "Adolescent, Adult, Autism Spectrum Disorder, Case-Control Studies, Child, Child, Preschool, Comparative Genomic Hybridization, DNA Copy Number Variations, Databases, Genetic, Datasets as Topic, Female, Genetic Association Studies, Humans, Infant, Inheritance Patterns, Intellectual Disability, Language Disorders, Male, Nerve Tissue Proteins, Phenotype, Sequence Deletion, Young Adult",

author = "Laura Addis and Ahn, {Joo Wook} and Richard Dobson and Abhishek Dixit and Ogilvie, {Caroline M} and Dalila Pinto and Vaags, {Andrea K} and Hilary Coon and Pauline Chaste and Scott Wilson and Parr, {Jeremy R} and Joris Andrieux and Bruno Lenne and Zeynep Tumer and Vincenzo Leuzzi and Kristina Aubell and Hannele Koillinen and Sarah Curran and Marshall, {Christian R} and Scherer, {Stephen W} and Strug, {Lisa J} and Collier, {David A} and Pal, {Deb K}",

note = "{\textcopyright} 2015 WILEY PERIODICALS, INC.",

year = "2015",

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doi = "10.1002/humu.22816",

language = "English",

volume = "36",

pages = "842--50",

journal = "Human Mutation",

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TY - JOUR

T1 - Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation

AU - Addis, Laura

AU - Ahn, Joo Wook

AU - Dobson, Richard

AU - Dixit, Abhishek

AU - Ogilvie, Caroline M

AU - Pinto, Dalila

AU - Vaags, Andrea K

AU - Coon, Hilary

AU - Chaste, Pauline

AU - Wilson, Scott

AU - Parr, Jeremy R

AU - Andrieux, Joris

AU - Lenne, Bruno

AU - Tumer, Zeynep

AU - Leuzzi, Vincenzo

AU - Aubell, Kristina

AU - Koillinen, Hannele

AU - Curran, Sarah

AU - Marshall, Christian R

AU - Scherer, Stephen W

AU - Strug, Lisa J

AU - Collier, David A

AU - Pal, Deb K

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Copy-number variations (CNVs) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4,092 UK individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridization, with WTCCC controls (n = 4,783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3,143) compared with six additional control groups (n = 6,469). In the clinical discovery series, we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism, and epilepsy. Six further cases with a primary diagnosis of autism spectrum disorder (ASD) and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11,252 controls. We found a significant excess of CNVs in discovery cases compared with controls, P = 7.5 × 10-3, as well as for autism, P = 2.7 × 10-3. Our results suggest that ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy. We have identified a significant excess (p = 7.5 × 10-3) of small deletions (shown as red lines on the figure) at the PAX6-ELP4 locus, 11p13, in three cohorts of patients with neurodevelopmental disorders. The deletions predispose to a range of phenotypes including autism spectrum disorder, language impairment, mental retardation and epilepsy, and likely disrupt the functions of the Elongator protein complex and/or the transcription factor PAX6.

AB - Copy-number variations (CNVs) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4,092 UK individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridization, with WTCCC controls (n = 4,783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3,143) compared with six additional control groups (n = 6,469). In the clinical discovery series, we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism, and epilepsy. Six further cases with a primary diagnosis of autism spectrum disorder (ASD) and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11,252 controls. We found a significant excess of CNVs in discovery cases compared with controls, P = 7.5 × 10-3, as well as for autism, P = 2.7 × 10-3. Our results suggest that ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy. We have identified a significant excess (p = 7.5 × 10-3) of small deletions (shown as red lines on the figure) at the PAX6-ELP4 locus, 11p13, in three cohorts of patients with neurodevelopmental disorders. The deletions predispose to a range of phenotypes including autism spectrum disorder, language impairment, mental retardation and epilepsy, and likely disrupt the functions of the Elongator protein complex and/or the transcription factor PAX6.

KW - Adolescent

KW - Adult

KW - Autism Spectrum Disorder

KW - Case-Control Studies

KW - Child

KW - Child, Preschool

KW - Comparative Genomic Hybridization

KW - DNA Copy Number Variations

KW - Databases, Genetic

KW - Datasets as Topic

KW - Female

KW - Genetic Association Studies

KW - Humans

KW - Infant

KW - Inheritance Patterns

KW - Intellectual Disability

KW - Language Disorders

KW - Male

KW - Nerve Tissue Proteins

KW - Phenotype

KW - Sequence Deletion

KW - Young Adult

U2 - 10.1002/humu.22816

DO - 10.1002/humu.22816

M3 - Journal article

C2 - 26010655

SN - 1059-7794

VL - 36

SP - 842

EP - 850

JO - Human Mutation

JF - Human Mutation

IS - 9

ER -

Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation

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