FOXP1-related intellectual disability syndrome: a recognisable entity

Ilse Meerschaut; Daniel Rochefort; Nicole Revençu; Justine Pètre; Christina Corsello; Guy A Rouleau; Fadi F Hamdan; Jacques L Michaud; Jenny Morton; Jessica Radley; Nicola Ragge; Sixto García-Miñaúr; Pablo Lapunzina; Maria Palomares Bralo; Maria Ángeles Mori; Stéphanie Moortgat; Valérie Benoit; Sandrine Mary; Nele Bockaert; Ann Oostra; Olivier Vanakker; Milen Velinov; Thomy Jl de Ravel; Djalila Mekahli; Jonathan Sebat; Keith K Vaux; Nataliya DiDonato; Andrea K Hanson-Kahn; Louanne Hudgins; Bruno Dallapiccola; Antonio Novelli; Luigi Tarani; Joris Andrieux; Michael J Parker; Katherine Neas; Berten Ceulemans; An-Sofie Schoonjans; Darina Prchalova; Marketa Havlovicova; Miroslava Hancarova; Magdalena Budisteanu; Annelies Dheedene; Björn Menten; Patrick A Dion; Damien Lederer; Bert Callewaert

doi:10.1136/jmedgenet-2017-104579

FOXP1-related intellectual disability syndrome: a recognisable entity

Ilse Meerschaut, Daniel Rochefort, Nicole Revençu, Justine Pètre, Christina Corsello, Guy A Rouleau, Fadi F Hamdan, Jacques L Michaud, Jenny Morton, Jessica Radley, Nicola Ragge, Sixto García-Miñaúr, Pablo Lapunzina, Maria Palomares Bralo, Maria Ángeles Mori, Stéphanie Moortgat, Valérie Benoit, Sandrine Mary, Nele Bockaert, Ann OostraOlivier Vanakker, Milen Velinov, Thomy Jl de Ravel, Djalila Mekahli, Jonathan Sebat, Keith K Vaux, Nataliya DiDonato, Andrea K Hanson-Kahn, Louanne Hudgins, Bruno Dallapiccola, Antonio Novelli, Luigi Tarani, Joris Andrieux, Michael J Parker, Katherine Neas, Berten Ceulemans, An-Sofie Schoonjans, Darina Prchalova, Marketa Havlovicova, Miroslava Hancarova, Magdalena Budisteanu, Annelies Dheedene, Björn Menten, Patrick A Dion, Damien Lederer, Bert Callewaert

Research output: Contribution to journal › Article › peer-review

46 Citations (Scopus)

Abstract

BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far.

METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting.

RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability.

CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.

Original language	English
Pages (from-to)	613-623
Number of pages	11
Journal	Journal of Medical Genetics
Volume	54
Issue number	9
DOIs	https://doi.org/10.1136/jmedgenet-2017-104579
Publication status	Published - Sep 2017

Bibliographical note

Keywords

Autism Spectrum Disorder/genetics
Face/abnormalities
Female
Forkhead Transcription Factors/chemistry
Humans
Intellectual Disability/genetics
Language Disorders/genetics
Male
Motor Skills Disorders/genetics
Mutation
Mutation, Missense
Neurodevelopmental Disorders/genetics
Phenotype
Protein Stability
Repressor Proteins/chemistry
Syndrome
Transcription, Genetic

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10.1136/jmedgenet-2017-104579

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Meerschaut, I., Rochefort, D., Revençu, N., Pètre, J., Corsello, C., Rouleau, G. A., Hamdan, F. F., Michaud, J. L., Morton, J., Radley, J., Ragge, N., García-Miñaúr, S., Lapunzina, P., Bralo, M. P., Mori, M. Á., Moortgat, S., Benoit, V., Mary, S., Bockaert, N., ... Callewaert, B. (2017). FOXP1-related intellectual disability syndrome: a recognisable entity. Journal of Medical Genetics, 54(9), 613-623. https://doi.org/10.1136/jmedgenet-2017-104579

Meerschaut, Ilse ; Rochefort, Daniel ; Revençu, Nicole ; Pètre, Justine ; Corsello, Christina ; Rouleau, Guy A ; Hamdan, Fadi F ; Michaud, Jacques L ; Morton, Jenny ; Radley, Jessica ; Ragge, Nicola ; García-Miñaúr, Sixto ; Lapunzina, Pablo ; Bralo, Maria Palomares ; Mori, Maria Ángeles ; Moortgat, Stéphanie ; Benoit, Valérie ; Mary, Sandrine ; Bockaert, Nele ; Oostra, Ann ; Vanakker, Olivier ; Velinov, Milen ; de Ravel, Thomy Jl ; Mekahli, Djalila ; Sebat, Jonathan ; Vaux, Keith K ; DiDonato, Nataliya ; Hanson-Kahn, Andrea K ; Hudgins, Louanne ; Dallapiccola, Bruno ; Novelli, Antonio ; Tarani, Luigi ; Andrieux, Joris ; Parker, Michael J ; Neas, Katherine ; Ceulemans, Berten ; Schoonjans, An-Sofie ; Prchalova, Darina ; Havlovicova, Marketa ; Hancarova, Miroslava ; Budisteanu, Magdalena ; Dheedene, Annelies ; Menten, Björn ; Dion, Patrick A ; Lederer, Damien ; Callewaert, Bert. / FOXP1-related intellectual disability syndrome : a recognisable entity. In: Journal of Medical Genetics. 2017 ; Vol. 54, No. 9. pp. 613-623.

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title = "FOXP1-related intellectual disability syndrome: a recognisable entity",

abstract = "BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far.METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting.RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability.CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.",

keywords = "Autism Spectrum Disorder/genetics, Face/abnormalities, Female, Forkhead Transcription Factors/chemistry, Humans, Intellectual Disability/genetics, Language Disorders/genetics, Male, Motor Skills Disorders/genetics, Mutation, Mutation, Missense, Neurodevelopmental Disorders/genetics, Phenotype, Protein Stability, Repressor Proteins/chemistry, Syndrome, Transcription, Genetic",

author = "Ilse Meerschaut and Daniel Rochefort and Nicole Reven{\c c}u and Justine P{\`e}tre and Christina Corsello and Rouleau, {Guy A} and Hamdan, {Fadi F} and Michaud, {Jacques L} and Jenny Morton and Jessica Radley and Nicola Ragge and Sixto Garc{\'i}a-Mi{\~n}a{\'u}r and Pablo Lapunzina and Bralo, {Maria Palomares} and Mori, {Maria {\'A}ngeles} and St{\'e}phanie Moortgat and Val{\'e}rie Benoit and Sandrine Mary and Nele Bockaert and Ann Oostra and Olivier Vanakker and Milen Velinov and {de Ravel}, {Thomy Jl} and Djalila Mekahli and Jonathan Sebat and Vaux, {Keith K} and Nataliya DiDonato and Hanson-Kahn, {Andrea K} and Louanne Hudgins and Bruno Dallapiccola and Antonio Novelli and Luigi Tarani and Joris Andrieux and Parker, {Michael J} and Katherine Neas and Berten Ceulemans and An-Sofie Schoonjans and Darina Prchalova and Marketa Havlovicova and Miroslava Hancarova and Magdalena Budisteanu and Annelies Dheedene and Bj{\"o}rn Menten and Dion, {Patrick A} and Damien Lederer and Bert Callewaert",

note = "{\textcopyright} Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.",

year = "2017",

month = sep,

doi = "10.1136/jmedgenet-2017-104579",

language = "English",

volume = "54",

pages = "613--623",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

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Meerschaut, I, Rochefort, D, Revençu, N, Pètre, J, Corsello, C, Rouleau, GA, Hamdan, FF, Michaud, JL, Morton, J, Radley, J, Ragge, N, García-Miñaúr, S, Lapunzina, P, Bralo, MP, Mori, MÁ, Moortgat, S, Benoit, V, Mary, S, Bockaert, N, Oostra, A, Vanakker, O, Velinov, M, de Ravel, TJ, Mekahli, D, Sebat, J, Vaux, KK, DiDonato, N, Hanson-Kahn, AK, Hudgins, L, Dallapiccola, B, Novelli, A, Tarani, L, Andrieux, J, Parker, MJ, Neas, K, Ceulemans, B, Schoonjans, A-S, Prchalova, D, Havlovicova, M, Hancarova, M, Budisteanu, M, Dheedene, A, Menten, B, Dion, PA, Lederer, D & Callewaert, B 2017, 'FOXP1-related intellectual disability syndrome: a recognisable entity', Journal of Medical Genetics, vol. 54, no. 9, pp. 613-623. https://doi.org/10.1136/jmedgenet-2017-104579

FOXP1-related intellectual disability syndrome : a recognisable entity. / Meerschaut, Ilse; Rochefort, Daniel; Revençu, Nicole; Pètre, Justine; Corsello, Christina; Rouleau, Guy A; Hamdan, Fadi F; Michaud, Jacques L; Morton, Jenny; Radley, Jessica; Ragge, Nicola; García-Miñaúr, Sixto; Lapunzina, Pablo; Bralo, Maria Palomares; Mori, Maria Ángeles; Moortgat, Stéphanie; Benoit, Valérie; Mary, Sandrine; Bockaert, Nele; Oostra, Ann; Vanakker, Olivier; Velinov, Milen; de Ravel, Thomy Jl; Mekahli, Djalila; Sebat, Jonathan; Vaux, Keith K; DiDonato, Nataliya; Hanson-Kahn, Andrea K; Hudgins, Louanne; Dallapiccola, Bruno; Novelli, Antonio; Tarani, Luigi; Andrieux, Joris; Parker, Michael J; Neas, Katherine; Ceulemans, Berten; Schoonjans, An-Sofie; Prchalova, Darina; Havlovicova, Marketa; Hancarova, Miroslava; Budisteanu, Magdalena; Dheedene, Annelies; Menten, Björn; Dion, Patrick A; Lederer, Damien; Callewaert, Bert.

In: Journal of Medical Genetics, Vol. 54, No. 9, 09.2017, p. 613-623.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - FOXP1-related intellectual disability syndrome

T2 - a recognisable entity

AU - Meerschaut, Ilse

AU - Rochefort, Daniel

AU - Revençu, Nicole

AU - Pètre, Justine

AU - Corsello, Christina

AU - Rouleau, Guy A

AU - Hamdan, Fadi F

AU - Michaud, Jacques L

AU - Morton, Jenny

AU - Radley, Jessica

AU - Ragge, Nicola

AU - García-Miñaúr, Sixto

AU - Lapunzina, Pablo

AU - Bralo, Maria Palomares

AU - Mori, Maria Ángeles

AU - Moortgat, Stéphanie

AU - Benoit, Valérie

AU - Mary, Sandrine

AU - Bockaert, Nele

AU - Oostra, Ann

AU - Vanakker, Olivier

AU - Velinov, Milen

AU - de Ravel, Thomy Jl

AU - Mekahli, Djalila

AU - Sebat, Jonathan

AU - Vaux, Keith K

AU - DiDonato, Nataliya

AU - Hanson-Kahn, Andrea K

AU - Hudgins, Louanne

AU - Dallapiccola, Bruno

AU - Novelli, Antonio

AU - Tarani, Luigi

AU - Andrieux, Joris

AU - Parker, Michael J

AU - Neas, Katherine

AU - Ceulemans, Berten

AU - Schoonjans, An-Sofie

AU - Prchalova, Darina

AU - Havlovicova, Marketa

AU - Hancarova, Miroslava

AU - Budisteanu, Magdalena

AU - Dheedene, Annelies

AU - Menten, Björn

AU - Dion, Patrick A

AU - Lederer, Damien

AU - Callewaert, Bert

PY - 2017/9

Y1 - 2017/9

N2 - BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far.METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting.RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability.CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.

AB - BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far.METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting.RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability.CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.

KW - Autism Spectrum Disorder/genetics

KW - Face/abnormalities

KW - Female

KW - Forkhead Transcription Factors/chemistry

KW - Humans

KW - Intellectual Disability/genetics

KW - Language Disorders/genetics

KW - Male

KW - Motor Skills Disorders/genetics

KW - Mutation

KW - Mutation, Missense

KW - Neurodevelopmental Disorders/genetics

KW - Phenotype

KW - Protein Stability

KW - Repressor Proteins/chemistry

KW - Syndrome

KW - Transcription, Genetic

U2 - 10.1136/jmedgenet-2017-104579

DO - 10.1136/jmedgenet-2017-104579

M3 - Article

C2 - 28735298

VL - 54

SP - 613

EP - 623

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 9

ER -

FOXP1-related intellectual disability syndrome: a recognisable entity

Abstract

Bibliographical note

Keywords

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