POU3F3-related disorder: Defining the phenotype and expanding the molecular spectrum

Alessandra Rossi; Lot Snijders Blok; Sonja Neuser; Chiara Klöckner; Konrad Platzer; Laurence Olivier Faivre; Heike Weigand; Maria L Dentici; Marco Tartaglia; Marcello Niceta; Paolo Alfieri; Siddharth Srivastava; David Coulter; Lacey Smith; Kristin Vinorum; Gerarda Cappuccio; Nicola Brunetti-Pierri; Deniz Torun; Mutluay Arslan; Mathilde F Lauridsen; Oliver Murch; Rachel Irving; Sally A Lynch; Sarju G Mehta; Jenny Carmichael; Evelien Zonneveld-Huijssoon; Bert de Vries; Tjitske Kleefstra; Katrine M Johannesen; Ian T Westphall; Susan S Hughes; Sarah Smithson; Julie Evans; Tracy Dudding-Byth; Marleen Simon; Ellen van Binsbergen; Johanna C Herkert; Gea Beunders; Henry Oppermann; Mert Bakal; Rikke S Møller; Guido Rubboli; Allan Bayat

doi:10.1111/cge.14353

POU3F3-related disorder: Defining the phenotype and expanding the molecular spectrum

Alessandra Rossi^*
, Lot Snijders Blok
, Sonja Neuser
, Chiara Klöckner
, Konrad Platzer
, Laurence Olivier Faivre
, Heike Weigand
, Maria L Dentici
, Marco Tartaglia
, Marcello Niceta
, Paolo Alfieri
, Siddharth Srivastava
, David Coulter
, Lacey Smith
, Kristin Vinorum
, Gerarda Cappuccio
, Nicola Brunetti-Pierri
, Deniz Torun
, Mutluay Arslan
, Mathilde F Lauridsen

Oliver Murch, Rachel Irving, Sally A Lynch, Sarju G Mehta, Jenny Carmichael, Evelien Zonneveld-Huijssoon, Bert de Vries, Tjitske Kleefstra, Katrine M Johannesen, Ian T Westphall, Susan S Hughes, Sarah Smithson, Julie Evans, Tracy Dudding-Byth, Marleen Simon, Ellen van Binsbergen, Johanna C Herkert, Gea Beunders, Henry Oppermann, Mert Bakal, Rikke S Møller, Guido Rubboli, Allan Bayat^*

^*Corresponding author for this work

Filadelfia

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

Abstract

POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.

Original language	English
Pages (from-to)	186-197
Number of pages	12
Journal	Clinical Genetics
Volume	104
Issue number	2
Early online date	10 May 2023
DOIs	https://doi.org/10.1111/cge.14353
Publication status	Published - Aug 2023

Funding

The authors would like to thank the families for their participation. This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from and via email from [email protected]. Funding for the DECIPHER project was provided by Wellcome. This study was also, in part, generated within the European Reference Network ITHACA (NBP). This work was in part supported by the Telethon Foundation, Telethon Undiagnosed Diseases Program (TUDP, GSP15001 to Nicola Brunetti-Pierri). Siddharth Srivastava is funded by NIH-NINDS (K23NS119666). Allan Bayat is funded by a BRIDGE-Translational Excellence Program grant funded by the Novo Nordisk Foundation, grant agreement number: NNF20SA0064340.

Funders	Funder number
Wellcome Trust
Fondazione Telethon
National Institutes of Health	K23NS119666
Novo Nordisk Foundation	NNF20SA0064340

Keywords

Autistic Disorder/genetics
Child
Developmental Disabilities/genetics
Epilepsy/genetics
Humans
Intellectual Disability/genetics
Mutation, Missense/genetics
POU Domain Factors/genetics
Phenotype
Cupped ears
Epilepsy
Neurodevelopmental disorder
Autism

Access to Document

10.1111/cge.14353

Cite this

Rossi, A., Blok, L. S., Neuser, S., Klöckner, C., Platzer, K., Faivre, L. O., Weigand, H., Dentici, M. L., Tartaglia, M., Niceta, M., Alfieri, P., Srivastava, S., Coulter, D., Smith, L., Vinorum, K., Cappuccio, G., Brunetti-Pierri, N., Torun, D., Arslan, M., ... Bayat, A. (2023). POU3F3-related disorder: Defining the phenotype and expanding the molecular spectrum. Clinical Genetics, 104(2), 186-197. https://doi.org/10.1111/cge.14353

@article{cebe3979c9af4f0db7624415edd8c5f4,

title = "POU3F3-related disorder: Defining the phenotype and expanding the molecular spectrum",

abstract = "POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.",

keywords = "Autistic Disorder/genetics, Child, Developmental Disabilities/genetics, Epilepsy/genetics, Humans, Intellectual Disability/genetics, Mutation, Missense/genetics, POU Domain Factors/genetics, Phenotype, Cupped ears, Epilepsy, Neurodevelopmental disorder, Autism",

author = "Alessandra Rossi and Blok, \{Lot Snijders\} and Sonja Neuser and Chiara Kl{\"o}ckner and Konrad Platzer and Faivre, \{Laurence Olivier\} and Heike Weigand and Dentici, \{Maria L\} and Marco Tartaglia and Marcello Niceta and Paolo Alfieri and Siddharth Srivastava and David Coulter and Lacey Smith and Kristin Vinorum and Gerarda Cappuccio and Nicola Brunetti-Pierri and Deniz Torun and Mutluay Arslan and Lauridsen, \{Mathilde F\} and Oliver Murch and Rachel Irving and Lynch, \{Sally A\} and Mehta, \{Sarju G\} and Jenny Carmichael and Evelien Zonneveld-Huijssoon and \{de Vries\}, Bert and Tjitske Kleefstra and Johannesen, \{Katrine M\} and Westphall, \{Ian T\} and Hughes, \{Susan S\} and Sarah Smithson and Julie Evans and Tracy Dudding-Byth and Marleen Simon and \{van Binsbergen\}, Ellen and Herkert, \{Johanna C\} and Gea Beunders and Henry Oppermann and Mert Bakal and M{\o}ller, \{Rikke S\} and Guido Rubboli and Allan Bayat",

note = "{\textcopyright} 2023 John Wiley \& Sons A/S. Published by John Wiley \& Sons Ltd.",

year = "2023",

month = aug,

doi = "10.1111/cge.14353",

language = "English",

volume = "104",

pages = "186--197",

journal = "Clinical Genetics",

issn = "0009-9163",

publisher = "Wiley-Blackwell",

number = "2",

}

Rossi, A, Blok, LS, Neuser, S, Klöckner, C, Platzer, K, Faivre, LO, Weigand, H, Dentici, ML, Tartaglia, M, Niceta, M, Alfieri, P, Srivastava, S, Coulter, D, Smith, L, Vinorum, K, Cappuccio, G, Brunetti-Pierri, N, Torun, D, Arslan, M, Lauridsen, MF, Murch, O, Irving, R, Lynch, SA, Mehta, SG, Carmichael, J, Zonneveld-Huijssoon, E, de Vries, B, Kleefstra, T, Johannesen, KM, Westphall, IT, Hughes, SS, Smithson, S, Evans, J, Dudding-Byth, T, Simon, M, van Binsbergen, E, Herkert, JC, Beunders, G, Oppermann, H, Bakal, M, Møller, RS , Rubboli, G & Bayat, A 2023, 'POU3F3-related disorder: Defining the phenotype and expanding the molecular spectrum', Clinical Genetics, vol. 104, no. 2, pp. 186-197. https://doi.org/10.1111/cge.14353

TY - JOUR

T1 - POU3F3-related disorder

T2 - Defining the phenotype and expanding the molecular spectrum

AU - Rossi, Alessandra

AU - Blok, Lot Snijders

AU - Neuser, Sonja

AU - Klöckner, Chiara

AU - Platzer, Konrad

AU - Faivre, Laurence Olivier

AU - Weigand, Heike

AU - Dentici, Maria L

AU - Tartaglia, Marco

AU - Niceta, Marcello

AU - Alfieri, Paolo

AU - Srivastava, Siddharth

AU - Coulter, David

AU - Smith, Lacey

AU - Vinorum, Kristin

AU - Cappuccio, Gerarda

AU - Brunetti-Pierri, Nicola

AU - Torun, Deniz

AU - Arslan, Mutluay

AU - Lauridsen, Mathilde F

AU - Murch, Oliver

AU - Irving, Rachel

AU - Lynch, Sally A

AU - Mehta, Sarju G

AU - Carmichael, Jenny

AU - Zonneveld-Huijssoon, Evelien

AU - de Vries, Bert

AU - Kleefstra, Tjitske

AU - Johannesen, Katrine M

AU - Westphall, Ian T

AU - Hughes, Susan S

AU - Smithson, Sarah

AU - Evans, Julie

AU - Dudding-Byth, Tracy

AU - Simon, Marleen

AU - van Binsbergen, Ellen

AU - Herkert, Johanna C

AU - Beunders, Gea

AU - Oppermann, Henry

AU - Bakal, Mert

AU - Møller, Rikke S

AU - Rubboli, Guido

AU - Bayat, Allan

PY - 2023/8

Y1 - 2023/8

N2 - POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.

AB - POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.

KW - Autistic Disorder/genetics

KW - Child

KW - Developmental Disabilities/genetics

KW - Epilepsy/genetics

KW - Humans

KW - Intellectual Disability/genetics

KW - Mutation, Missense/genetics

KW - POU Domain Factors/genetics

KW - Phenotype

KW - Cupped ears

KW - Epilepsy

KW - Neurodevelopmental disorder

KW - Autism

U2 - 10.1111/cge.14353

DO - 10.1111/cge.14353

M3 - Article

C2 - 37165752

SN - 0009-9163

VL - 104

SP - 186

EP - 197

JO - Clinical Genetics

JF - Clinical Genetics

IS - 2

ER -

POU3F3-related disorder: Defining the phenotype and expanding the molecular spectrum

Abstract

Funding

Keywords

Access to Document

Fingerprint

Cite this