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 LauridsenOliver 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 af dette arbejde

Publikation: Bidrag til tidsskriftArtikelForskningpeer review


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 We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals.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.

Sider (fra-til)186-197
Antal sider12
TidsskriftClinical Genetics
Udgave nummer2
Tidlig onlinedato10 maj 2023
StatusUdgivet - aug. 2023

Bibliografisk note

© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


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