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. 2023 Aug;104(2):186-197.
doi: 10.1111/cge.14353. Epub 2023 May 10.

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

Alessandra Rossi  1   2 , Lot Snijders Blok  3 , Sonja Neuser  4 , Chiara Klöckner  4 , Konrad Platzer  4 , Laurence Olivier Faivre  5   6 , Heike Weigand  7 , Maria L Dentici  8   9 , Marco Tartaglia  8 , Marcello Niceta  8 , Paolo Alfieri  10 , Siddharth Srivastava  11 , David Coulter  11 , Lacey Smith  11 , Kristin Vinorum  12 , Gerarda Cappuccio  13   14 , Nicola Brunetti-Pierri  13   14   15 , Deniz Torun  16 , Mutluay Arslan  17 , Mathilde F Lauridsen  18 , Oliver Murch  19 , Rachel Irving  19 , Sally A Lynch  20 , Sarju G Mehta  21 , Jenny Carmichael  21 , Evelien Zonneveld-Huijssoon  22 , Bert de Vries  3 , Tjitske Kleefstra  3 , Katrine M Johannesen  1   23 , Ian T Westphall  24 , Susan S Hughes  25 , Sarah Smithson  26 , Julie Evans  27 , Tracy Dudding-Byth  28 , Marleen Simon  29 , Ellen van Binsbergen  29 , Johanna C Herkert  22 , Gea Beunders  22 , Henry Oppermann  4 , Mert Bakal  30 , Rikke S Møller  1   31 , Guido Rubboli  1   32 , Allan Bayat  1   31   33
Affiliations

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

Alessandra Rossi et al. Clin Genet. 2023 Aug.

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 We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals.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: POU3F3; autism; cupped ears; epilepsy; neurodevelopmental disorder.

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Conflict of interest statement

Potential conflicts of interest

Nothing to report.

Figures

Figure 1A-B; C-D.
Figure 1A-B; C-D.
A-B. Individual 15. Interictal EEG showing runs of irregular delta activities with diffuse spike-slow wave complexes and background slowing. Ictal EEG showing diffuse recruiting rhythmic fast discharge associated with a tonic seizure. C-D. Individual 10. EEG recorded during sleep showed generalized epileptiform discharge of polyspike-and-slow-wave (C) originating from right frontal /centro-frontal followed by alpha-activity with discrete right-sided prevalence, and (D) originating from the vertex followed by alpha-activity with discrete right-sided prevalence.
Figure 2.
Figure 2.
Facial features of 11 individuals with a pathogenic POU3F3 variant, showing cupped and/or prominent and often low-set ears. Other overlapping features are full lips, bulbous nasal tip, narrow palpebral fissures, hypertelorism, and epicanthal folds. Ind 5: 8 m. Ind 11: 3 y 4 m. Ind 13: 15 y 0 m. Ind 18: 9 y 0 m. Ind 19: 10 y 0 m. Ind 20: 8 y 0 m. Ind 21: at birth; 4 y 0 m. Ind 23: 7 y 9 m. Ind 25: 3 y 0 m. Ind 26: 6 y 0 m. Ind 28: 3,5 m; 3 y 0 m; 6 y 0m. Ind: Individual. m: months. y: years
Figure 3A-B-C.
Figure 3A-B-C.
Characterization of POU3F3 variants A. Linear overview of the POU3F3-protein (blue) with the POU-specific (POU-S, green) and Homeobox (POU-H, yellow) domains. Published (lower line) and novel (upper line) variants are shown at their respective location within the linear protein. Truncating variants in blue, missense variants in orange. Variants, which were identified in individuals with seizures, are marked with an asterisk. Below the linear protein model, every dot represents one missense variant in gnomAD. An overview with variant specifics per individual is provided in Table S1. B. Density plot of all missense variants (de novo pathogenic or likely pathogenic variants in orange and variants present in gnomAD in green). C. Conservation of amino acids of all missense variants throughout evolution. All missense variants are included and colored according to their functional domain position: green and yellow designate the functional domains of POU-specific (POU-S) and Homeobox (POU-H), respectively.
Figure 4A-B; C-D.
Figure 4A-B; C-D.
A-B. Representative three dimensional overview of the two POU3F3 domains with amino acid positions (highlighted as spheres in red) affected by disease-associated missense variants within the cohort and literature (based on AlphaFold structure aligned with DNA molecule). Panel A represents the POU-S domain in green and panel B the POU-H domain in blue with the DNA molecule in orange in the middle. The rest of the POU3F3 protein is colored in grey. C-D. Two chosen examples of amino acid changes at positions 340 (C) and 407 (D). Left panels show unchanged amino acid structure, while each of the right panels show structural consequences of respective amino acid change.
See this image and copyright information in PMC

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