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

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 We recruited unpublished individuals with POU3F3 variants through...

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Bibliographic Details
Published in:	Clinical genetics Vol. 104; no. 2; pp. 186 - 197
Main Authors:	Rossi, Alessandra, Blok, Lot Snijders, Neuser, Sonja, Klöckner, Chiara, Platzer, Konrad, Faivre, Laurence Olivier, Weigand, Heike, Dentici, Maria L., Tartaglia, Marco, Niceta, Marcello, Alfieri, Paolo, Srivastava, Siddharth, Coulter, David, Smith, Lacey, Vinorum, Kristin, Cappuccio, Gerarda, Brunetti‐Pierri, Nicola, Torun, Deniz, Arslan, Mutluay, Lauridsen, Mathilde F., Murch, Oliver, Irving, Rachel, Lynch, Sally A., Mehta, Sarju G., Carmichael, Jenny, Zonneveld‐Huijssoon, Evelien, Vries, Bert, Kleefstra, Tjitske, Johannesen, Katrine M., Westphall, Ian T., Hughes, Susan S., Smithson, Sarah, Evans, Julie, Dudding‐Byth, Tracy, Simon, Marleen, Binsbergen, Ellen, Herkert, Johanna C., Beunders, Gea, Oppermann, Henry, Bakal, Mert, Møller, Rikke S., Rubboli, Guido, Bayat, Allan
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-08-2023
Subjects:	Autism Autistic Disorder - genetics Child Comorbidity cupped ears Developmental Disabilities - genetics Epilepsy Epilepsy - genetics Genotype & phenotype Genotypes Hearing loss Humans Intellectual Disability - genetics Mutation, Missense - genetics neurodevelopmental disorder Phenotype Phenotypes POU Domain Factors - genetics POU3F3 epilepsy neurodevelopmental disorder POU3F3 autism cupped ears
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Summary:	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 We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals.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. Clinicians should suspect POU3F3‐related disorder when a patient presents with developmental delay mainly affecting speech, psychiatric comorbidities and facial dysmorphisms. Additional features include gastrointestinal comorbidities, hearing loss, epilepsy, hypotonia, sleep disturbances, skeletal malformations and joint hypermobility.
Bibliography:	Guido Rubboli and Allan Bayat contributed equally to the manuscript. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AR and AB contributed to the conception and design of the study. AR, AB, CK, SN, KP, LSB, LF, HW, MLD, MT, MN, PA, SS, DC, LS, KV, GC, NBP, DT, MA, MFL, OM, RI, SAL, SGM, JC, EZH, BDV, TK, KMJ, ITW, SSH, SS, JE, TDB, MS, EVB, JCH, GB, MB and HO contributed to the acquisition and analysis of data. AR, AB, GR, RM, CK and SN contributed to drafting the text and preparing the figures. These authors contributed equally to the manuscript. Authors contribution
ISSN:	0009-9163 1399-0004 1399-0004
DOI:	10.1111/cge.14353