Dataset Information

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 We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals.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

SUBMITTER: Rossi A

PROVIDER: S-EPMC10330344 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

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

Clinical genetics 20230510 2

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 i ...[more]

PMID: 37165752

Similar Datasets

Project description:CYP26B1 metabolizes retinoic acid in the developing embryo to regulate its levels. A limited number of individuals with pathogenic variants in CYP26B1 have been documented with a varied phenotypic spectrum, spanning from a severe manifestation involving skull anomalies, craniosynostosis, encephalocele, radio-humeral fusion, oligodactyly, and a narrow thorax, to a milder presentation characterized by craniosynostosis, restricted radio-humeral joint mobility, hearing loss, and intellectual disability. Here, we report two families with CYP26B1-related phenotypes and describe the data obtained from functional studies of the variants. Exome and Sanger sequencing were used for variant identification in family 1 and family 2, respectively. Family 1 reflects a mild phenotype, which includes craniofacial dysmorphism with brachycephaly (without craniosynostosis), arachnodactyly, reduced radioulnar joint movement, conductive hearing loss, learning disability-and compound heterozygous CYP26B1 variants: (p.[(Pro118Leu)];[(Arg234Gln)]) were found. In family 2, a stillborn fetus presented a lethal phenotype with spina bifida occulta, hydrocephalus, poor skeletal mineralization, synostosis, limb defects, and a synonymous homozygous variant in CYP26B1: c.1083C > A. A minigene assay revealed that the synonymous variant created a new splice site, removing part of exon 5 (p.Val361_Asp382del). Enzymatic activity was assessed using a luciferase assay, demonstrating a notable reduction in exogenous retinoic acid metabolism for the variant p.Val361_Asp382del. (~ 3.5 × decrease compared to wild-type); comparatively, the variants p.(Pro118Leu) and p.(Arg234Gln) demonstrated a partial loss of metabolism (1.7× and 2.3× reduction, respectively). A proximity-dependent biotin identification assay reaffirmed previously reported ER-resident protein interactions. Additional work into these interactions is critical to determine if CYP26B1 is involved with other biological events on the ER. Immunofluorescence assay suggests that mutant CYP26B1 is still localized in the endoplasmic reticulum. These results indicate that novel pathogenic variants in CYP26B1 result in varying levels of enzymatic activity that impact retinoic acid metabolism and relate to the distinct phenotypes observed.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets