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

Rossi, Alessandra; Blok, Lot; Neuser, Sonja; Klöckner, Chiara; Platzer, Konrad; Faivre, Laurence; Weigand, Heike; Dentici, Maria; 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; Murch, Oliver; Irving, Rachel; Lynch, Sally; Mehta, Sarju; Carmichael, Jenny; Zonneveld-Huijssoon, Evelien; de Vries, Bert; Kleefstra, Tjitske; Johannesen, Katrine; Westphall, Ian; Hughes, Susan; Smithson, Sarah; Evans, Julie; Dudding-Byth, Tracy; Simon, Marleen; van Binsbergen, Ellen; Herkert, Johanna; Beunders, Gea; Oppermann, Henry; Bakal, Mert; Møller, Rikke; Rubboli, Guido; Bayat, Allan

doi:10.1111/cge.14353

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

Rossi A., Blok L. S., Neuser S., Klöckner C., Platzer K., Faivre L. O., ...Daha Fazla

Clinical Genetics, cilt.104, sa.2, ss.186-197, 2023 (SCI-Expanded, Scopus)

Yayın Türü: Makale / Tam Makale
Cilt numarası: 104 Sayı: 2
Basım Tarihi: 2023
Doi Numarası: 10.1111/cge.14353
Dergi Adı: Clinical Genetics
Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, EMBASE
Sayfa Sayıları: ss.186-197
Anahtar Kelimeler: autism, cupped ears, epilepsy, neurodevelopmental disorder
Sağlık Bilimleri Üniversitesi Adresli: Evet

Özet

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 We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals.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