Intellectual disabilityGene: POU3F3
POU3F3 has been identified by Konstantinos Varvagiannis following a publication by Snijders Blok et al. (PMID: 31303265) who reported on 19 individuals with heterozygous POU3F3 variants. Variants consisted of 12 nonsense/frameshift variants, 5 missense ones as well as 1 in-frame deletion.
Nearly all individuals underwent trio WES it was found that all variants were de novo, except individuals 18 & 19 who were a mother and daughter and only duo sequenced.
All individual reported to have some form of developmental delay and ID. Although severity of ID varied from mild to severe and level of severity was not recorded in 9/19 cases.
POU3F3 is currently not associated with any phenotypes in OMIM or in Gene2Phenotype. Although the ID phenotype was broad there are sufficient number of variants in unrelated cases to classify POU3F3 as Green.
Created: 5 Aug 2019, 2:37 p.m. | Last Modified: 5 Aug 2019, 2:37 p.m.
Panel Version: 2.995
Snijders Blok et al. (2019, DOI: https://doi.org/10.1016/j.ajhg.2019.06.007) report on 19 individuals with heterozygous POU3F3 variants.
Features included hypotonia in some, DD/ID (19/19) with impairment in speech and language skills, and autism-like symptoms with formal ASD diagnosis in 7(/19). Epilepsy was reported for 2 individuals. Overlapping facial features were noted among these individuals.
POU3F3 encodes a member of the class III POU family of transcription factors expressed in the central nervous system (Sumiyama et al. 1996, PMID: 8703082 cited in OMIM) and as the authors comment holds a role in regulation of key processes, eg. cortical neuronal migration, upper-layer specification and production and neurogenesis (PMIDs cited: 11859196, 12130536, 22892427, 17141158).
In almost all subjects (17/19) the variant had occurred as a de novo event, while one individual had inherited the variant from a similarly affected parent.
In total 12 nonsense/frameshift variants, 5 missense ones as well as 1 in-frame deletion were identified following (mostly) trio exome sequencing. All variants were absent from gnomAD, with in silico predictions in favour of pathogenicity.
The few missense variants and the in-frame deletion were found either in the POU-specific (NM_006236.2:c.1085G>T / p.Arg362Leu found in 2 subjects) or the POU-homeobox domain (where 2 variants affected the same residue, namely p.Arg407Gly/Leu, the other variant was p.Asn456Ser).
POU3F3 is an intronless gene and as a result truncating variants are not subject to NMD. The gene appears to be intolerant to LoF variants (pLI of 0.89 in gnomAD).
Western blot analysis of YFP-tagged POU3F3 variants (in HEK293 cell lysates) showed that the YFP-fusion proteins were expressed and had the expected molecular weights.
For several truncating variants tested as well as the in-frame deletion, aberrant subcellular localization pattern was demonstrated although this was not the case for 4 missense variants.
In vitro studies were carried out and suggested that POU3F3, as is known to be the case for POU3F2, is able to activate an intronic binding site in FOXP2. Using a luciferase assay, transcriptional activation was severely impaired for truncating variants tested, significantly lower for many missense ones with the exception of those affecting Arg407 in which case luciferase expression was either similar to wt (for Arg407Gly) or even increased in the case of Arg407Leu.
As the authors comment, both loss- and gain- of function mechanisms may underly pathogenicity of variants.
The ability of mutant proteins to form dimers either with wt or themselves was tested. Dimerization capacity was intact for most missense variants but was lost/decreased for truncating variants. The in-frame deletion resulted in impaired dimerization with wt, although homo-dimerization was found to be normal.
Dheedene et al. (2014 - PMID: 24550763) had previously reported on a boy with ID. aCGH had demonstrated a de novo 360-kb deletion of 2q12.1 spanning only POU3F3 and MRPS9 the latter encoding a mitochondrial ribosomal protein (which would be most compatible with a - yet undescribed - recessive inheritance pattern / disorder).
POU3F3 is not associated with any phenotype in OMIM/G2P.
The gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc, among the principal authors of the study).
As a result POU3F3 seems to fulfill criteria for inclusion in the current panel probably as green [DD/ID was a universal feature - severity of ID was relevant in 5/10 individuals for whom details were available, functional evidence provided] or amber.
Sources: Literature, Radboud University Medical Center, Nijmegen
Created: 14 Jul 2019, 10:20 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Generalized hypotonia; Delayed speech and language development; Global developmental delay; Intellectual disability; Autistic behavior
Variants in this GENE are reported as part of current diagnostic practice
Phenotypes for gene: POU3F3 were changed from Generalized hypotonia; Delayed speech and language development; Global developmental delay; Intellectual disability; Autistic behavior to Snijders Blok-Fisher syndrome, 618604; Generalized hypotonia; Delayed speech and language development; Global developmental delay; Intellectual disability; Autistic behavior
Gene: pou3f3 has been classified as Green List (High Evidence).
Publications for gene: POU3F3 were set to https://doi.org/10.1016/j.ajhg.2019.06.007; 24550763
gene: POU3F3 was added gene: POU3F3 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: POU3F3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: POU3F3 were set to https://doi.org/10.1016/j.ajhg.2019.06.007; 24550763 Phenotypes for gene: POU3F3 were set to Generalized hypotonia; Delayed speech and language development; Global developmental delay; Intellectual disability; Autistic behavior Penetrance for gene: POU3F3 were set to unknown Review for gene: POU3F3 was set to GREEN gene: POU3F3 was marked as current diagnostic