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Intellectual disability

Gene: PBX1

Green List (high evidence)

PBX1 (PBX homeobox 1)
EnsemblGeneIds (GRCh38): ENSG00000185630
EnsemblGeneIds (GRCh37): ENSG00000185630
OMIM: 176310, Gene2Phenotype
PBX1 is in 6 panels

3 reviews

Eleanor Williams (Genomics England Curator)

Comment on list classification: More than 3 cases where patients show developmental delay as part of the phenotype.
Created: 14 Feb 2019, 4:27 p.m.
Associated with Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay in OMIM, but with no phenotype in Gene2Phenotype.

PMID: 28270404 (Le Tanno et al 2017) - eight patients presenting with CAKUT carrying an 1q23.3q24.1 microdeletion. They defined a 276-kb minimal common region that only overlaps with the PBX1 gene. Developmental delay was a constant feature among the eight patients, mostly global except for PT4 for which no language delay was evidenced.

PMID: 28566479 (Heidet et al 2017) - identified five heterozygous loss of function mutations/deletions in patients with CAKUT. 2 of the patients also showed intellectual disability or developmental delay. Of these 2 one had a p.Arg184* nonsense mutation and the other had a heterozygous deletion removing the whole PBX1 gene.

PMID: 29036646 (Slavotinek et al 2017) - eight patients who are heterozygous for de novo, deleterious sequence variants in PBX1. Developmental delays were present in 6 of the patients. Only 1 patient was severely delayed. Functional studies on five PBX1 sequence variants revealed perturbation of intrinsic, PBX-dependent transactivation ability and altered nuclear translocation, suggesting abnormal interactions between mutant PBX1 proteins and wild-type TALE or HOX cofactors.
Created: 14 Feb 2019, 4:08 p.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Heterozygous mutations or deletions of PBX1 cause Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (MIM 617641).

Several studies have been published reporting on the phenotype either associated to 1q23 deletions (PMID: 28270404 - 8 unrelated patients some of whom had deletions affecting only PBX1) or PBX1 mutations (PMID: 28566479 - 3 unrelated patients, PMID: 29036646 - 8 unrelated individuals).

The phenotype - which presents highly variable expressivity - is better summarized in OMIM (all previous publications discussed). DD was noted in many individuals while PMID 29036646 insists on the associated ID. These features - and ID in particular - are however not universal.

Mouse models support the role of PBX1 as well as other extensive functional studies.

Missense, LoF variants and larger deletions encompassing PBX1 have been reported. While these findings support haploinsufficiency as the underlying mechanism, a dominant-negative effect is discussed as a possibility at least for the missense variants.

In line with these PBX1 has a pLI score of 0.91 (but % HI of 0.85 in Decipher) while - as the authors of the last article note - the missense variants reported appear to be located in a missense depleted region (visualisation of the variants as well as of the missense constraint in https://decipher.sanger.ac.uk/gene/PBX1#overview/protein-info).

For a few truncating variants studied, for which NMD would be expected, protein production was not significantly perturbed upon Western blot (PMID: 29036646).

PBX1 is not associated with any phenotype in G2P.

This gene is included in gene panels for intellectual disability offered by various diagnostic laboratories.

As a result, PBX1 can be considered for upgrade to green (or amber).
Created: 10 Dec 2018, 9:42 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

Variants in this GENE are reported as part of current diagnostic practice

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Multiple affected individuals with de novo variants in this gene reported in the literature. ID is part of the phenotype.
Created: 22 Jun 2018, 12:04 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
Phenotypes
  • Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay
OMIM
176310
Clinvar variants
Variants in PBX1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

14 Feb 2019, Gel status: 3

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: PBX1 were set to 28566479, 29036646

14 Feb 2019, Gel status: 3

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: pbx1 has been classified as Green List (High Evidence).

29 Sep 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to PBX1.

22 Jun 2018, Gel status: 0

Added New Source

Zornitza Stark (Australian Genomics)

PBX1 was added to Intellectual disability panel. Sources: Literature

22 Jun 2018, Gel status: 0

Created

Zornitza Stark (Australian Genomics)

PBX1 was created by Zornitza Stark