Intellectual disability - microarray and sequencing
Gene: PBX1 Green List (high evidence)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.
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
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
Publications for gene: PBX1 were set to 28566479, 29036646
Gene: pbx1 has been classified as Green List (High Evidence).
Source Victorian Clinical Genetics Services was added to PBX1.
PBX1 was added to Intellectual disability panel. Sources: Literature
PBX1 was created by Zornitza Stark
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.