Mendeliome
Gene: TBX6 Green List (high evidence)Green List (high evidence)
TBX6 encodes transcription-factor box 6, a transcription factor critical to paraxial mesoderm segmentation and somitogenesis during embryonic development. TBX6 haploinsufficiency is believed to drive the skeletal and kidney phenotypes associated with the 16p11.2 deletion syndrome.
Ma et al (2022) reported 16 rare variants in TBX6 from Mayer-Rokitansky-Küster-Hauser syndrome cohort (1 truncating, 15 VUS). They observed a significant mutational burden of TBX6 in affected individuals vs controls. Of the 15 variants with uncertain effects, 7 were shown to induce a loss-of-function effect through various mechanisms (i.e. impaired normal splicing of TBX6 messenger RNA, decreased protein expression, perturbed transcriptional activity, and protein mislocalization). There was observed incomplete penetrance and variable expressivity in families carrying deleterious variants.
Li et al (2022) reported 7 individuals with vertebral and rib malformations and structural kidney differences associated with heterozygous TBX6 gene deletion in trans with a hypomorphic TBX6 allele or biallelic TBX6 variants.Created: 25 Jul 2023, 4:36 a.m. | Last Modified: 25 Jul 2023, 4:36 a.m.
Panel Version: 1.1010
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Mayer-Rokitansky-Küster-Hauser syndrome; Combined skeletal-kidney dysplasia syndrome
Publications
Variants in this GENE are reported as part of current diagnostic practice
Comment when marking as ready: Biallelic variants associated with spondylocostal dysostosis in >3 unrelated individuals
Mouse model recapitulates phenotypeCreated: 20 Apr 2020, 5:31 a.m. | Last Modified: 20 Apr 2020, 5:31 a.m.
Panel Version: 0.2418
Green List (high evidence)
108 Chinese CVM cases identified 10 (9.3%) carried TBX6 null mutations in combination with common hypomorphic variants at the second TBX6 allele. Similar phenotype observed in mice with combined null and hypomorphic alleles of Tbx6 (PMID: 30307510)
200 patients with Congenital scoliosis (CS) or Spondylocostal dysostosis (SCD) were investigated for TBX6 variants. Five 16p11.2 deletions, one splice-site variant and five missense variants were identified in 10 patients. All CS patients with missense variants had the risk haplotype in the opposite allele, while a SCD patient with bi-allelic missense variants did not have the haplotype. Functional studies showed mislocalisation. Conclusion - Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis (PMID: 31015262)Created: 20 Apr 2020, 4:34 a.m. | Last Modified: 20 Apr 2020, 4:34 a.m.
Panel Version: 0.2377
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
congenital vertebral malformations, congenital scoliosis, spondylocostal dysostosis
Publications
Variants in this GENE are reported as part of current diagnostic practice
Green List (high evidence)
>3 families with SPONDYLOCOSTAL DYSOSTOSIS 5. Bi-allelic loss of function variants of TBX6 cause a spectrum of phenotypes including CS and SCD, depending on the severity of the loss of TBX6 function.Created: 20 Apr 2020, 3:35 a.m. | Last Modified: 20 Apr 2020, 3:35 a.m.
Panel Version: 0.2365
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Skeletal dysplasia; spondylocostal dysostosis; congenital scoliosis
Publications
Variants in this GENE are reported as part of current diagnostic practice
Phenotypes for gene: TBX6 were changed from Spondylocostal dysostosis 5, 122600 to Spondylocostal dysostosis 5, 122600; Mayer-Rokitansky-Küster-Hauser syndrome, MONDO:0017771, TBX6-related
Phenotypes for gene: TBX6 were changed from Skeletal dysplasia; spondylocostal dysostosis; congenital scoliosis to Spondylocostal dysostosis 5, 122600
Phenotypes for gene: TBX6 were changed from to Skeletal dysplasia; spondylocostal dysostosis; congenital scoliosis
Publications for gene: TBX6 were set to
Gene: tbx6 has been classified as Green List (High Evidence).
Mode of inheritance for gene: TBX6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
gene: TBX6 was added gene: TBX6 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: TBX6 was set to Unknown
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 panelapp@genomicsengland.co.uk
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.