Intellectual disability - microarray and sequencing
Gene: TANC2The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
Comment on list classification: This gene should be promoted to Green at the next GMS panel update - multiple unrelated families with a comparable neurodevelopmental disorder (including ID). As highlighted in review by Zornitza Stark, most reported SNVs are de novo putative disruptive variants, or missense variants that are predicted in silico to have a damaging or possibly damaging effect. Gene expression and function are neurodevelopmentally-relevant, and there is some limited functional data.
Gene-disease association is also now listed in both OMIM and Gene2Phenotype.Created: 25 Jan 2021, 12:09 p.m. | Last Modified: 25 Jan 2021, 12:09 p.m.
Panel Version: 3.731
Removed 'watchlist' tag and added 'for-review' tag as there is now sufficient evidence to promote this gene to GreenCreated: 25 Jan 2021, 11:43 a.m. | Last Modified: 25 Jan 2021, 11:43 a.m.
Panel Version: 3.729
TANC2 is now associated with a relevant phenotype in OMIM and has a 'possible' disease confidence rating for 'TANC2-related neurodevelopmental and psychiatric disorder' in Gene2Phenotype.
20 individuals described in PMID: 31616000 (2019) with a neurodevelopmental disorder (including ID/GDD) and various 'likely gene-disruptive' variants in this gene (previously reviewed below)
PMID: 33160097 (2020) reports a further individual with a 17q23.3 de novo microdeletion disrupting exons 3–7 of the TANC2 gene. The patient presented craniofacial dysmorphic features, hypotonia, absent speech and gait, and profound ID - supporting the role of TANC2 in neurodevelopmental phenotypes.
TANC2 encodes a synaptic scaffold protein that interacts and co-localises with multiple postsynaptic-density proteins in dendrites to regulate dendritic spines and excitatory synapse formation. Stucchi et al. (2018) (PMID:30021165) showed that proteins with disruptive variants (including p.R1066* reported in patient from PMID:31616000) failed to accumulate at the dendritic spinesCreated: 25 Jan 2021, 11:36 a.m. | Last Modified: 25 Jan 2021, 11:36 a.m.
Panel Version: 3.729
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Intellectual developmental disorder with autistic features and language delay, with or without seizures, OMIM:618906
Publications
19 families with neurodevelopmental phenotypes and variants in this gene. The majority of variants are de novo, highly damaging (truncating/splice site) variants, which would easily meet ACMG criteria for pathogenicity. Gene is highly conserved and intolerant to truncating mutations (pLI score = 1, RVIS% = 0.4). Overall, the evidence for gene-disease association is very strong, despite OMIM/G2P lagging behind.Created: 29 Feb 2020, 9:28 a.m. | Last Modified: 29 Feb 2020, 9:28 a.m.
Panel Version: 3.3
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Intellectual disability; autism; epilepsy
Publications
Variants in this GENE are reported as part of current diagnostic practice
Recent publication PMC6794285 https://www.nature.com/articles/s41467-019-12435-8
Describes loss of function variants in TANC2 in 20 pediatric patients presenting with autism, intellectual disability, and delayed language and motor development. Variants observed included missense, nonsense, splice, frameshift and structural variation. variants were de novo or inherited from an affected parent.
Paper describes genetic and clinical features of cases. Suggest that this gene should be elevated to amber or red after review.Created: 23 Oct 2019, 5:53 p.m. | Last Modified: 23 Oct 2019, 5:53 p.m.
Panel Version: 2.1066
Comment on list classification: Updated rating from Red to Amber based on PMID:31616000 2019 article suggested by Andrea Haworth. Sufficient unrelated cases (19/20) with an ID/DD phenotype but the pathogenicity of the variants has not yet been verified. Not yet associated with a disorder in Gene2Phenotype or OMIM. Currently only 1 paper, therefore Amber with 'watchlist' tag is appropriate pending functional studies.Created: 24 Oct 2019, 11:10 a.m. | Last Modified: 24 Oct 2019, 11:10 a.m.
Panel Version: 2.1076
Summary of PMID:31616000 (PMC:6794285) suggested by Andrea Haworth reviewer: Guo et al assembled phenotypic data for 19 probands and 1 affected sibling with TANC2 variants. Variants include 16 LGD (likely gene-disruptive) variants and three intragenic microdeletions. Phenotypes included ASD, ID, speech-language delay and childhood motor delay:
- 15/20 individuals had ASD/autism features (7 with a formal diagnosis).
- 19/20 individuals had some form of ID (17 with a formal diagnosis of borderline to severe ID, and 2 with learning difficulties without a formal diagnosis).
- 18/20 showed speech-language delay.
- 13/19 individuals had childhood motor delay.
- 11/20 individuals had a formal diagnosis of epilepsy (9) or suffered recurrent seizures (2).Created: 24 Oct 2019, 11:07 a.m. | Last Modified: 24 Oct 2019, 11:07 a.m.
Panel Version: 2.1075
Comment on mode of inheritance: Set MOI as MONOALLELIC based on PMID:31616000 (Figure 2).Created: 24 Oct 2019, 11:04 a.m. | Last Modified: 24 Oct 2019, 11:04 a.m.
Panel Version: 2.1074
Listed as a candidate ID gene in PMID:26350204 but insufficient ID evidence for inclusion on diagnostic panel.Created: 31 Oct 2017, 9:24 a.m.
Publications
Tag for-review was removed from gene: TANC2.
Source Expert Review Green was added to TANC2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: tanc2 has been classified as Amber List (Moderate Evidence).
Publications for gene: TANC2 were set to 26350204; 31616000
Tag watchlist was removed from gene: TANC2. Tag for-review tag was added to gene: TANC2.
Tag watchlist tag was added to gene: TANC2.
Phenotypes for gene: TANC2 were changed from NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Childhood speech delay; Childhood motor delay to Intellectual developmental disorder with autistic features and language delay, with or without seizures, 618906
Gene: tanc2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: TANC2 were changed from to NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Childhood speech delay; Childhood motor delay
Mode of inheritance for gene: TANC2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TANC2 were set to 26350204
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Publications for gene TANC2 was set to ['26350204']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
TANC2 was created by ellenmcdonagh
TANC2 was added to Intellectual disabilitypanel. Sources: Expert Review Red