Ataxia and cerebellar anomalies - narrow panel

Gene: CTBP1

Green List (high evidence)

from review of gene on Intellectual disability (Version 2.981) panel, it was suggested by the Genomics England clinical team that the phenotype would also be suitable for the 'ataxia and cerebellar anomalies - narrow panel'


Comment on list classification: Gene added to panel and rated Green by Chris Buxton. Changed rating to Green after agreement from Genomics England clinical team- sufficient cases and relevant phenotype. Have added missense tag, because only one missense tag reported so far.
Rebecca Foulger (Genomics England curator), 25 Jul 2019


There are 12 individuals reported from 3 papers (2 papers from the same group). All 12 individuals have the same heterozygous missense variant (R331W in NM_001012614.1; R342W in NM_001328.2). It is a de novo variant in all cases except one where it's inherited from a somatic parent. The phenotype of all 12 is summarised in Table 1 of PMID:31041561. Global DD is a consistent feature (varying severity). ID is recorded in several patients. Developmental motor regression recorded in 4 patients (2 of which also had cognitive regression). Authors note that healthy individuals with heterozygous LOF alleles have been reported.
Rebecca Foulger (Genomics England curator), 25 Jul 2019


27094857 Beck 2016; 4 unrelated probands with denovo R342W missense with s syndromic disorder of developmental delay, intellectual disability, failure to thrive, hypotonia, ataxia, and tooth enamel defects. 31041561 Beck 2019: 7 additional unrelated probands with denovo R342W missense with a syndromic intellectual disability, ataxia, hypotonia, and tooth enamel defect disorder. Insilico modelling supports a conclusion of dysregulation of the normal apoptosis pathway via reduced chromatin/histone binding. Mechanism is proposed to be ?GoF via reduction of transcription repression.
Chris Buxton (North Bristol NHS Trust), 18 Jul 2019


12 individuals with a recurrent missense variant in CTBP1 have been reported, all summarized in the last article: - Beck et al. 2016 (PMID: 27094857) : 4 individuals - Sommerville et al. 2017 (PMID: 28955726) : 1 subject - Beck et al. 2019 (PMID: 31041561) : 7 further individuals Features included hypotonia, DD/ID, ataxia and tooth enamel defects. The degree of ID - when present - appeared to be highly variable based at least on the first two reports (3 individuals with severe ID, 1 with borderline-normal intellectual functioning, 1 did not exhibit ID) where this feature was further commented on. A recurrent missense variant was found in all 12 affected individuals [NM_001328.2:c.1024C>T - p.(Arg342Trp) or NM_001012614.1:c.991C>T - p.(Arg331Trp)]. De novo occurrence this SNV was shown for (almost) all individuals, although in one case maternal sequencing reads were compatible with low-level somatic mosaicism (4/75 reads) not detected by Sanger sequencing. The mother of this individual was phenotypically normal. The variant is absent from gnomAD. Several in silico predictions (SIFT, PolyPhen2, MutationTaster, etc) suggest a deleterious effect. Given recurrence of this specific variant, and presence of LoF ones in healthy individuals (pLI of 0.98 though in gnomAD) Beck et al. suggested a dominant negative or a gain-of-function effect rather than a loss of function mechanism. Exclusion of alternative causes: was mainly discussed for the subject reported by Sommerville et al., due to the primary suspicion of a mitochondrial disorder (sequencing and research for mtDNA rearrangements, additional analysis of nuclear genes for mitochondrial disorders). Expression: CTBP1 encodes C-terminal binding protein 1, with expression among others in brain and cerebellum (https://gtexportal.org/home/gene/CTBP1). Role and Functional studies: - The major nuclear isoform of CTBP1 (corresponding to NM_001328.2) and of its paralog CTBP2 function as transcriptional regulators (corepressors). The PLDLS(Pro-Leu-Asp-Leu-Ser)-binding cleft domain where this variant lies, acts as a high-affinity protein-binding interface to recruit DNA-binding repressors and chromatin modifying enzymes (PMID: 17967884). - In a human glioblastoma cell line interaction of various cofactors with (Flag-tagged) CTBP1 was studied by immunoprecitipation with the Flag antibody and subsequent proteomic (LC-MS) analysis. This demonstrated reduced interaction in the case of R342W (compared to wt) with Zn-finger transcription factors, histone deacetylases, histone methyltransferases, histone H3-K4 demethylase etc. Western blot analyses also revealed reduced interaction of the R342W with several CTBP cofactors. - RNA-seq analysis in glioblastoma cell line revealed similar overall transcriptional profiles between wt and R342W though multiple RNA species showed significant differences (eg. genes involved in the biological processes of mitotic nuclear division, DNA repair, transcription and regulation of transcription among those that were most upregulated and genes involved in brain development among the most downregulated). - Patient fibroblasts under conditions of glucose deprivation exhibited strikingly more cell death compared to control fibroblasts. Study of mRNA levels of pro-apoptotic genes by q-RT-PCR revealed that Noxa expression under glucose deprivation vs under normal glucose was 8 to 10-fold enhanced for control fibroblasts, but more than 30-fold enhanced in the case patient fibroblasts. Western blot analyses were also in line with this. - Mitochondrial dysfunction (probably secondary) with evidence of decreased complex I (and complex IV) activities in skeletal muscle was the case for 2 individuals among multiple patients who had muscle biopsies. Animal models: - Beck et al. discuss previously published mouse models where Ctbp1/2 both play overlapping transcriptional roles during development. Homozygous deletion of Ctbp2 is embryonically lethal (>E10.5). Homozygous deletion of Ctbp1 results in viable mice with reduced size and lifespan (Cited: Hildebrand et al. 2002 - PMID: 12101226) - As commented on by Sommerville et al., Ctbp1 knockout in mouse embryonic fibroblasts resulted in elongated mitochondria, abnormal mitochondrial cristae, diminished ATP and O2 consumption and mitochondrial membrane potential (Cited: Kim and Youn 2009 - PMID: 19136938). ---- CTBP1 is associated with Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (617915) in OMIM. It is not associated with any phenotype in G2P. Some diagnostic laboratories (eg. GeneDx participating in the first study and others) include this gene in panels for intellectual disability. ---- As a result, CTBP1 can be added in the current panel probably as green.
Konstantinos Varvagiannis (Other), 7 Jul 2019
Sources: Literature

Created: 25 Jul 2019, 4:33 p.m. | Last Modified: 25 Jul 2019, 4:36 p.m.

Panel Version: 1.4

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

Phenotypes
Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome, 617915

Publications

• 27094857
• 28955726
• 31041561

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments