Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: TERT

I don't know

Clinical correlation will be required (this is the case for many genes in this panel!!)

Created: 29 Jun 2018, 3:32 p.m.

Comment on list classification: Keeping gene as amber after review from Genomics England clinical team. Lack of PID phenotype in the majority of individuals.

Created: 19 Jun 2018, 9:30 a.m.

Asked for Genomics England clinical team input as to whether this gene should be rated green, even though there are enough cases, since there is incomplete penetrance and variable clinical phenotypes relating to immunodeficiency.

Created: 14 Jun 2018, 12:44 p.m.

Comment on phenotypes: Added Phenotype MIM numbers.

Created: 14 Jun 2018, 12:36 p.m.

Comment on publications: Added publications relating to reported variants

Created: 14 Jun 2018, 12:35 p.m.

Comment on mode of inheritance: {Dyskeratosis congenita, autosomal dominant 2} inheritance appears to be monoallelic, {Dyskeratosis congenita, autosomal recessive 4} inheritance appears to be biallelic. Confirmed by OMIM entry. Note also anticipation may be seen.

Created: 14 Jun 2018, 12:34 p.m.

Added missense tag as all variants to date are missense.

Created: 14 Jun 2018, 12:31 p.m.

OMIM reports that TERT is associated with {Dyskeratosis congenita, autosomal dominant 2} and {Dyskeratosis congenita, autosomal recessive 4}. Armanios et al. (2005) (PMID: 16247010) report a heterozygous mutation (K902N substitution in a highly conserved residue) in the TERT gene in 6 members of a family with autosomal dominant dyskeratosis congenita-2. In vitro functional expression studies showed that the K902N mutant protein had almost no telomerase activity, resulting in haploinsufficiency. Anticipation of clinical features was observed. Basel-Vanagaite et al. (2008) (PMID: 18460650]) identified a heterozygous mutation in the TERT gene (R631Q, conserved residue in motif 2 of the RT domain) in affected members of an Iraqi Jewish family with autosomal dominant dyskeratosis congenita-2. Marrone et al. (2007) (PMID: 17785587) reported two variants in unrelated patients with autosomal recessive dyskeratosis congenita-4; R811C is in nonconserved region of the RT domain, R901W is in a conserved region of the RT domain. Du et al. (2008) (PMID: 18042801) report another case of autosomal recessive dyskeratosis congenita-4 with the individual having a P704S variant. In a PubMed search a report by Vulliamy et al 2005 (PMID: 15885610) was found which reports on several TERT variants including two non-sense mutations R979W and F1127L that may have functional consequences in patients with dyskeratosis congenita/aplastic anemia, however only mutations in the TERT gene were looked for in these patients. More than 3 cases of plausible disease causing mutations. All missense. Note anticipation may be a feature of this gene-disease association.

Created: 14 Jun 2018, 12:29 p.m.

I don't know

OriginaI Metadata from IUIS classification table (December, 2019). IUIS Genetic defect (original gene symbol in IUIS download): TERT .PanelApp HGNC gene symbol check: TERT . IUIS Disease: AD/AR-DKC due to TERT deficiency . IUIS Inheritance: AD or AR .T cells: normal to low / normal to low, .B cells: Normal to low / normal to low, .IUIS Other affected cells: Hematopoietic stem cell / Hematopoietic stem cell. IUIS Associated features: Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay / Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay. IUIS Major category: Bone marrow failure, UIS Subcategory: none given

Created: 28 Feb 2020, 5 p.m. | Last Modified: 28 Feb 2020, 5 p.m.

Panel Version: 2.28

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): TERT .PanelApp HGNC gene symbol check: TERT . IUIS Disease: AD/AR-DKC due to TERT deficiency . IUIS Inheritance: AD or AR .T cells: Variable, .B cells: Variable, .IUIS Other affected cells: N/A. IUIS Associated features: Intrauterine growth retardation, microcephaly, nail dystrophy, sparse scalp hair and eyelashes, hyperpigmentation of skin, palmar hyperkeratosis, premalignant oral leukoplakia, pancytopenia, myelodysplasia, +/- recurrent infections. A severe phenotype with developmental delay and cerebellar hypoplasia known as Hoyeraal-Hreidarsson Syndrome (HHS) may occur in some DKC patients. IUIS Major category: Combined immunodeficiencies with associated or syndromic features. IUIS Subcategory: DyskeratosIs Congenita (DKC), Myelodysplasia, Short Telomeres

Created: 2 Jul 2018, 10:35 a.m.

This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s)
GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.

Created: 19 Apr 2018, 1:08 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: TERT, PanelApp HGNC gene symbol check: TERT, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Other well defined PIDs / Dyskeratosis congenita / Dyskeratosis congenita; Other well defined PIDs / Dyskeratosis congenita / Hoyeraal-Hreidarsson syndrome

Created: 17 Apr 2018, 12:29 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: TERT, GRID_Gene_Symbol: TERT, GRID_Transcript_ENS_Community submitted: ENST00000310581, GRID_Transcript_RefSeq: NM_198253.2, GRID_Transcript_ENS_used_on_Production: ENST00000310581

Created: 17 Apr 2018, 12:12 p.m.