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Genes: ACD; CTC1; DKC1; NAF1; NHP2; NOP10; PARN; POT1; RTEL1; STN1; TERC; TERT; TINF2; WRAP53; ZCCHC8
*Please note that
Short telomere syndromes are a spectrum of disease phenotypes that result from variants in genes involved in telomere maintenance PMID 22965356. The most common clinical manifestations are listed here and they may co-occur in patients and affected families.
Idiopathic pulmonary fibrosis is an age-related disorder characterized by scarring of the lungs. It runs in families and ~20% of idiopathic pulmonary fibrosis patients have an affected first degree relative PMID 22079513. Other types of lung disease cluster in families with germline defects in telomere maintenance including non-specific interstitial pneumonitis, pleuroparenchymal fibroelastosis (PPFE), chronic hypersensitivity pneumonitis and emphysema PMID 17392301, PMID 29703687, PMID 25562321.
Bone marrow failure includes spectrum of failed hematopoiesis and includes isolated cytopenias, overt aplastic anemia as well as myelodysplastic syndrome.
Immunodeficiency may also be a manifestation of primary short telomere syndromes alone or in combination with bone marrow failure PMID 30179220. Hoyeraal-Hreidarsson syndrome (HHS) is a severe short telomere syndrome that is classically associated with immunodeficiency, colitis PMID 23279657, intrauterine growth restriction, microcephaly, and cerebellar hypoplasia.
Dyskeratosis congenita is a classic short telomere disorder characterized by characteristic mucocutaneous findings namely nail dystrophy, oral leukoplakia and skin hyperpigmentation. Revesz syndrome is a rare bilateral exudative retinopathy which has been seen in pediatric patients with short telomere syndromes including Hoyeraal-Hreidarsson syndrome.
Coats plus syndrome is rare and has distinguishing features from other short telomere syndromes such as intracranial calcifications. It is most commonly caused by biallelic variants in CTC1 PMID 22267198.
Autosomal dominant, autosomal recessive, X-linked recessive, and de novo
Telomere length is the strongest predictor of disease phenotype as well as severity in this group of disorders PMID 29463756. Genetic anticipation may show evolving patterns of disease in autosomal dominant families with older generations affected by pulmonary disease and younger generations by bone marrow failure PMID 21436073. Some clinical phenotypes that have genotype correlations additionally include:
- Hoyeraal-Hreidarsson syndrome is commonly caused by mutations in DKC1 or TINF2 but has also been reported with biallelic variants in TERT, RTEL1 and PARN PMID 25940403.
- Revesz syndrome is often associated with variants in TINF2 PMID 18252230.
- Biallelic variants in CTC1 usually manifest as Coats plus syndrome (intracranial calcifications, retinal exudates, osteopenia, gastrointestinal bleeding). CTC1 biallelic variants may also be seen in rare cases of isolated bone marrow failure PMID 22532422.
Reversion has been described in patients with TERC variants PMID 22341970 and in one adult with a TINF2 variant PMID 25539146. If a patient who meets diagnostic criteria for short telomere syndrome has a negative molecular testing, it might be beneficial to repeat the sequencing from a non-hematopoietic tissue (e.g. fibroblast).
DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the Burrows-Wheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22 and DDL.TWIST.Exome.Dosage.v1.2020_12_20.
Discrimination of genetic causes of short telomere disorders; identification of causative variants in known or highly suspicious cases; facilitation of targeted testing of relatives of probands and/or predictive or prenatal testing.
Variants in telomerase and telomere maintenance genes manifest in a number of clinical presentations that span infancy to adulthood. Testing telomere length by flow cytometry and FISH can functionally identify some of these patients and may also predictive of the severity of disease PMID 21436073. Approximately, 30% of patients with familial forms of pulmonary fibrosis and telomere-related lung disease carry variants in telomerase and telomere maintenance PMID 25539146. In sporadic cases of idiopathic pulmonary fibrosis, an estimated 5% of patients carry a variant. For unselected patients with idiopathic pulmonary fibrosis (i.e. a mix of familial and sporadic disease) approximately 10% carry germline variants in the common telomere maintenance genes PMID 28099038. For patients with familial clustering of bone marrow failure and idiopathic pulmonary fibrosis, approximately 80% carry variants in telomere maintenance genes PMID 21436073. Variants in telomere-related genes are likely the most common cause of inherited forms of bone marrow failure PMID 29146883. Telomere-mediated disease may also more rarely manifest as classic dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome or other more rare phenotypes as aforementioned where the yield of identifying the short telomere defect by flowFISH (link) is high and for identifying a disease-causing variant up to 80%.
Telomere length testing by flowFISH is offered through the Johns Hopkins Molecular Diagnostics Laboratory.
Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial DNA variants or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.
Other testing relevant to the valuation of inherited pulmonary fibrosis: PulmZoom
3-6ml whole blood in EDTA (purple topped) tubes
Saliva collected in an appropriate collection device (Oragene®-DNA 500 or 600 device)
DNA extracted from fibroblast or lymphocyte cell line (must be extracted in a CLIA-certified laboratory)
Turn Around Time
Approximately 6-8 weeks
Fee and CPT Codes
Exome Panel: $2915
CPT Code: 81479
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