Alternative titles; symbols
HGNC Approved Gene Symbol: RTEL1
Cytogenetic location: 20q13.33 Genomic coordinates (GRCh38) : 20:63,657,810-63,696,253 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.33 | Dyskeratosis congenita, autosomal dominant 4 | 615190 | Autosomal dominant; Autosomal recessive | 3 |
| Dyskeratosis congenita, autosomal recessive 5 | 615190 | Autosomal dominant; Autosomal recessive | 3 | |
| Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 3 | 616373 | Autosomal dominant | 3 |
The RTEL1 gene encodes an essential iron-sulfur (FeS)-containing DNA helicase that is crucial for telomere maintenance and DNA repair. It has also been implicated as an antirecombinase in that it disrupts D-loop formation during homologous recombination and is essential for the disassembly of T-loops at the end of telomeres during DNA replication (summary by Walne et al., 2013).
By sequence analysis and RT-PCR, Bai et al. (2000) isolated the NHL gene. The predicted 1,219-amino acid NHL protein shares 26% identity with the RAD3/ERCC2 (126340) family of DNA helicases. The 7 domains characteristic of helicases are highly conserved in NHL.
Ding et al. (2004) identified a mouse gene similar to the C. elegans Dog1 DNA helicase-like gene (605882) within a chromosome region associated with species-specific telomere length regulation (Zhu et al., 1998). They named the gene Rtel and cloned full-length Rtel cDNAs. The predicted full-length Rtel protein contains 1,209 amino acids and shares 74% identity with its human homolog, NHL. The human and mouse proteins both have 7 characteristic helicase motifs and a C-terminal PIP box, which is typically found in proteins that interact with proliferating cell nuclear antigen (PCNA; 176740). Ding et al. (2004) also identified several splice variants involving the last 4 exons of the Rtel gene. Northern blot analysis of adult mouse tissues detected Rtel expression in spleen, thymus, Peyer patch, kidney, and intestine, but not in brain, heart, lung, skeletal muscle, skin, and white fat tissue. In the adult mouse gonad, Rtel was expressed highly in testis, mainly in spermatogonia and meiotic spermatocytes. During embryonic mouse development, Rtel expression was widespread in dividing cells. Rtel expression in mouse embryonic stem cells appeared to be restricted to the nucleus in numerous foci that were similar to but overlapped only partially with replication foci containing Pcna.
Alternative splicing generates 2 main RTEL1 variants in human cells: variant 2, containing 1,219 amino acids, and variant 6, containing 1,300 amino acids. The 2 variants differ in their C-terminal regions (summary by Le Guen et al., 2013).
By genomic sequence analysis, Bai et al. (2000) determined that the NHL gene contains 35 exons. Ding et al. (2004) determined that the mouse Rtel gene contains 34 exons and spans 36.6 kb.
By genomic sequence analysis, Bai et al. (2000) mapped the NHL gene to chromosome 20q13.3. Ding et al. (2004) mapped the mouse Rtel gene within 1 Mb of the telomere on chromosome 2q.
Youds et al. (2010) showed that the antirecombinase RTEL1 is required to prevent excess meiotic crossovers, probably by promoting meiotic synthesis-dependent strand annealing. Two distinct classes of meiotic crossovers are increased in Rtel1 mutants, and crossover inhibition and homeostasis are compromised. Youds et al. (2010) proposed that RTEL1 implements the second level of crossover control by promoting noncrossovers.
Deng et al. (2013) demonstrated that RTEL1 interacts with TRF1 (600951), a protein involved in the shelterin complex that protects telomere ends during DNA replication.
Vannier et al. (2013) established that RTEL1 associates with the replisome through binding to PCNA. Mouse cells disrupted for the Rtel1-Pcna interaction (mutant in PIP; 176720) exhibited accelerated senescence, replication fork instability, reduced replication fork extension rates, and increased origin usage. Although T-loop disassembly at telomeres was unaffected in the mutant cells, telomere replication was compromised, leading to fragile sites at telomeres. Rtel1-Pip mutant mice were viable, but loss of the Rtel1-Pcna interaction accelerated the onset of tumorigenesis in p53 (191170)-deficient mice. Vannier et al. (2013) proposed that RTEL1 plays a critical role in both telomere and genomewide replication, which is crucial for genetic stability and tumor avoidance.
Autosomal Recessive Dyskeratosis Congenita 5
In 10 patients from 7 families with severe autosomal recessive dyskeratosis congenita-5 (DKCB5; 615190), Walne et al. (2013) identified 11 different mutations in the RTEL1 gene (see, e.g., 608833.0001-608833.0006). The initial mutations were identified by exome sequencing of 1 family. The remaining 6 families were found from a larger cohort of 23 families with a similar phenotype. All mutations segregated with the disease in an autosomal recessive pattern of inheritance. The patients had onset of bone marrow failure and immunodeficiency in early childhood. Most patients also had growth and developmental delay and cerebellar hypoplasia. Patients with RTEL1 mutations had significantly shorter telomere lengths in leukocytes compared to controls. Evidence suggests that RTEL1 is necessary to cause T-loop disassembly at the telomere during DNA replication. When RTEL1 is inactivated, T-loops are inappropriately cleaved into T-circles by the SLX4 complex (613278), which results in a loss of telomere length. Using a T-circle amplification assay, Walne et al. (2013) found that patients with RTEL1 mutations had increased T-circle formation compared to controls and to patients with DKC1 mutations (300126). These results suggested that the mutations affect the ability of RTEL1 to correctly process T-loops, thus resulting in telomere shortening and a relative increase in T-circle formation. Walne et al. (2013) postulated a disease-causing mechanism that results in the shortening of telomeres due to impaired telomere maintenance without affecting the telomerase complex. No RTEL1 mutations were found in 102 index cases with milder dyskeratosis congenita or related bone marrow-failure syndromes, suggesting that RTEL1 mutations are specific for the severe HHS phenotype.
In 3 patients, including 2 sibs, with DKCB5 manifest as Hoyeraal-Hreidarsson syndrome, Le Guen et al. (2013) identified compound heterozygous mutations in the RTEL1 gene (608833.0007-608833.0010). The mutations, which were found by whole-genome linkage analysis combined with whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Leukocytes from all patients and cultured fibroblasts from 2 patients showed shortened telomeres compared to controls. Patient cells also showed hallmarks of genome instability, including spontaneous DNA damage, anaphase bridges, and telomeric aberrations.
In a boy with severe DKCB5 manifest as Hoyeraal-Hreidarsson syndrome, Ballew et al. (2013) identified compound heterozygous mutations in the RTEL1 gene (R998X, 608833.0004 and E615D, 608833.0011). The mutations were found by whole-exome sequencing and were not present in several large control databases, including UCSC GoldenPath, Exome Variant Server, Kaviar, dbSNP, and 1000 Genomes Project, or in 366 in-house exomes.
Autosomal Dominant Dyskeratosis Congenita 4
In 2 brothers with severe autosomal dominant dyskeratosis congenita manifest as Hoyeraal-Hreidarsson syndrome (see 615190), Ballew et al. (2013) identified a heterozygous mutation in the RTEL1 gene (R1010X; 608833.0012). The mutation, which was identified by whole-exome sequencing, was also present in the clinically unaffected mother, who had shortened telomeres. The mutation was found to have a minor allele frequency of 0.015% in the Exome Sequencing Project database, but was not found in the 1000 Genomes Project, Kaviar, or dbSNP database.
Ballew et al. (2013) identified a heterozygous mutation in the RTEL1 gene (E615D; 608833.0011) in the mother and brother of a boy with HHS due to biallelic RTEL1 mutations. The mother and brother were clinically unaffected, but both had shortened telomeres. The brother also had hypocellular bone marrow and was being followed for development of DKC. The findings suggested that heterozygosity for the E615D mutation may also cause certain disease manifestations, consistent with autosomal dominant inheritance.
In a 25-year-old man with autosomal dominant dyskeratosis congenita-4, Ballew et al. (2013) identified a heterozygous mutation in the RTEL1 gene (A645T; 608833.0013). His sister had nail dysplasia, short stature, and dental caries, but DNA was not available from her or from their parents.
Telomere-Related Pulmonary Fibrosis and/or Bone Marrow Failure Syndrome 3
In affected members of 5 unrelated families with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT3; 616373), Stuart et al. (2015) identified 5 different heterozygous mutations in the RTEL1 gene (see, e.g., 608833.0014-608833.0017). The mutations were found by whole-exome sequencing of 99 probands with a family history of pulmonary fibrosis. Among all families, at least 5 clinically unaffected individuals carried a pathogenic mutation, consistent with incomplete penetrance. There was also evidence of environmental influences, e.g., a history of smoking and occupational factors. Functional studies of the variants were not performed.
Lamm et al. (2009) and Deng et al. (2013) reported that a relative of sibs with biallelic RTEL1 mutations, who carried a heterozygous mutation (M492I; 608833.0003), had died of pulmonary fibrosis at age 58 years.
In 9 unrelated families with PFBMFT3, Cogan et al. (2015) identified 9 different heterozygous mutations in the RTEL1 gene (see, e.g., 608833.0002; 608833.0018-608833.0020). The mutation in the first family was found by whole-exome sequencing of 25 families; subsequent mutations were found by sequencing the RTEL1 gene in 163 additional kindreds with the disorder. Overall, RTEL1 mutations were identified in 9 (4.7%) of 188 families who underwent sequencing. Peripheral blood cells derived from mutation carriers showed shortened telomeres and increased T-circle formation compared to controls, consistent with a loss of RTEL1 function. None of the families had a history or clinical features of bone marrow failure, hematopoietic malignancy, or dyskeratosis congenita.
Ding et al. (2004) inactivated Rtel expression in mice. Rtel -/- mice died between days 10 and 11.5 of gestation with defects in the nervous system, heart, vasculature, and extraembryonic tissues. Rtel -/- embryonic stem cells showed telomere loss and displayed many chromosome breaks and fusions upon differentiation in vitro. Crosses of Rtel +/- mice with Mus spretus showed that Rtel from the Mus musculus parent was required for telomere elongation of Mus spretus chromosomes in F1 cells. Ding et al. (2004) concluded that Rtel is an essential gene that regulates telomere length and prevents genetic instability.
In a patient with autosomal recessive dyskeratosis congenita-5 (DKCB5; 615190), Walne et al. (2013) identified compound heterozygosity for 2 mutations in the RTEL1 gene: a c.2288G-T transversion in exon 25, resulting in a gly763-to-val (G763V) substitution at a conserved residue in the Rad3-related helicase domain, and a c.3791G-A transition in exon 35, resulting in an arg1264-to-his (R1264H; 608833.0002) substitution. The mutations, which were identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not present in several large control databases.
Dyskeratosis Congenita, Autosomal Recessive 5
For discussion of the arg1264-to-his (R1264H) mutation in the RTEL1 gene that was found in compound heterozygous state in a patient with autosomal recessive dyskeratosis congenita-5 (DKCB5; 615190) by Walne et al. (2013), see 608833.0001.
Pulmonary Fibrosis and/or Bone Marrow Failure Syndrome, Telomere-Related, 3
In affected members of a family (family E) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT3; 616373), Cogan et al. (2015) identified a heterozygous c.3791G-A transition in the RTEL1 gene, resulting in an arg1264-to-his (R1264H) substitution in the 1,300-residue isoform.
In 3 sibs with autosomal recessive dyskeratosis congenita-5 (DKCB5; 615190) manifest as Hoyeraal-Hreidarsson syndrome from a family originally reported by Lamm et al. (2009), Walne et al. (2013) identified compound heterozygosity for 2 mutations in the RTEL1 gene: a c.1548G-T transversion (c.1548G-T, NM_032957.4) in exon 17, resulting in a met516-to-ile (M516I) substitution at a conserved residue in the Rad3-related helicase domain, and a c.2992C-T transition (c.2992C-T, NM_032957.4) in exon 30, resulting in an arg998-to-ter (R998X; 608833.0004) substitution. The 1548G-T mutation was found in 1 of 12,937 control exomes, whereas the R998X mutation was not found in several large control databases.
Deng et al. (2013) also studied the family reported by Lamm et al. (2009). By whole-exome sequencing using a different transcript from that used by Walne et al. (2013), Deng et al. (2013) identified 2 compound heterozygous mutations in the RTEL1 gene: c.2920C-T (c.2920C-T, NM_016434) resulting in arg974-to-ter (R974X), and c.1476G-T (c.1476G-T, NM_016434) resulting in met492-to-ile (M492I, MET492ILE). Deng et al. (2013) noted that the transcript used by Walne et al. (2013) for sequencing represented a 1,243-amino acid splice variant employing a 24-amino acid exon not present in the transcript used by them. The M492I substitution occurred between the helicase ATP binding domain and the C-terminal domain 2. The R974X mutation resulted in termination downstream of the helicase domain, but it left out 2 PIP boxes. RT-PCR analysis suggested that the truncating mutation resulted in nonsense-mediated mRNA decay. The unaffected parents were heterozygous for 1 of the mutations. Lymphoblastoid cells derived from the patients showed telomere shortening, increased senescence, and an increased frequency of telomere defects, such as fragile telomeres and signal-free ends, but no increase in pathogenic T-circle formation on 2D gel electrophoresis. Leukocytes from the heterozygous parents also showed relatively short telomeres and a shorter telomeric 3-prime overhang compared to controls. Ectopic expression of wildtype RTEL1 suppressed the telomere defects in both patient and parental cells. Parental cells with the M492I mutation showed a more severe phenotype, with activation of the ATM (607585) pathway, endoreduplication, and the failure of cells to immortalize. Patient fibroblasts showed normal lengths, but did have telomere defects and impaired growth. There was an inability of active telomerase to maintain stable telomeres in both fibroblasts and lymphoid cells, pointing to a primary defect that compromises both suppression of the DNA damage response and telomerase recruitment or activation. A paternal great-uncle of the sibs, who was heterozygous for M492I, died of pulmonary fibrosis at age 58 years, suggesting that he had a form of DKC.
For discussion of the arg998-to-ter (R998X) mutation in the RTEL1 gene that was found in compound heterozygous state in patients with autosomal recessive dyskeratosis congenita-5 (DKCB5; 615190) by Walne et al. (2013) and Ballew et al. (2013), see 608833.0003 and 608833.0011, respectively. This mutation was also found in compound heterozygous state by Deng et al. (2013) and referred to as ARG974TER; see 608833.0003.
In 3 unrelated patients with autosomal recessive dyskeratosis congenita-5 (DKCB5; 615190), Walne et al. (2013) identified a heterozygous c.2941C-T transition (c.2941C-T, NM_032957.4) in exon 30 of the RTEL1 gene, resulting in an arg981-to-trp (R981W) substitution at a conserved residue. Each of the patients carried R981W in compound heterozygosity with another pathogenic RTEL1 mutation (see, e.g., E275K, 608833.0006). None of the mutations were found in several large control databases.
In a patient with autosomal recessive dyskeratosis congenita-5 (DKCB5; 615190), Walne et al. (2013) identified compound heterozygosity for 2 mutations in the RTEL1 gene: an c.823G-A transition (c.823G-A, NM_032957.4) in exon 9, resulting in a glu275-to-lys (E275K) substitution at a highly conserved residue in the DEAH box, and R981W (608833.0005).
In 2 sibs with a severe form of autosomal recessive dyskeratosis congenita-5 (DKCB5; 615190) manifest as Hoyeraal-Hreidarsson syndrome, Le Guen et al. (2013) identified compound heterozygosity for 2 mutations in the RTEL1 gene: a c.2097C-G transversion in exon 24, resulting in an ile699-to-met (I699M) substitution in the catalytic core, and a c.3730T-C transition in exon 34B, resulting in a cys1244-to-arg (C1244R; 608833.0008) substitution affecting only isoform 6. The mutations, which were found by whole-genome linkage analysis combined with whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was present in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases or in an in-house database. The I699M substitution is located at the HD1/HD2 interface, which forms a composite ATP-binding site, and likely plays a role in stability of this site. The C1244R substitution is located at a conserved region in a globular domain of the C-terminal region of RTEL1 isoform 6, which may play a role in zinc binding and thus impact functional properties. Patient fibroblasts showed a slight reduction in RTEL1 expression. The patients had intrauterine growth retardation, hypotrophy, microcephaly, bone marrow failure, immunodeficiency, and cerebellar atrophy. Both died of severe infection in early childhood. The cellular phenotype in these patients consisted of short telomeres and hallmarks of genomic instability, including spontaneous DNA damage, anaphase bridges, telomeric aberrations, and accelerated cellular senescence, consistent with defective DNA replication and repair.
For discussion of the cys1244-to-arg (C1244R) mutation in the RTEL1 gene that was found in compound heterozygous state in patients with autosomal recessive dyskeratosis congenita-5 (DKCB5; 615190) by Le Guen et al. (2013), see 608833.0007.
In a 5-year-old girl with a severe form of autosomal recessive dyskeratosis congenita-5 (DKCB5; 615190) manifest as Hoyeraal-Hreidarsson syndrome, Le Guen et al. (2013) identified compound heterozygosity for 2 mutations in the RTEL1 gene: a c.2233G-A transition in exon 25, resulting in a val745-to-met (V745M) substitution in the catalytic core, and a G-to-A transition in intron 24 (IVS24+5G-A; 608833.0010), resulting in a splice site mutation. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was present in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases or in an in-house database. The V745M substitution occurs within a C-terminal extension of the HD2 domain and likely participates in stability of an inner core alpha-helix. Patient lymphoblastoid cells showed severely decreased protein expression. Clinically, the patient had intrauterine growth retardation, poor growth, microcephaly, bone marrow failure, immunodeficiency, cerebellar atrophy, dysmorphic corpus callosum, oral leukoplakia, inflammatory colitis, and nail dystrophy. The cellular phenotype consisted of short telomeres and hallmarks of genomic instability, including spontaneous DNA damage, anaphase bridges, telomeric aberrations, and accelerated cellular senescence, consistent with defective DNA replication and repair.
For discussion of the splice site mutation in the RTEL1 gene (IVS24+5G-A) that was found in compound heterozygous state in a patient with autosomal recessive dyskeratosis congenita-5 (DKCB5; 615190) by Le Guen et al. (2013), see 608833.0009.
In a boy with severe autosomal recessive dyskeratosis congenita-5 (DKCB5; 615190) manifest as Hoyeraal-Hreidarsson syndrome, Ballew et al. (2013) identified compound heterozygous mutations in the RTEL1 gene: a G-to-T transversion, resulting in a glu615-to-asp (E615D) substitution at a highly conserved residue in the helicase domain, and R998X (608833.0004). The mutations were found by whole-exome sequencing and were not present in several large control databases, including UCSC GoldenPath, Exome Variant Server, Kaviar, dbSNP, and 1000 Genomes Project, or in 366 in-house exomes. Each clinically unaffected parent and a clinically unaffected brother were heterozygous for 1 of the mutations. The boy had microcephaly, developmental delay, cerebellar hypoplasia, bone marrow failure, and decreased telomere lengths. The brother, who was heterozygous for the E615D mutation, had hypocellular bone marrow and short telomeres. The mother, who was heterozygous for E615D, also had short telomeres, whereas the father, who was heterozygous for the truncating mutation, had normal telomeres. The findings suggested that heterozygosity for E615D may also cause manifestations, consistent with autosomal dominant inheritance.
In 2 brothers with severe autosomal dominant dyskeratosis congenita-4 (DKCA4; see 615190) manifest as Hoyeraal-Hreidarsson syndrome, Ballew et al. (2013) identified a heterozygous C-to-T transition in the RTEL1 gene, resulting in an arg1010-to-ter (R1010X) substitution and the loss of the PIP motif. The mutation, which was identified by whole-exome sequencing, was also present in the clinically unaffected mother. The mutation was found to have a minor allele frequency of 0.015% in the Exome Sequencing Project database, but was not found in the 1000 Genomes Project, Kaviar, or dbSNP databases. The boys had microcephaly, cerebellar hypoplasia, developmental delay, bone marrow failure, and very short telomeres. The mother was clinically unaffected, but had shortened telomeres. Mutations in known DKC genes were excluded. Ballew et al. (2013) suggested that genetic anticipation may be present in this family.
In a 25-year-old man with autosomal dominant dyskeratosis congenita-4 (DKCA4; see 615190), Ballew et al. (2013) identified a heterozygous G-to-A transition in the RTEL1 gene, resulting in an ala645-to-thr (A645T) substitution at a highly conserved residue in the catalytic domain. The mutation was found by exome sequencing, and was not present in several large control databases, including UCSC GoldenPath, Exome Variant Server, Kaviar, dbSNP, and 1000 Genomes Project, or in 366 in-house exomes. The patient had mild developmental delay, learning difficulties, ADHD, depression, short stature, bone marrow failure, and short telomeres. His sister had nail dysplasia, short stature, and dental caries, but DNA was not available from her or from the parents.
In 2 affected members of a family (F415) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT3; 616373), Stuart et al. (2015) identified a heterozygous 1-bp deletion (c.602delG, NM_001283009.1) in the RTEL1 gene, resulting in a frameshift and premature termination (Gly201GlufsTer15). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. Telomere length in the proband was about 2% of control length. There were 2 unaffected mutation carriers, consistent with incomplete penetrance. One affected member with the mutation had a 10 pack-year smoking history and had worked as a railroad engineer for 40 years. Functional studies of the variant were not performed.
In 3 affected members of a family (F343) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT3; 616373), Stuart et al. (2015) identified a heterozygous c.1451C-T transition (c.1451C-T, NM_001283009.1) in the RTEL1 gene, resulting in a pro484-to-leu (P484L) substitution at a highly conserved residue in the RAD3 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. DNA from 2 other affected members of the family was not available, but the mutation was inferred in 1 of them on the basis of location in the pedigree. Telomere length in the proband was less than 1% of control length. There were 3 unaffected mutation carriers, consistent with incomplete penetrance. Several of those affected had a long history of smoking as well as occupational factors that may have been contributory. Functional studies of the variant were not performed.
In a man (F337) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT3; 616373), Stuart et al. (2015) identified a heterozygous c.2005C-T transition (c.2005C-T, NM_001283009.1) in the RTEL1 gene, resulting in a gln693-to-ter (Q693X) substitution in the helicase C domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. DNA from 2 other affected members of the patient's family was not available, but the mutation was inferred in 1 of them on the basis of location in the pedigree. Telomere length in the proband was less than 1% of control length. There was 1 unaffected mutation carrier, consistent with incomplete penetrance. One of the affected family members had a 10 pack-year smoking history. Functional studies of the variant were not performed.
In a man (CKG571) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT3; 616373) and a significant family history of the disorder, Stuart et al. (2015) identified a heterozygous c.3371A-C transversion (c.3371A-C, NM_001283009.1) in the RTEL1 gene, resulting in a his1124-to-pro (H1124P) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. DNA from 3 other affected members of the patient's family was not available. Telomere length in the patient was less than 1% of control length. The patient had a 92 pack-year smoking history and had worked as a bricklayer for 30 years. Functional studies of the variant were not performed.
In 8 affected individuals from a large family (family A) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT3; 616373), Cogan et al. (2015) identified a heterozygous 9-bp deletion (c.2219_2227del) in the RTEL1 gene, resulting in an in-frame deletion of 3 amino acids (740_742delHVI) in the helicase domain. The numbering of this deletion refers to the 1,219/1,300-residue RTEL1 isoform. The mutation was found by a combination of whole-exome sequencing and candidate gene selection and was confirmed by Sanger sequencing. The mutation was present in all affected family members, but there was also evidence of incomplete penetrance. The mutation was not found in the Exome Sequencing Project database.
In affected members of a family (family D) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT3; 616373), Cogan et al. (2015) identified a heterozygous G-to-C transversion in intron 25 of the RTEL1 gene (c.2413+1G-C), resulting in a splice site mutation in the 1,219/1,300-residue isoform.
In affected members of a family (family I) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT3; 616373), Cogan et al. (2015) identified a heterozygous c.2957G-A transition in the RTEL1 gene, resulting in an arg986-to-gln (R986Q) substitution in the 1,219/1,300-residue isoform. The variant was found once in the Exome Sequencing Project database.
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