Publications by authors named "Neelam Giri"

77 Publications

Disease Progression and Clinical Outcomes in Telomere Biology Disorders.

Blood 2021 Dec 1. Epub 2021 Dec 1.

National Cancer Institute, Bethesda, Maryland, United States.

Dyskeratosis congenita related telomere biology disorders (DC/TBDs) are characterized by very short telomeres caused by germline pathogenic variants in telomere biology genes. Clinical presentations can affect all organs and inheritance patterns include autosomal dominant (AD), autosomal recessive (AR), X-linked (XLR) or de novo. This study examined the associations between mode of inheritance with phenotypes and long-term clinical outcomes. Two hundred thirty-one individuals with DC/TBDs [144 male, 86.6% known genotype, median age at diagnosis 19.4 years (0-71.6)], enrolled in the National Cancer Institute's Inherited Bone Marrow Failure Syndrome Study, underwent detailed clinical assessments and longitudinal follow-up [median follow-up 5.2 years (0-36.7)]. Patients were grouped by inheritance pattern, considering AD-nonTINF2, AR/XLR, and TINF2 variants separately. Severe bone marrow failure, severe liver disease and gastrointestinal telangiectasias were more prevalent in AR/XLR or TINF2 disease, whereas pulmonary fibrosis developed predominantly in adults with AD disease. After adjusting for age at DC/TBD diagnosis, we observed the highest cancer risk in AR/XLR individuals. At last follow-up, 42% of patients were deceased with a median overall survival of 52.8 years [95% confidence interval (CI) 45.5-57.6] and the hematopoietic cell or solid organ transplant-free median survival was 45.3 years (95% CI 37.4-52.1). Significantly better overall survival was present in AD versus AR/XLR/TINF2 disease (p<0.01), while patients with AR/XLR and TINF2 disease had similar survival probabilities. This long-term study of the clinical manifestations of DC/TBDs creates a foundation for incorporating the mode of inheritance into evidence-based clinical care guidelines, and risk stratification in patients with DC/TBDs. clinicaltrials.gov NCT00027274.
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http://dx.doi.org/10.1182/blood.2021013523DOI Listing
December 2021

Genotype-cancer association in patients with Fanconi anemia due to pathogenic variants in FANCD1 (BRCA2) or FANCN (PALB2).

Cancer Genet 2021 Nov 4;258-259:101-109. Epub 2021 Oct 4.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome and a cancer predisposition disorder. Cancers in FA include acute leukemia and solid tumors; the most frequent solid tumor is head and neck squamous cell carcinoma. FA is a primarily autosomal recessive disorder. Several of the genes in which biallelic pathogenic variants cause FA are also autosomal monoallelic cancer predisposition genes e.g. FANCD1 (BRCA2) and FANCN (PALB2). We observed that patients with FA due to biallelic or homozygous pathogenic variants in FANCD1 and FANCN have a unique cancer association. We curated published cases plus our NCI cohort cases, including 71 patients in the FANCD1 group (94 cancers and 69 variants) and 16 patients in the FANCN group (23 cancers and 20 variants). Only patients in FANCD1 and FANCN groups had one or more of these tumors: brain tumors (primarily medulloblastoma), Wilms tumor and neuroblastoma; this is a genotype-specific cancer combination of tumors of embryonal origin. Acute leukemias, seen in all FA genotypes, also occurred in FANCD1 and FANCN group patients at young ages. In silico predictions of pathogenicity for FANCD1 variants were compared with results from a mouse embryonic stem cell-based functional assay. Patients with two null FANCD1 variants did not have an increased frequency of cancer nor earlier onset of cancer compared with those with hypomorphic variants. Patients with FA and these specific cancers should consider genetic testing focused on FANCD1 and FANCN, and patients with these genotypes may consider ongoing surveillance for these specific cancers.
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http://dx.doi.org/10.1016/j.cancergen.2021.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8628873PMC
November 2021

Pathogenic germline variant alters hematopoietic gene expression profiles.

Cold Spring Harb Mol Case Stud 2021 08 2;7(4). Epub 2021 Aug 2.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA.

encodes Ikaros, a zinc finger-containing transcription factor crucial to the development of the hematopoietic system. Germline pathogenic variants in have been reported in patients with acute lymphocytic leukemia and immunodeficiency syndromes. Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by erythroid hypoplasia, associated with a spectrum of congenital anomalies and an elevated risk of certain cancers. DBA is usually caused by heterozygous pathogenic variants in genes that function in ribosomal biogenesis; however, in many cases the genetic etiology is unknown. We identified a germline variant, rs757907717 C > T, in identical twins with DBA-like features and autoimmune gastrointestinal disease. rs757907717 C > T results in a p.R381C amino acid change in the IKZF1 Ik-x isoform (p.R423C on isoform Ik-1), which we show is associated with altered global gene expression and perturbation of transcriptional networks involved in hematopoietic system development. These data suggest that this missense substitution caused a DBA-like syndrome in this family because of alterations in hematopoiesis, including dysregulation of networks essential for normal erythropoiesis and the immune system.
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http://dx.doi.org/10.1101/mcs.a006015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327879PMC
August 2021

Gynaecological and reproductive health of women with telomere biology disorders.

Br J Haematol 2021 06 21;193(6):1238-1246. Epub 2021 May 21.

National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.

Reproductive health may be adversely impacted in women with dyskeratosis congenita (DC) and related telomere biology disorders (TBD). We evaluated gynaecological problems, fertility, and pregnancy outcomes in 39 females aged 10-81 years who were followed longitudinally in our DC/TBD cohort. Twenty-six had bone marrow failure and 12 underwent haematopoietic cell transplantation. All attained menarche at a normal age. Thirteen women reported menorrhagia; ten used hormonal contraception to reduce bleeding. Nine experienced natural normal-aged menopause. Gynaecological problems (endometriosis = 3, pelvic varicosities = 1, cervical intraepithelial neoplasia = 1, and uterine prolapse = 2) resulted in surgical menopause in seven. Twenty-five of 26 women attempting fertility carried 80 pregnancies with 49 (61%) resulting in livebirths. Ten (38%) women experienced 28 (35%) miscarriages, notably recurrent pregnancy loss in five (19%). Preeclampsia (n = 6, 24%) and progressive cytopenias (n = 10, 40%) resulted in maternal-fetal compromise, including preterm (n = 5) and caesarean deliveries (n = 18, 37%). Gynaecological/reproductive problems were noted mainly in women with autosomal-dominant inheritance; others were still young or died early. Although women with TBDs had normal menarche, fertility, and menopause, gynaecological problems and pregnancy complications leading to caesarean section, preterm delivery, or transfusion support were frequent. Women with TBDs will benefit from multidisciplinary, coordinated care by haematology, gynaecology and maternal-fetal medicine.
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http://dx.doi.org/10.1111/bjh.17545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363207PMC
June 2021

Gastrointestinal Hemorrhage: A Manifestation of the Telomere Biology Disorders.

J Pediatr 2021 03 21;230:55-61.e4. Epub 2020 Sep 21.

Section of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.

Objective: To describe the clinical features, therapeutic interventions, and patient outcomes of gastrointestinal (GI) hemorrhage in individuals with a telomere biology disorder, including dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus.

Study Design: Clinical Care Consortium for Telomere Associated Ailments members were invited to contribute data on individuals with telomere biology disorders at their institutions who experienced GI bleeding. Patient demographic, laboratory, imaging, procedural, and treatment information and outcomes were extracted from the medical record.

Results: Sixteen patients who experienced GI hemorrhage were identified at 11 centers. Among 14 patients who underwent genetic testing, 8 had mutations in TINF2, 4 had mutations in CTC1 or STN1, and 1 patient each had a mutation in TERC and RTEL1. Ten patients had a history of hematopoietic cell transplantation. The patients with Coats plus and those without Coats plus had similar clinical features and courses. Angiodysplasia of the stomach and/or small bowel was described in 8 of the 12 patients who underwent endoscopy; only 4 had esophageal varices. Various medical interventions were trialed. No single intervention was uniformly associated with cessation of bleeding, although 1 patient had a sustained response to treatment with bevacizumab. Recurrence was common, and the overall long-term outcome for affected patients was poor.

Conclusions: GI bleeding in patients with telomere biology disorders is associated with significant morbidity and with vascular ectasias rather than varices.
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http://dx.doi.org/10.1016/j.jpeds.2020.09.038DOI Listing
March 2021

Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction.

EMBO J 2020 11 16;39(21):e103420. Epub 2020 Sep 16.

Biomedical Research Center, National Institute on Aging/National Institutes of Health, Baltimore, MD, USA.

Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.
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http://dx.doi.org/10.15252/embj.2019103420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604620PMC
November 2020

Expansion of germline RPS20 mutation phenotype to include Diamond-Blackfan anemia.

Hum Mutat 2020 11 30;41(11):1918-1930. Epub 2020 Aug 30.

Department of Pediatrics, Section of Hematology/Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.

Diamond-Blackfan anemia (DBA) is a ribosomopathy of variable expressivity and penetrance characterized by red cell aplasia, congenital anomalies, and predisposition to certain cancers, including early-onset colorectal cancer (CRC). DBA is primarily caused by a dominant mutation of a ribosomal protein (RP) gene, although approximately 20% of patients remain genetically uncharacterized despite exome sequencing and copy number analysis. Although somatic loss-of-function mutations in RP genes have been reported in sporadic cancers, with the exceptions of 5q-myelodysplastic syndrome (RPS14) and microsatellite unstable CRC (RPL22), these cancers are not enriched in DBA. Conversely, pathogenic variants in RPS20 were previously implicated in familial CRC; however, none of the reported individuals had classical DBA features. We describe two unrelated children with DBA lacking variants in known DBA genes who were found by exome sequencing to have de novo novel missense variants in RPS20. The variants affect the same amino acid but result in different substitutions and reduce the RPS20 protein level. Yeast models with mutation of the cognate residue resulted in defects in growth, ribosome biogenesis, and polysome formation. These findings expand the phenotypic spectrum of RPS20 mutation beyond familial CRC to include DBA, which itself is associated with increased risk of CRC.
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http://dx.doi.org/10.1002/humu.24092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857045PMC
November 2020

Germline mutation of , a major p53 regulator, in a familial syndrome of defective telomere maintenance.

Sci Adv 2020 04 10;6(15):eaay3511. Epub 2020 Apr 10.

Genetics of Tumor Suppression, Institut Curie, Paris, France.

Dyskeratosis congenita is a cancer-prone inherited bone marrow failure syndrome caused by telomere dysfunction. A mouse model recently suggested that p53 regulates telomere metabolism, but the clinical relevance of this finding remained uncertain. Here, a germline missense mutation of , a negative regulator of p53, was found in a family with features suggestive of dyskeratosis congenita, e.g., bone marrow hypocellularity, short telomeres, tongue squamous cell carcinoma, and acute myeloid leukemia. Using a mouse model, we show that this mutation (p.T454M) leads to increased p53 activity, decreased telomere length, and bone marrow failure. Variations in p53 activity markedly altered the phenotype of mutant mice, suggesting an explanation for the variable expressivity of disease symptoms in the family. Our data indicate that a germline activation of the p53 pathway may cause telomere dysfunction and point to polymorphisms affecting this pathway as potential genetic modifiers of telomere biology and bone marrow function.
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http://dx.doi.org/10.1126/sciadv.aay3511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148086PMC
April 2020

Genotype-phenotype association and variant characterization in Diamond-Blackfan anemia caused by pathogenic variants in .

Haematologica 2021 05 1;106(5):1303-1310. Epub 2021 May 1.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA.

Diamond Blackfan anemia (DBA) is predominantly an autosomal dominant inherited red cell aplasia primarily caused by pathogenic germline variants in ribosomal protein genes. DBA due to pathogenic RPL35A variants has been associated with large 3q29 deletions and phenotypes not common in DBA. We conducted a multi-institutional genotype-phenotype study of 45 patients with DBA associated with pathogenic RPL35A germline variants and curated the variant data on 21 additional cases from the literature. Genotype-phenotype analyses were conducted comparing patients with large deletions versus all other pathogenic variants in RPL35A. Twenty-two of the 45 cases had large deletions in RPL35A. After adjusting for multiple tests, a statistically significant association was observed between patients with a large deletion and steroid-resistant anemia, neutropenia, craniofacial abnormalities, chronic gastrointestinal problems, and intellectual disabilities (p<0.01) compared with all other pathogenic variants. Non-large deletion pathogenic variants were spread across RPL35A with no apparent hot spot and 56% of the individual family variants were observed more than once. In this, the largest known study of DBA patients with pathogenic RPL35A variants, we determined that patients with large deletions have a more severe phenotype that is clinically different from those with non-large deletion variants. Genes of interest also deleted in the 3q29 region that could be associated with some of these phenotypic features include LMLN and IQCG. Management of DBA due to large RPL35A deletions may be challenging due to complex problems and require comprehensive assessments by multiple specialists including immunologic, gastrointestinal, and developmental evaluations to provide optimal multidisciplinary care.
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http://dx.doi.org/10.3324/haematol.2020.246629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094096PMC
May 2021

CNS manifestations in patients with telomere biology disorders.

Neurol Genet 2019 Dec 29;5(6):370. Epub 2019 Oct 29.

Clinical Genetics Branch (S.B., N.G., B.P.A., S.A.S.) and Biostatistics Branch (A.F.B.), Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville; Office of the Clinical Director (M.P.), National Institute of Mental Health, National Institutes of Health, Bethesda, MD; Department of Neurology (A.G.), Children's National Medical Center, Washington, DC; and Department of Radiology and Imaging Sciences (E.H.B.), Clinical Center, National Institutes of Health, Bethesda, MD.

Objective: We systematically evaluated CNS manifestations in patients with inherited telomere biology disorders (TBDs) to better understand the clinical and biological consequences of germline aberrations in telomere biology.

Methods: Forty-four participants with TBDs (31 dyskeratosis congenita, 12 Hoyeraal-Hreidarsson syndrome, and 1 Revesz syndrome) enrolled in an institutional review board-approved longitudinal cohort study underwent detailed clinical assessments, brain MRI, and genetic testing. Lymphocyte telomere length Z-scores were calculated to adjust for age.

Results: In this cohort, 25/44 (57%) patients with a TBD had at least 1 structural brain abnormality or variant, most commonly cerebellar hypoplasia (39%). Twenty-one patients (48%) had neurodevelopmental disorder or psychomotor abnormality. Twelve had psychiatric diagnoses, including depression and/or anxiety disorders. Other findings such as hypomyelination, prominent cisterna magna, and cavum septum pellucidum were more frequent than in the general population ( < 0.001). Shorter lymphocyte telomere length was associated with an increased number of MRI findings ( = 0.02) and neurodevelopmental abnormalities ( < 0.001). Patients with autosomal recessive or X-linked TBDs had more neurologic findings than those with autosomal dominant disease.

Conclusions: Structural brain abnormalities and variants are common in TBDs, as are neurologic and psychiatric symptoms. The connection between neurodevelopment and telomere biology warrants future study.
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http://dx.doi.org/10.1212/NXG.0000000000000370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878838PMC
December 2019

1q21.1 deletion and a rare functional polymorphism in siblings with thrombocytopenia-absent radius-like phenotypes.

Cold Spring Harb Mol Case Stud 2019 12 13;5(6). Epub 2019 Dec 13.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20859, USA.

Thrombocytopenia-absent radii (TAR) syndrome, characterized by neonatal thrombocytopenia and bilateral radial aplasia with thumbs present, is typically caused by the inheritance of a 1q21.1 deletion and a single-nucelotide polymorphism in on the nondeleted allele. We evaluated two siblings with TAR-like dysmorphology but lacking thrombocytopenia in infancy. Family NCI-107 participated in an IRB-approved cohort study and underwent comprehensive clinical and genomic evaluations, including aCGH, whole-exome, whole-genome, and targeted sequencing. Gene expression assays and electromobility shift assays (EMSAs) were performed to evaluate the variant of interest. The previously identified TAR-associated 1q21.1 deletion was present in the affected siblings and one healthy parent. Multiple sequencing approaches did not identify previously described TAR-associated SNPs or mutations in relevant genes. We discovered rs61746197 A > G heterozygosity in the parent without the deletion and apparent hemizygosity in both siblings. rs61746197 A > G overlaps a RelA-p65 binding motif, and EMSAs indicate the A allele has higher transcription factor binding efficiency than the G allele. Stimulation of K562 cells to induce megakaryocyte differentiation abrogated the shift of both reference and alternative probes. The 1q21.1 TAR-associated deletion in combination with the G variant of rs61746197 on the nondeleted allele is associated with a TAR-like phenotype. rs61746197 G could be a functional enhancer/repressor element, but more studies are required to identify the specific factor(s) responsible. Overall, our findings suggest a role of rs61746197 A > G and human disease in the setting of a 1q21.1 deletion on the other chromosome.
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http://dx.doi.org/10.1101/mcs.a004564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913155PMC
December 2019

Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder.

ERJ Open Res 2019 Oct 15;5(4). Epub 2019 Nov 15.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Pulmonary fibrosis and pulmonary arteriovenous malformations are known manifestations of dyskeratosis congenita (DC), a telomere biology disorder (TBD) and inherited bone marrow failure syndrome caused by germline mutations in telomere maintenance genes resulting in very short telomeres. Baseline pulmonary function tests (PFTs) and long-term clinical outcomes have not been thoroughly studied in DC/TBDs. In this retrospective study, 43 patients with DC and 67 unaffected relatives underwent baseline PFTs and were followed for a median of 8 years (range 1-14). Logistic regression and competing risk models were used to compare PFT results in relation to clinical and genetic characteristics, and patient outcomes. Restrictive abnormalities on spirometry and moderate-to-severe reduction in diffusing capacity of the lung for carbon monoxide were significantly more frequent in patients with DC than relatives (42% 12%; p=0.008). The cumulative incidence of pulmonary disease by age 20 years was 55% in patients with DC with baseline PFT abnormalities compared with 17% in those with normal PFTs (p=0.02). None of the relatives developed pulmonary disease. X-linked recessive, autosomal recessive inheritance or heterozygous variants were associated with early-onset pulmonary disease that mainly developed after haematopoietic cell transplantation (HCT). Overall, seven of 14 patients developed pulmonary disease post-HCT at a median of 4.7 years (range 0.7-12). The cumulative incidence of pulmonary fibrosis in patients with heterozygous non- pathogenic variants was 70% by age 60 years. Baseline PFT abnormalities are common in patients with DC and associated with progression to significant pulmonary disease. Prospective studies are warranted to facilitate clinical trial development for patients with DC and related TBDs.
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http://dx.doi.org/10.1183/23120541.00209-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856494PMC
October 2019

Genotype-phenotype associations in Fanconi anemia: A literature review.

Blood Rev 2019 09 16;37:100589. Epub 2019 Jul 16.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20850, USA. Electronic address:

Fanconi anemia (FA) is a genomic instability syndrome with predisposition to congenital abnormalities, bone marrow failure, and cancer. Classical and most frequent congenital abnormalities include all those seen in VACTERL-H association and those described under the PHENOS acronym. Pathogenic variants in at least 22 genes are associated with FA, which code for proteins that comprise the FA/BRCA DNA repair pathway. We reviewed 187 publications and 1101 cases of FA in which the gene or complementation group was identified and analyzed those in whom physical findings were sought. We conducted genotype-phenotype analyses considering the specific gene, the location in the FA/BRCA DNA repair pathway, and the type of variant (null or hypomorphic) as exposures. The outcomes were the presence of any physical abnormality or specific categories of abnormalities. Seventy-nine percent of the patients had at least one physical abnormality. Pathogenic variants in FANCB, FANCD2, the ID complex and downstream genes were associated with several specific anomalies. Patients with biallelic or hemizygous null variants had a higher proportion of at least one abnormality, renal malformations, microcephaly, short stature and the combination of VACTERL-H compared with those with hypomorphic genotypes. VACTERL-H alone or in combination with PHENOS is highly associated with FA, but the absence of those features does not rule out the diagnosis of FA.
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http://dx.doi.org/10.1016/j.blre.2019.100589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730648PMC
September 2019

Understanding the evolving phenotype of vascular complications in telomere biology disorders.

Angiogenesis 2019 02 25;22(1):95-102. Epub 2018 Aug 25.

Dyskeratosis Congenita Outreach, Inc., New York, NY, USA.

Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.
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http://dx.doi.org/10.1007/s10456-018-9640-7DOI Listing
February 2019

Serum alpha fetoprotein levels in Fanconi anaemia.

Br J Haematol 2019 03 20;184(6):1074-1076. Epub 2018 Aug 20.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

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http://dx.doi.org/10.1111/bjh.15517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383512PMC
March 2019

Similar telomere attrition rates in androgen-treated and untreated patients with dyskeratosis congenita.

Blood Adv 2018 06;2(11):1243-1249

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD; and.

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome and the prototypic telomere biology disorder (TBD). Leukocyte telomere length (TL) less than the first percentile for age, measured by flow cytometry with in situ hybridization (flow FISH), is diagnostic of DC. Androgens are a therapeutic option for DC/TBD-associated bone marrow failure (BMF). One report has shown an apparent increase in TL in patients while on treatment with the attenuated androgen danazol. The aim of this study was to compare TL over time in 10 androgen-treated and 16 untreated patients with DC. All subjects were enrolled in institutional review board-approved longitudinal cohort studies of inherited BMF. TL in 6-panel leukocyte subsets was measured by flow FISH. Generalized estimating equations (GEE) methodology was used to compare TL changes over time between groups. Unadjusted analyses showed annual median total lymphocyte TL attrition of -62 base pairs/year (bp/y) in androgen-treated patients with DC compared with -76 bp/y in untreated DC patients ( = .71). Longitudinal analysis using a GEE model, adjusted for age at sample collection, showed no statistically significant difference in TL change over time between treated and untreated patients ( = .24). The results were similar for each individual leukocyte subset evaluated. In summary, our data show the expected age-associated longitudinal telomere shortening in patients with DC, irrespective of androgen therapy. Caution is warranted when recommending androgen therapy for non-BMF manifestations of DC or TBDs until the biological mechanisms are better understood.
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http://dx.doi.org/10.1182/bloodadvances.2018016964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998921PMC
June 2018

Complex phenotype of dyskeratosis congenita and mood dysregulation with novel homozygous RTEL1 and TPH1 variants.

Am J Med Genet A 2018 06 25;176(6):1432-1437. Epub 2018 Apr 25.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health, Rockville, Maryland.

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome caused by germline mutations in telomere biology genes. Patients have extremely short telomeres for their age and a complex phenotype including oral leukoplakia, abnormal skin pigmentation, and dysplastic nails in addition to bone marrow failure, pulmonary fibrosis, stenosis of the esophagus, lacrimal ducts and urethra, developmental anomalies, and high risk of cancer. We evaluated a patient with features of DC, mood dysregulation, diabetes, and lack of pubertal development. Family history was not available but genome-wide genotyping was consistent with consanguinity. Whole exome sequencing identified 82 variants of interest in 80 genes based on the following criteria: homozygous, <0.1% minor allele frequency in public and in-house databases, nonsynonymous, and predicted deleterious by multiple in silico prediction programs. Six genes were identified likely contributory to the clinical presentation. The cause of DC is likely due to homozygous splice site variants in regulator of telomere elongation helicase 1, a known DC and telomere biology gene. A homozygous, missense variant in tryptophan hydroxylase 1 may be clinically important as this gene encodes the rate limiting step in serotonin biosynthesis, a biologic pathway connected with mood disorders. Four additional genes (SCN4A, LRP4, GDAP1L1, and SPTBN5) had rare, missense homozygous variants that we speculate may contribute to portions of the clinical phenotype. This case illustrates the value of conducting detailed clinical and genomic evaluations on rare patients in order to identify new areas of research into the functional consequences of rare variants and their contribution to human disease.
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http://dx.doi.org/10.1002/ajmg.a.38706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992073PMC
June 2018

Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up.

Haematologica 2018 01 19;103(1):30-39. Epub 2017 Oct 19.

Biostatistics Branches, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

The National Cancer Institute Inherited Bone Marrow Failure Syndromes Cohort enrolls patients with the four major syndromes: Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, and follows them with a common comprehensive protocol. The current analysis includes more than double the numbers of patients and person-years since our first report, published in 2010. Patients with Fanconi anemia and dyskeratosis congenita developed head and neck and anogenital squamous cell carcinomas at rates that were hundreds-fold greater than those of the general population. In competing risk analyses the cumulative incidence of severe bone marrow failure, leading to stem cell transplantation or death, was more than 70% by age 60. Patients with Diamond-Blackfan anemia developed lung, colon, and cervical cancer at rates greater than those of the general population. The cumulative incidence of severe bone marrow failure in those with Diamond-Blackfan anemia was 50% by age 60. The smaller group, with Shwachman-Diamond syndrome, have not as yet developed a significant number of solid tumors, but 40% developed bone marrow failure by age 50. The risk of solid tumors following stem cell transplantation in Fanconi anemia and in dyskeratosis congenita was significantly higher than in non-transplanted patients. There was no clear association of genotype with cancer in any of the syndromes. Cancer was most common in Fanconi anemia, followed by dyskeratosis congenita; Diamond-Blackfan anemia and Shwachman-Diamond syndrome are less cancer-prone, but nonetheless all patients are at increased risks of bone marrow failure and specific cancers. .
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http://dx.doi.org/10.3324/haematol.2017.178111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777188PMC
January 2018

Beyond the triad: Inheritance, mucocutaneous phenotype, and mortality in a cohort of patients with dyskeratosis congenita.

J Am Acad Dermatol 2018 04 16;78(4):804-806. Epub 2017 Oct 16.

Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2017.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857208PMC
April 2018

Progressive reticulate skin pigmentation and anonychia in a patient with bone marrow failure.

J Am Acad Dermatol 2017 Dec 21;77(6):1194-1198. Epub 2017 Oct 21.

Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

KEY TEACHING POINTS.
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http://dx.doi.org/10.1016/j.jaad.2017.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685909PMC
December 2017

Pregnancies in patients with inherited bone marrow failure syndromes in the NCI cohort.

Blood 2017 10 24;130(14):1674-1676. Epub 2017 Aug 24.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, and.

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http://dx.doi.org/10.1182/blood-2017-08-802991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630015PMC
October 2017

Correlation of Leukocyte Telomere Length Measurement Methods in Patients with Dyskeratosis Congenita and in Their Unaffected Relatives.

Int J Mol Sci 2017 Aug 13;18(8). Epub 2017 Aug 13.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Several methods have been employed to measure telomere length (TL) in human studies. It has been difficult to directly compare the results from these studies because of differences in the laboratory techniques and output parameters. We compared TL measurements (TLMs) by the three most commonly used methods, quantitative polymerase chain reaction (qPCR), flow cytometry with fluorescence in situ hybridization (flow FISH) and Southern blot, in a cohort of patients with the telomere biology disorder dyskeratosis congenita (DC) and in their unaffected relatives (controls). We observed a strong correlation between the Southern blot average TL and the flow FISH total lymphocyte TL in both the DC patients and their unaffected relatives (² of 0.68 and 0.73, respectively). The correlation between the qPCR average TL and that of the Southern blot method was modest (² of 0.54 in DC patients and of 0.43 in unaffected relatives). Similar results were noted when comparing the qPCR average TL and the flow FISH total lymphocyte TL (² of 0.49 in DC patients and of 0.42 in unaffected relatives). In conclusion, the strengths of the correlations between the three widely used TL assays (qPCR, flow FISH, and Southern blot) were significantly different. Careful consideration is warranted when selecting the method of TL measurement for research and for clinical studies.
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http://dx.doi.org/10.3390/ijms18081765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578154PMC
August 2017

Pregnancy outcomes in mothers of offspring with inherited bone marrow failure syndromes.

Pediatr Blood Cancer 2018 Jan 12;65(1). Epub 2017 Aug 12.

Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, Rockville, Maryland.

Background: Children with inherited bone marrow failure syndromes (IBMFSs) may be symptomatic in utero, resulting in maternal and fetal problems during the pregnancy. Subsequent pregnancies by their mothers should be considered "high risk".

Methods: We retrospectively analyzed outcomes of 575 pregnancies in 165 unaffected mothers of offspring with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS) for events noted during pregnancy, labor, and delivery. We compared outcomes of pregnancies with affected and unaffected offspring within each group of mothers and with the general population.

Results: The rates of miscarriage (12-20%), elective abortion (5-10%), and live birth (68-78%) among mothers of all IBMFS groups were similar and comparable with general population rates but recurrent miscarriages (≥2) were significantly more common in mothers of offspring with DBA and SDS. Offspring with FA were more frequently born small for gestational age (SGA) than unaffected babies (39% vs. 4%) and had fetal malformations (46%) with 18% having three or more, often necessitating early delivery and surgery; offspring with DC had higher rates of SGA (39% vs. 8%) and fetal distress (26% vs. 3%); and offspring with DBA had fetal hypoxia (19% vs. 1%) leading to preterm and emergency cesarean deliveries (26% vs. 6%). Offspring with early-onset severe phenotypes had the most prenatal and peripartum adverse events.

Conclusion: We identified the high-risk nature of pregnancies in mothers with IBMFS-affected fetuses, suggesting the need for prepregnancy counseling and monitoring of subsequent pregnancies by high-risk fetal-maternal specialists.
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http://dx.doi.org/10.1002/pbc.26757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408308PMC
January 2018

Bone mineral density in patients with inherited bone marrow failure syndromes.

Pediatr Res 2017 Sep 31;82(3):458-464. Epub 2017 May 31.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA.

BackgroundPatients with inherited bone marrow failure syndromes (IBMFS) may have several risk factors for low bone mineral density (BMD). We aimed to evaluate the prevalence of low BMD in IBMFS and determine the associated risk factors.MethodsPatients with IBMFS with at least one dual-energy X-ray absorptiometry (DXA) scan were evaluated. Diagnosis of each IBMFS, Fanconi anemia (FA), dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome was confirmed by syndrome-specific tests. Data were gathered on age, height, and clinical history. DXA scans were completed at the lumbar spine, femoral neck, and forearm. BMD was adjusted for height (HAZ) in children (age ≤20 years). Low BMD was defined as a BMD Z-score and HAZ ≤-2 in adults and children, respectively, in addition to patients currently on bisphosphonate therapy.ResultsNine of thirty-five adults (26%) and eleven of forty children (27%) had low BMD. Adults with FA had significantly lower BMD Z-scores than those with other diagnoses; however, HAZ did not vary significantly in children by diagnosis. Risk factors included hypogonadism, iron overload, and glucocorticoid use.ConclusionsAdults and children with IBMFS have high prevalence of low BMD. Prompt recognition of risk factors and management are essential to optimize bone health.
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http://dx.doi.org/10.1038/pr.2017.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570650PMC
September 2017

Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation.

J Med Genet 2017 06 9;54(6):417-425. Epub 2017 Mar 9.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

Background: Diamond-Blackfan anaemia (DBA) is an inherited bone marrow failure syndrome (IBMFS) characterised by erythroid hypoplasia. It is associated with congenital anomalies and a high risk of developing specific cancers. DBA is caused predominantly by autosomal dominant pathogenic variants in at least 15 genes affecting ribosomal biogenesis and function. Two X-linked recessive genes have been identified.

Objectives: We aim to identify the genetic aetiology of DBA.

Methods: Of 87 families with DBA enrolled in an institutional review board-approved cohort study (ClinicalTrials.gov Identifier:NCT00027274), 61 had genetic testing information available. Thirty-five families did not have a known genetic cause and thus underwent comprehensive genomic evaluation with whole exome sequencing, deletion and CNV analyses to identify their disease-associated pathogenic variant. Controls for functional studies were healthy mutation-negative individuals enrolled in the same study.

Results: Our analyses uncovered heterozygous pathogenic variants in two previously undescribed genes in two families. One family had a non-synonymous variant (p.K77N) in ; the second family had a non-synonymous variant (p. L51S) in . Both of these variants result in pre-rRNA processing defects. We identified heterozygous pathogenic variants in previously known DBA genes in 16 of 35 families. Seventeen families who underwent genetic analyses are yet to have a genetic cause of disease identified.

Conclusions: Overall, heterozygous pathogenic variants in ribosomal genes were identified in 44 of the 61 families (72%). De novo pathogenic variants were observed in 57% of patients with DBA. Ongoing studies of DBA genomics will be important to understand this complex disorder.
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http://dx.doi.org/10.1136/jmedgenet-2016-104346DOI Listing
June 2017

Investigation of chromosome X inactivation and clinical phenotypes in female carriers of DKC1 mutations.

Am J Hematol 2016 12 4;91(12):1215-1220. Epub 2016 Nov 4.

Molecular and Cellular Pharmacology Group, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.

Dyskeratosis congenita (DC) is an inherited bone marrow failure and cancer susceptibility syndrome caused by germline mutations in telomere biology genes. Germline mutations in DKC1, which encodes the protein dyskerin, cause X-linked recessive DC. Because of skewed X-chromosome inactivation, female DKC1 mutation carriers do not typically develop clinical features of DC. This study evaluated female DKC1 mutation carriers with DC-associated phenotypes to elucidate the molecular features of their mutations, in comparison with unaffected carriers and mutation-negative female controls. All female DKC1 mutation carriers had normal leukocyte subset telomere lengths and similarly skewed X-inactivation in multiple tissue types, regardless of phenotype. We observed dyskerin expression, telomerase RNA accumulation, and pseudouridylation present in all mutation carriers at levels comparable to healthy wild-type controls. Our study suggests that mechanisms in addition to X chromosome inactivation, such as germline mosaicism or epigenetics, may contribute to DC-like phenotypes present in female DKC1 mutation carriers. Future studies are warranted to understand the molecular mechanisms associated with the phenotypic variability in female DKC1 mutation carriers, and to identify those at risk of disease. Am. J. Hematol. 91:1215-1220, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajh.24545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466628PMC
December 2016

Otologic manifestations of Fanconi anemia and other inherited bone marrow failure syndromes.

Pediatr Blood Cancer 2016 12 18;63(12):2139-2145. Epub 2016 Jul 18.

National Cancer Institute, National Institutes of Health, Rockville, Maryland.

Background: The inherited bone marrow failure syndromes (IBMFSs) are diverse disorders with syndrome-specific features; their otologic and audiologic manifestations have not been well described. Our objective was to characterize these in patients with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS), and to determine the association between physical findings and hearing loss.

Methods: Patients with an IBMFS underwent comprehensive clinical and laboratory evaluations and testing for syndrome-specific gene mutations. Hearing loss was measured by pure tone audiometry and otologic abnormalities by otomicroscopy.

Results: Patients included 33 with FA, 37 with DC, 32 with DBA, and nine with SDS. Hearing loss was most frequent in patients with FA (45%) and DBA (14%). The most common type of hearing loss in FA was conductive (65%). Absent or hypoplastic radius, noted in 21% of the patients with FA, was associated with hearing loss in all cases. Otomicroscopy was abnormal in 66% of patients with FA. Characteristic ear abnormalities included small tympanic membrane (66%), malformed malleus (57%), aberrant tympanic bony island (48%), narrow external auditory canal (EAC) (32%), and abnormal course of chorda tympani (34%). Ear malformations were almost always associated with hearing loss. Hearing loss was rare in patients with DC and SDS.

Conclusions: FA is the major IBMFS with associated hearing loss, which is most commonly conductive. Radial hypoplasia or aplasia and characteristic congenital ear malformations are associated with hearing loss in patients with FA. Recognition of these syndrome-specific abnormalities should lead to earlier management of hearing loss.
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http://dx.doi.org/10.1002/pbc.26155DOI Listing
December 2016

The limitations of qPCR telomere length measurement in diagnosing dyskeratosis congenita.

Mol Genet Genomic Med 2016 Jul 20;4(4):475-9. Epub 2016 Mar 20.

Clinical Genetics Branch Division of Cancer Epidemiology and Genetics National Cancer Institute, National Institutes of Health 9609 Medical Center Drive Rockville Maryland 20850.

Background: Telomere length <1st percentile-for-age in leukocyte subsets by flow cytometry with fluorescence in situ hybridization (flow FISH) is highly sensitive and specific in diagnosing patients with dyskeratosis congenita (DC), a telomere biology disorder.

Methods: We evaluated the clinical utility of the high-throughput quantitative real-time PCR (qPCR) relative telomere length (RTL) measurement as a diagnostic test for DC in patients with a priori clinical and/or genetic DC diagnoses. We calculated the sensitivity and specificity of RTL at different age-specific percentile cutoffs in 31 patients with DC and 51 mutation-negative relatives, and evaluated RTL difference by disease genotype.

Results: qPCR RTL <1st percentile-for-age failed to identify more than 60% of the patients already known to have DC (sensitivity = 39%, specificity = 98%). Three-quarters of DC patients had RTL below the 10th percentile-for-age (sensitivity = 74%), as did 12% of the unaffected relatives (specificity = 88%).

Conclusions: Our findings suggest that the qPCR RTL method is not optimal for diagnosing DC. In light of these limitations, leukocyte flow FISH telomere length remains the recommended molecular test for diagnosing DC.
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http://dx.doi.org/10.1002/mgg3.220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947866PMC
July 2016
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