scholarly journals Characterization of Pathogenic Variants and Clinical Phenotypes in 117 Japanese Fanconi Anemia Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3860-3860
Author(s):  
Minako Mori ◽  
Asuka Hira ◽  
Kenichi Yoshida ◽  
Hideki Muramatsu ◽  
Yusuke Okuno ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Exome Sequencing ◽  
Molecular Diagnosis ◽  
Fanconi Anemia ◽  
Direct Sequencing ◽  
Bone Marrow Failure ◽  
Whole Genome ◽  
Aberrant Splicing ◽  
Large Deletions ◽  
Complementation Groups

Abstract Objective: Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome associated with multiple congenital abnormalities and predisposition to malignancies, resulting from mutations in one of the 22 known FA genes (FANCA to W). The proteins encoded by these genes participate in DNA repair pathway (the FA pathway) for endogenous aldehyde damage. Compared to the situation in the US or Europe, the number of Japanese FA patients with genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated FA genes in Japanese population and clarify the genotype-phenotype correlations. Results: We studied 117 Japanese FA patients from 103 families (1996 to 2018). The diagnosis of FA was confirmed on the basis of chromosomal breakage tests and clinical features. Molecular diagnosis was obtained in 107 (91.5%) of the 117 patients through direct sequencing of FANCA and FANCG, MLPA analysis for FANCA, targeted exome sequencing (targeted-seq), and whole exome sequencing (WES) analysis (Figure 1). To provide genetic subtyping for the 10 unclassified cases, we tried to apply various technologies. Array CGH revealed large deletions in two FA-B and one FA-T cases. Whole genome sequencing and RNA-sequencing analysis identified splicing site or aberrant splicing mutations among three cases (one FA-B, one FA-C, and one FA-N). Collectively, 113 (97%) of Japanese 117 FA patients were successfully subtyped and a total of 219 mutated alleles were identified. FA-A and FA-G accounted for the disease in 58% and 25% of FA patients, respectively, whereas each of the other complementation groups accounted for less than 5% of FA cases. FANCB was the third most common complementation group (n=4) and only one FA-C case was identified in Japanese FA patients. In the 68 FA-A patients, we identified 130 mutant alleles that included 55 different FANCA variants (17 nucleotide substitutions, 16 small deletions/insertions, 12 large deletions, 1 large duplication and 9 splice site mutation). FANCA c.2546delC was the most prevalent (41/130 alleles; 32%). In the 29 FA-G patients, 57 mutant alleles were identified and seven different FANCG variants were detected. FANCG c.307+1G>C and 1066C>T accounted for most of FANCG mutant alleles (49/57; 88%) in the Japanese FA-G patients. The three hotspot mutations (FANCA c.2546delC, FANCG c.307+1G>C and c.1066C>T) existed at low prevalence (0.04-0.1%) in the whole-genome reference panel of 3554 Japanese individuals (3.5KJPN, Tohoku Megabank). Consistent with the paucity of the FA-C patients as opposed to the previous report (Blood 2000), the FANCC IVS4+4A mutation was absent in the 3.5KJPN database. We were able to examine the hematological outcomes in a subset of our cases (52 FA-A and 23 FA-G). Interestingly, the FA-G patients developed bone marrow failure (BMF) at a significantly younger age than FA-A patients (median age at onset of BMF: 3.1 years vs 5 years). Furthermore, the patients with the FANCA c.2546delC mutation had an increased risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), compared to FA-A patients without the mutation. In the rare complementation groups of FA, two FA-B cases with complete loss of FANCB gene and one FA-I patient with N-terminal premature termination codons revealed severe somatic abnormalities, consistent with VACTERL-H association. Two FANCD1 (BRCA2) patients and one FANCN (PALB2) patients did not experience bone marrow failure but developed early-onset malignancies (immature teratoma, T-lymphoblastic lymphoma, adenosquamous lung carcinoma, Wilms tumor). Conclusion: This is the largest series of subtyped Japanese FA patients to date and the results would be useful for future clinical management. To provide molecular diagnosis for FA in Japan, we suggest to start with PCR-direct sequencing of the three common mutations (FANCA c.2546delC, FANCG c.307+1G>C and FANCG c.1066C>T) along with MLPA assay for FANCA. These analyses would enable the identification of about 50% of the mutant alleles. For the rest of the cases, WES or targeted-seq analysis should be useful, however, large deletions and aberrant splicing need to be kept in mind. Disclosures Takaori-Kondo: Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Janssen Pharmaceuticals: Honoraria.

Israeli Fanconi Anemia Registry

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4125-4125
Author(s):  
Hannah Tamary ◽  
Blanche P. Alter ◽  
Daniella Nishri ◽  
Philip S Rosenberg
Keyword(s):  
Bone Marrow ◽  
Solid Tumors ◽  
Fanconi Anemia ◽  
Congenital Abnormality ◽  
Bone Marrow Failure ◽  
Epidemiological Data ◽  
Quantitative Model ◽  
Complementation Group ◽  
Adverse Outcomes ◽  
Complementation Groups

Abstract Using epidemiological data from retrospective cohorts of patients with Fanconi Anemia (FA) in North America and Germany a quantitative model to estimate bone marrow failure (BMF) and cancer risk was previously generated. To evaluate generalizability to another population, and to determine the risks for adverse outcomes in Israel, we created an Israeli FA registry and used the model to evaluate complications. We reviewed patient charts of 66 patients with FA diagnosed in Israel between 1964–2005. The data base included demographic information, as well as data describing the congenital abnormalities, FA complementation groups, BMT course and malignancies. Thirty six (36) patients were of Jewish origin [Ashkenzi 7, Sephardic 23, mixed 6] and 30 of Arabic origin. The first adverse event was bone marrow failure (BMF) in 35 patients (53%), hematological malignancy in 7 (11%) and 2 solid tumors in each of 3 patients (5%). The cause-specific hazard of BMF peaked at 10.5%/year at age 10 years (95% CI: 6.7–14.1%/year). The hazard of AML/ALL and MDS were stable at 0.9%/year (95% CI: 0.42–1.85%/year) and 1.4%/year (95% CI: 0.76–2.49%/year) respectively. The cumulative incidence of each outcome to age 32 was 70% for BMF, 13% for AML/ALL, and 17% for solid tumor. A five item congenital abnormality score was significantly associated with the risk of BMF (P = 0.009). The ratio of observed to expected cancer was 71 for all cancers [50 for solid tumors, 175 for leukemia] and >11,000 for myelodysplastic syndrome. Significantly elevated ratios of observed to expected cancers were observed for head and neck squamous cell carcinoma in 2 patients (986-fold), tumor of larynx (13,238-fold), vulva (3,701-fold), cervix (244-fold) and breast (88-fold). The complementation group was known in 41 patients [A 25 (63%), C 9 (22%), G 6 (15%), and D1 1 (2%)]. However, associations between complementation groups and specific outcomes were not significant. Despite the different ethnic background and the smaller number of FA patients in the Israeli cohort the risk estimates compared with the US and German cohorts were similar. As previously suggested the congenital abnormality score was significantly associated with the risk of BMF; an extraordinary risk of developing AML/MDS and later specific solid tumors was also found.

scholarly journals A Dutch Fanconi AnemiaFANCCFounder Mutation in Canadian Manitoba Mennonites

Anemia ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Yne de Vries ◽  
Nikki Lwiwski ◽  
Marieke Levitus ◽  
Bertus Kuyt ◽  
Sara J. Israels ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Complementation Group ◽  
Cross Linking ◽  
Founder Mutations ◽  
Developmental Abnormalities ◽  
Dna Instability ◽  
Common Founder ◽  
Complementation Groups

Fanconi anemia (FA) is a recessive DNA instability disorder associated with developmental abnormalities, bone marrow failure, and a predisposition to cancer. Based on their sensitivity to DNA cross-linking agents, FA cells have been assigned to 15 complementation groups, and the associated genes have been identified. Founder mutations have been found in different FA genes in several populations. The majority of Dutch FA patients belongs to complementation group FA-C. Here, we report 15 patients of Dutch ancestry and a large Canadian Manitoba Mennonite kindred carrying theFANCCc.67delG mutation. Genealogical investigation into the ancestors of the Dutch patients shows that these ancestors lived in four distinct areas in The Netherlands. We also show that the Dutch and Manitoba MennoniteFANCCc.67delG patients share the same haplotype surrounding this mutation, indicating a common founder.

The DNA Synthesis Inhibitor, Hydroxyurea, as a Potential Novel Therapeutic Approach for Fanconi Anemia: Further Studies in Complementation Group D1.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4214-4214
Author(s):  
W. Clark Lambert ◽  
Monique M Brown
Keyword(s):  
Bone Marrow ◽  
Dna Synthesis ◽  
Effective Treatment ◽  
Sickle Cell ◽  
Fanconi Anemia ◽  
Sickle Cell Anemia ◽  
Bone Marrow Failure ◽  
Complementation Group ◽  
Lymphoblastoid Cells ◽  
Complementation Groups

Abstract Abstract 4214 Fanconi anemia (FA) is an inherited, cancer-prone bone marrow failure disease. FA is heterogeneous, with 13 complementation groups, but all groups have in common hypersensitivity to agents that produce DNA interstrand cross links (DISCLs), with associated increased clastogenicity, as a diagnostic hallmark. Although progress has been made in treating FA, particularly using bone marrow transplantation (BMT) to prevent bone marrow failure and leukemogenesis, BMT is not a trivial procedure, and treatment remains challenging. Head and neck cancers, which occur in high frequency in FA, are a particular problem that is not well remedied by BMT. Lymphoblastoid cells from normal subjects and from patients with FA were treated in culture with psoralen plus ultraviolet A radiation (PUVA) in a regimen shown to produce DISCLs. Following this, cells were treated with hydroxyurea, 5-fluorouracil, or high dose thymidine, in doses we have shown to produce a marked decrease in rate of DNA synthesis, for 24 hours. We have previously shown that clastogenicity and cytotoxicity, measured as trypan blue exclusion as well as colony forming ability (CFA), are markedly increased in FA cells, complementation groups A, B, C, and E, associated with deficiencies in their corresponding FA core proteins, but these increases are not observed in these FA cells subsequently treated with any of these other, DNA synthesis retarding agents, which effectively correct the FA phenotype in culture. FA A and C cells genetically corrected for the FANC A and G gene, respectively, display normal clastogenicity and cytotoxicity following PUVA, and do not show this correction following subsequent treatment with hydroxyurea, 5-fluorouracil, or high dose thymidine. We now report similar results for short term cell viability, and similar, although less marked, results for clastogenicity in FA complementation group D1 cells, associated with a deficiency in BRCA2. When all drugs were removed after these treatments and the cells cultured for 10 days without any drug in CFA assays, the FA group D1 cells resembled normals, however, and did not show this correction. We propose that the mechanism in FA A, B, C and G cells is related to a decrease in the rate of DNA synthesis, which we have shown occurs in normal but not FA cells following PUVA, and which is also produced by these other agents in the concentrations used here. The partial correction observed in FA group D1 cells may be due to this or a different mechanism. Partial or complete correction appears to apply to multiple FA complementation groups. Hydroxyurea has been used for many years as a safe and effective treatment for sickle cell anemia and other diseases. It is now proposed as a possible treatment for FA to delay or even prevent development of bone marrow failure and/or other complications, including leukemogenesis and carcinogenesis, with or without prior BMT. In some cases it may serve as a viable alternative where BMT is not fungible. Alternatively it may obviate the need for BMT altogether in responsive patients, or be effectively used in combination with other modalities. Complementation group may be important in determining which patients may be less responsive or require modified regimens. Disclosures: Off Label Use: We have obtained laboratory results which show partial or complete restoration of cytotoxicity and clastogenicity, as well as colony forming ability in the absence of drug in FA A, B, C, and G but not D1 cells, following treatment with a DNA cross-linking agent, in Fanconi anemia lymphoblastoid cells, by subsequent application of hydroxyurea, to normal levels. Hydroxyurea has been used for many years as a safe and effective treatment for sickle cell anemia. It is now proposed as a possible treatment for Fanconi anemia to delay or even prevent development of bone marrow failure and/or other complications, including leukemogenesis and carcinogenesis. It may be less effective in FA complementation group D1. Disclosures: Off Label Use: We have obtained laboratory results which show partial or complete restoration of cytotoxicity and clastogenicity, as well as colony forming ability in the absence of drug, following treatment with a DNA cross-linking agent, in Fanconi anemia lymphoblastoid cells, by subsequent application of hydroxyurea, to normal levels. Hydroxyurea has been used for many years as a safe and effective treatment for sickle cell anemia. It is now proposed as a possible treatment for Fanconi anemia to delay or even prevent development of bone marrow failure and/or other complications, including leukemogenesis and carcinogenesis..

Diagnosis of Fanconi Anemia By Chromosome Breakage Tests Using 3 Different Scoring Systems and Whole Genome Sequencing Among Patients with Aplastic Anemia in Korean

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4792-4792
Author(s):  
Si Nae Park ◽  
Nam Hee Kim ◽  
Kyongok Im ◽  
Jee Soo Lee ◽  
Sungbin Choi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Scoring Systems ◽  
Chromosome Breakage ◽  
Whole Genome ◽  
Bone Marrow Failure Syndrome

Abstract BACKGROUD: Fanconi anemia (FA), an inherited bone marrow failure syndrome with impaired DNA repair system, is characterized by cytopenias, congenital abnormalities, and predisposition to malignancy as a consequence of chromosomal instability and hypersensitivity to DNA interstrand cross-linking agents. Differential diagnosis of FA and aplastic anemia requires integrated work-up including physical findings, bone marrow histologic findings and chromosome breakage test. Yet, there have been no consensus criteria for chromosome breakage test, which depend on each laboratory's own decision. The aim of our study was 1) to investigate the incidence of FA showing positive results for chromosome breakage test among patients diagnosed with aplastic anemia, and 2) to investigate the frequency of the gene mutations related to inherited bone marrow failure syndrome in patients with aplastic anemia. In addition to chromosome breakage test, we performed whole genome sequencing with bone marrow mononuclear cells in 18 pediatric patients with aplastic anemia whose bone marrow specimen was available. METHOD: We reviewed total 79 chromosome breakage tests from 67 patients who had been on suspicion of aplastic anemia between May 2005 and April 2015. MMC and DEB stress test were performed at concentration of 50ng/mL and 100ng/mL both on peripheral blood of suspicious patients and normal controls, respectively. The scoring of chromosome breakages test was performed, based on widely used 3 different scoring systems: those proposed by Jean Soulier, Barch MJ, and Arleen D. Auerbach. In each cases, we applied 3 different scoring systems and compared the concordance rate. In 16 among 67 patients, we performed whole genome sequencing. RESULTS: The median age of the pediatric patients was 11years (range, 7months - 19 years) and the male-to-female ratio was 1.39:1. Of 67 enrolled patients, 8 had been tested twice or 3 times because of ambiguous results. In these cases, we chose the last results. Five of 67 patients satisfied the all three criteria mentioned above, which shows 7.5% (5/67) of positive rates. Other 3 of 67 patients met only one or more of Soulier's prerequisites. Among those, one fulfilled both Barch MJ's system and Aeurbach's, and remain 2 patients were positive in each system, respectively. Mutation variants of BMF syndrome related genes were detected in 25% (4/16 patients); RPS19 (1 patient), PAX5 (1 patient), and FANC (3 patient). Inherited predisposition to myeloid leukemia related genes were detected in 56.3% (9/16 patients) and gene variants were MSH6 (5 patients), ATM (2 patients), PMS2 (1 patients), and MLH1 (1 patients). Coexisting somatic mutations of oncogene (ERB2) was detected in 6.3% (1/16 patients). Among 3 patients with fanconi anemia gene mutations, 2 patients showed positive results for chromosome breakage test and the other1patient showed negative results for chromosome breakage test. CONCLUSION: The frequency of FA based on chromosome breakage test among patients with pancytopenia suspicious of aplastic anemia was 7.5% by Soulier's prerequisites, but 9.0% when based on either of 3 different criteria. Molecular testing can additionally detect FA in 4 (25.0%) among 16 patients showing negative result by chromosome breakage test. Our study shows it is necessary to standardize a diagnostic scoring system as well as to develop complementary molecular test for accurate diagnosis of FA. Disclosures No relevant conflicts of interest to declare.

scholarly journals FANCA Variants in Exons 27-30 Are Associated with Solid Tumors in Fanconi Anemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2192-2192
Author(s):  
Burak Altintas ◽  
Neelam Giri ◽  
Lisa J. McReynolds ◽  
Blanche P. Alter
Keyword(s):  
Bone Marrow ◽  
Solid Tumors ◽  
Fanconi Anemia ◽  
Solid Tumor ◽  
Cox Regression ◽  
Bone Marrow Failure ◽  
Large Deletion ◽  
Interaction Region ◽  
Small Indels ◽  
Large Deletions

Abstract Fanconi anemia (FA) is predominantly an autosomal recessive inherited bone marrow failure syndrome (IBMFS) characterized by congenital anomalies, bone marrow failure (BMF) and an increased cancer risk. It is caused by pathogenic variants in more than 22 genes in the FA/BRCA DNA repair pathway. Approximately 60% of patients have biallelic variants in FANCA. We sought to identify phenotypic differences and clinical outcomes of patients with diverse FANCA variants. We analyzed data from 86 patients with variants in FANCA enrolled in the National Cancer Institute (NCI) IBMFS study (ClinicalTrials.gov identifier 00027274). FANCA variants were determined through review of genetic test reports or whole exome sequencing done as part of the study. The variants were plotted using the online tool ProteinPaint (https://proteinpaint.stjude.org, Figure 1A). Clinical data were extracted from review of medical records and/or evaluations at the NIH. We compared patients with: 1) hypomorphic (hypomorphic variant on one or both alleles) versus null genotype (null variants on both alleles), 2) single nucleotide variant (SNV)/small insertions/deletions (indels) on both alleles versus SNV/small indels on one allele plus large multi-exon deletion on the other allele versus large multi-exon deletions on both alleles. We further compared patients with one or biallelic variants involving the BRCA1 interaction region in the N-terminal domain, FAAP20-binding domain, and variants in exons 27 to 30 where we saw an accumulation of variants, with patients who did not have variants in these regions. We evaluated physical abnormalities that are part of VACTERL-H (Vertebral, Anal, Cardiac, Tracheo-esophageal fistula, Esophageal or duodenal atresia, Renal, upper Limb abnormalities, Hydrocephalus) association and PHENOS (skin Pigmentation abnormalities, small Head, small Eyes, central Nervous system, Otologic abnormalities, Short stature). We focused on the presence, severity and age at BMF, and development of cancers and age at first solid tumor. Frequencies were compared by Fisher's exact test, and a multiple Cox regression model was used to estimate hazard ratio of solid tumors in patients with variants in different regions of FANCA, adjusting for age and hematopoietic cell transplant status of patients with cancer. Analyses were performed using Excel and RStudio, p-value <0.05 was considered significant. The phenotypes, BMF and cancer outcomes were similar between patients with hypomorphic and null genotypes. Similarly, comparison between patients with SNV/small indels, SNV/small indel plus large deletion, and biallelic large deletions did not reveal significant associations. Comparison according the location of the variants on FANCA protein showed that VACTERL-H and VACTERL-H plus PHENOS were less common in patients with at least one SNV/small indel in the BRCA1 interaction region of FANCA compared with patients without variants in this region (2/33 vs 12/51, p= 0.04; 1/33 vs 11/51, p= 0.024, respectively). These associations were not observed when we included patients with large deletions encompassing the BRCA1 interaction region. Eighteen of the 86 patients developed solid tumors; 15/45 patients with an SNV/small indel and/or large deletion within or including exons 27-30 region developed solid tumors compared with 3/41 patients without variants in this region (p= 0.003). Cox regression analysis showed that patients with variants within or involving exons 27-30 were at higher risk of developing solid tumors compared with those without variants in this region (HR: 6.2, 95% CI: 1.36-28.2, Figure 1B). There was no difference between the age at first cancer or type of solid tumors in patients with and without the variant involving this region. The frequency, severity, and age of BMF were also similar between the groups. Our data highlight the possibility that variants involving exons 27-30 within the C-terminal domain of FANCA may be associated with solid tumor development. FANCA forms a homodimer through the interaction between C-terminal domains; variants in this region may affect dimerization and further protein function. Functional analysis and in vivo studies of individual variants in this region and effects of the variants in trans might provide new insights into oncogenesis in FA and may have implications in personalized cancer screening. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Oxandrolone for the treatment of bone marrow failure in Fanconi anemia

2013 ◽  
Vol 61 (1) ◽  
pp. 11-19 ◽  
Author(s):  
Susan R. Rose ◽  
Mi-Ok Kim ◽  
Leslie Korbee ◽  
Kimberly A. Wilson ◽  
M. Douglas Ris ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Failure

scholarly journals ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ADULT PATIENTS WITH FANCONI ANEMIA.

2016 ◽  
Vol 8 ◽  
pp. 2016054 ◽  
Author(s):  
Hosein Kamranzadeh fumani ◽  
Mohammad Zokaasadi ◽  
Amir Kasaeian ◽  
Kamran Alimoghaddam ◽  
Asadollah Mousavi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Term Survival ◽  
Hematopoietic Stem

Background & objectives: Fanconi anemia (FA) is a rare genetic disorder caused by an impaired DNA repair mechanism which leads to an increased tendency toward malignancies and progressive bone marrow failure. The only curative management available for hematologic abnormalities in FA patients is hematopoietic stem cell transplantation (HSCT). This study aimed to evaluate the role of HSCT in FA patients.Methods: Twenty FA patients with ages of 16 or more who underwent HSCT between 2002 and 2015 enrolled in this study. All transplants were allogeneic and the stem cell source was peripheral blood and all patients had a full HLA-matched donor.Results: Eleven patients were female and 9 male (55% and 45%). Mean age was 24.05 years. Mortality rate was 50% (n=10) and the main cause of death was GVHD. Survival analysis showed an overall 5-year survival of 53.63% and 13 year survival of 45.96 % among patients.Conclusion: HSCT is the only curative management for bone marrow failure in FA patients and despite high rate of mortality and morbidity it seems to be an appropriate treatment with an acceptable long term survival rate for adolescent and adult group.

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