Comprehensive molecular study identified 12 complementation groups with 56 novel FANC gene variants in Indian Fanconi anemia subjects

2021 ◽  
Author(s):  
Merin George ◽  
Avani Solanki ◽  
Niranjan Chavan ◽  
Aruna Rajendran ◽  
Revathi Raj ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Molecular Study ◽  
Gene Variants ◽  
Complementation Groups

scholarly journals Fanconi anemia gene variants in therapy-related myeloid neoplasms

2015 ◽  
Vol 5 (7) ◽  
pp. e323-e323 ◽  
Author(s):  
M T Voso ◽  
E Fabiani ◽  
Z Zang ◽  
L Fianchi ◽  
G Falconi ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Gene Variants ◽  
Myeloid Neoplasms ◽  
Fanconi Anemia Gene

The IVS4 + 4 A to T mutation of the Fanconi anemia geneFANCC is not associated with a severe phenotype in Japanese patients

Blood ◽  
2000 ◽  
Vol 95 (4) ◽  
pp. 1493-1498 ◽  
Author(s):  
Makoto Futaki ◽  
Takayuki Yamashita ◽  
Hiroshi Yagasaki ◽  
Tatsushi Toda ◽  
Miharu Yabe ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Clinical Phenotype ◽  
Japanese Patients ◽  
Single Strand Conformation Polymorphism ◽  
Common Mutation ◽  
Ashkenazi Jewish ◽  
Severe Phenotype ◽  
Significant Difference ◽  
Complementation Groups ◽  
Intron 4

Fanconi anemia (FA) is an autosomal recessive disease characterized by congenital anomalies, aplastic anemia, and a susceptibility to leukemia. There are at least 8 complementation groups (A through H). Extensive analyses of the FA group C gene FANCC in Western countries revealed that 10% to 15% of FA patients have mutations of this gene. The most common mutation is IVS4 + 4 A to T (IVS4), a splice mutation in intron 4, which has been found only in patients of Ashkenazi Jewish ancestry. When we screened 29 Japanese patients (20 unrelated patients and 4 families) using polymerase chain reaction–single strand conformation polymorphism, we found 8 unrelated patients homozygous for IVS4. This is apparently the first non–Ashkenazi-Jewish population for whom this mutation has been detected. The Ashkenazi Jewish patients homozygous for IVS4 have a severe phenotype, in comparison with other FA patients. Our analyses of Japanese patients indicate no significant difference between IVS4 homozygotes and other patients with regard to severity of a clinical phenotype. Thus, ethnic background may have a significant effect on a clinical phenotype in FA patients carrying the same mutation.

Protein Replacement by Receptor-Mediated Endocytosis Corrects the Sensitivity of Fanconi Anemia Group C Cells to Mitomycin C

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 363-369 ◽  
Author(s):  
Hagop Youssoufian ◽  
Frank A.E. Kruyt ◽  
Xiaotong Li
Keyword(s):  
Mitomycin C ◽  
Fanconi Anemia ◽  
Hematopoietic Cells ◽  
Chimeric Protein ◽  
Direct Gene Transfer ◽  
C Cells ◽  
Receptor Mediated Endocytosis ◽  
Culture Model ◽  
Complementation Groups ◽  
Anemia Group

Abstract Current methods for direct gene transfer into hematopoietic cells are inefficient. Here we show that functional complementation of Fanconi anemia (FA) group C cells by protein replacement can be as efficacious as by transfection with wild-type FAC cDNA. We expressed a chimeric protein (called His-ILFAC) consisting of the mature coding portion of gibbon interleukin-3 (IL-3) and full-length FAC inEscherichia coli. The purified bacterial protein is internalized by hematopoietic cells via IL-3 receptors. The intracellular half-life of His-ILFAC is approximately 60 minutes, which is comparable to that of the transgene-encoded FAC protein. In this cell-culture model His-ILFAC completely corrects the sensitivity of FA group C cells to mitomycin C, but it has no effect on FA cells that belong to complementation groups A and B. We suggest that receptor-mediated endocytosis of cytokine-fusion proteins may be of general use to deliver macromolecules into hematopoietic progenitor cells.

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.

Identification of two complementation groups in Fanconi anemia

1985 ◽  
Vol 11 (1) ◽  
pp. 35-41 ◽  
Author(s):  
G. Duckworth-Rysiecki ◽  
K. Cornish ◽  
C. A. Clarke ◽  
M. Buchwald
Keyword(s):  
Fanconi Anemia ◽  
Complementation Groups

scholarly journals Functional Activity of the Fanconi Anemia Protein FAA Requires FAC Binding and Nuclear Localization

1998 ◽  
Vol 18 (10) ◽  
pp. 5952-5960 ◽  
Author(s):  
Dieter Näf ◽  
Gary M. Kupfer ◽  
Ahmed Suliman ◽  
Kathleen Lambert ◽  
Alan D. D’Andrea
Keyword(s):  
Nuclear Localization ◽  
Fanconi Anemia ◽  
Functional Activity ◽  
Simian Virus 40 ◽  
T Antigen ◽  
Nuclear Accumulation ◽  
Wild Type ◽  
Amino Terminal ◽  
Complementation Groups ◽  
Mutant Forms

ABSTRACT Fanconi anemia (FA) is an autosomal recessive disease characterized by genomic instability, cancer susceptibility, and cellular hypersensitivity to DNA-cross-linking agents. Eight complementation groups of FA (FA-A through FA-H) have been identified. Two FA genes, corresponding to complementation groups FA-A and FA-C, have been cloned, but the functions of the encoded FAA and FAC proteins remain unknown. We have recently demonstrated that FAA and FAC interact to form a nuclear complex. In this study, we have analyzed a series of mutant forms of the FAA protein with respect to functional activity, FAC binding, and nuclear localization. Mutation or deletion of the amino-terminal nuclear localization signal (NLS) of FAA results in loss of functional activity, loss of FAC binding, and cytoplasmic retention of FAA. Replacement of the NLS sequence with a heterologous NLS sequence, derived from the simian virus 40 T antigen, results in nuclear localization but does not rescue functional activity or FAC binding. Nuclear localization of the FAA protein is therefore necessary but not sufficient for FAA function. Mutant forms of FAA which fail to bind to FAC also fail to promote the nuclear accumulation of FAC. In addition, wild-type FAC promotes the accumulation of wild-type FAA in the nucleus. Our results suggest that FAA and FAC perform a concerted function in the cell nucleus, required for the maintenance of chromosomal stability.

scholarly journals Fanconi Anemia Proteins FANCA, FANCC, and FANCG/XRCC9 Interact in a Functional Nuclear Complex

1999 ◽  
Vol 19 (7) ◽  
pp. 4866-4873 ◽  
Author(s):  
Irene Garcia-Higuera ◽  
Yanan Kuang ◽  
Dieter Näf ◽  
Jennifer Wasik ◽  
Alan D. D’Andrea
Keyword(s):  
Nuclear Localization ◽  
Fanconi Anemia ◽  
Autosomal Recessive ◽  
Nuclear Protein ◽  
Cancer Susceptibility ◽  
Clinical Phenotype ◽  
Normal Cells ◽  
Amino Terminal ◽  
Nuclear Complex ◽  
Complementation Groups

ABSTRACT Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome with at least eight complementation groups (A to H). Three FA genes, corresponding to complementation groups A, C, and G, have been cloned, but their cellular function remains unknown. We have previously demonstrated that the FANCA and FANCC proteins interact and form a nuclear complex in normal cells, suggesting that the proteins cooperate in a nuclear function. In this report, we demonstrate that the recently cloned FANCG/XRCC9 protein is required for binding of the FANCA and FANCC proteins. Moreover, the FANCG protein is a component of a nuclear protein complex containing FANCA and FANCC. The amino-terminal region of the FANCA protein is required for FANCG binding, FANCC binding, nuclear localization, and functional activity of the complex. Our results demonstrate that the three cloned FA proteins cooperate in a large multisubunit complex. Disruption of this complex results in the specific cellular and clinical phenotype common to most FA complementation groups.

Genotype-Phenotype Associations in Patients with Fanconi Anemia: National Cancer Institute Cohort

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-5
Author(s):  
Burak Altintas ◽  
Neelam Giri ◽  
Lisa J. McReynolds ◽  
Blanche P. Alter
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Upper Limb ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Skin Pigmentation ◽  
Autosomal Recessive Disorder ◽  
Gene Variants ◽  
Pathway Gene ◽  
Significant Difference

Fanconi anemia (FA) is a predominantly autosomal recessive disorder resulting from mutations in one of >22 genes involved in the FA/BRCA DNA repair pathway. FA is characterized by multiple congenital abnormalities, progressive bone marrow failure (BMF) and cancer predisposition. Genetic heterogeneity and diverse clinical presentations challenge early diagnosis and optimal management. We previously reviewed the genotype-phenotype associations in FA from literature cases (Fiesco-Roa MO et al. Blood Rev. 2019). We now report the results from the NCI cohort. We studied 147 patients with FA in the NCI inherited bone marrow failure syndromes Cohort Study (ClinicalTrials.gov, NCT00027274) to explore genotype phenotype associations by genes, location in the FA/BRCA pathway (upstream, ID complex, downstream), and compare information on the clinic cohort (CC) and field cohort (FC) patients. 57 patients (CC) were evaluated at the NIH Clinical Center between 2002 and 2020. Details on 90 patients in the FC were obtained from the review of medical records. The sex ratio (M:F) was similar (0.6:1 and 0.8:1). Patients in the FC were younger than in the CC (p=0.004) with median ages 27 (3-68) years for the CC and 19 (0-57) for the FC. The main genotypes in the CC were 59% FANCA, 17% FANCC, 6% FANCI and in the FC were 60% FANCA, 13% FANCC and 8% FANCG. At least one FA type physical abnormality was present in all CC patients and 73/79 (92%) FC patients (phenotype data not reported on 11 FC patients). >3/8 VACTERL-H features (Vertebral, Anal, Cardiac, Tracheo-esophageal fistula (TEF), Esophageal or duodenal atresia, Renal, upper Limb (radial ray) and Hydrocephalus) were present in 32% of CC patients and 16% of FC (p=0.04). At least 4/6 PHENOS features (skin Pigmentation, small Head, small Eyes, other central Nervous system (CNS) anomalies, Otology and Short stature) were present in 54% of CC patients and 34% FC (p=0.02). The types and frequencies of phenotypic abnormalities are shown in figure 1. 17 patients in the CC (30%) and 10 in the FC (13%) had both VACTERL-H and PHENOS (p=0.01). We excluded patients with unknown genotype or phenotype from further analysis. In the CC, cardiac abnormalities were more common in patients with FANCI or ID complex gene variants than in all others (p=0.02 and 0.001, respectively) as were VACTERL-H and structural CNS abnormalities in patients with ID complex variants (p=0.03 and 0.006, respectively). In the FC, VACTERL-H, imperforate anus and hydrocephalus were more common in patients with FANCD1 genotype (p=0.03, 0.009 and 0.004, respectively) and downstream pathway gene variants (p=0.004, <0.001 and 0.03, respectively). PHENOS, renal and neurodevelopmental abnormalities were less common in patients with upstream genes variants (p=0.001, 0.009 and <0.001, respectively). Upper limb abnormalities were less common in patients with FANCC genotype (p=0.007). BMF was present in 121/147 (88%) patients; 33% had been transfusion-dependent and 26% received androgen therapy. Clonal cytogenetic abnormalities were seen in 30%; 17% developed myelodysplastic syndrome at a median age of 17 (1.4-44) years and 6 patients developed acute myeloid leukemia at a median age of 19 (12-29) years. 72 (49%) patients underwent bone marrow transplant at a median age of 9.5 (1.5-44) years for BMF, MDS or leukemia. There was no significant difference between the FC and CC. The median survival age of our cohort is 38 (95% CI 34-43) years and at least 80% of our patients are >18 years of age. Kaplan-Meier survival estimates are presented in figure 2. Solid tumors developed in 30/135 (22%) patients with available data; median age at first cancer was 30 (2-44) years. The most common tumor was head and neck squamous cell carcinoma (n=15 patients), followed by skin (n=8) and anogenital cancers (n=6); many patients developed multiple cancers. Detailed hematologic, cancer, endocrine outcomes and survival analyses are ongoing. Overall, renal and upper limb abnormalities were reported in most of the patients in both CC and FC, as shown previously (Alter BP et al. Mol Syndromol. 2013). Data from the CC were more complete than from the review of charts from the FC highlighting that the clinical in person evaluation of patients provides detailed characterization of FA phenotypes and more accurate assessment of genotype-phenotype associations. This will facilitate timely diagnosis, surveillance and clinical management of patients with FA. Disclosures No relevant conflicts of interest to declare.

The Cellular Control Enzyme PolyADP Ribosyl Transferase Is Eliminated in Cultured Fanconi Anemia Fibroblasts at Confluency

2003 ◽  
Vol 384 (1) ◽  
pp. 169-174 ◽  
Author(s):  
M.H. Ramirez ◽  
C. Adelfalk ◽  
M. Kontou ◽  
M. Hirsch-Kauffmann ◽  
M. Schweiger
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Redox Potential ◽  
Cell Survival ◽  
Fanconi Anemia ◽  
Hereditary Disease ◽  
Pathogenic Mechanisms ◽  
Complementation Groups ◽  
Cellular Control

AbstractFanconi anemia (FA) is a hereditary disease of unknown pathogenic mechanisms, although mutations in seven different genes can be causative. Six of these genes have been cloned and sequenced. Only slight homology to the DNA of any other known gene has been found with the exception of FANCG which is identical to XRCC9. The function of these genes, including XRCC9, is presently unknown. Since pADP ribosyl transferase (pADPRT) plays a role in apoptosis, and apoptosis is affected in FA cells, we studied the correlation between pADPRT and FA cells. We reinvestigated the previously reported lack of pADPRT activity in fibroblasts from patients with Fanconi anemia. Here we describe the role of the lower redox potential of FA cells and demonstrate that this is an efficient strategy in the prevention of cell death due to the lack of energy under oxidative stress. This strategy is advantageous for the cells under the nonreplicative condition of confluency in which the risk of mutation is low and the prevention of apoptosis permits cell survival. pADPRT is not diminished to the same extent in all complementation groups of FA. It is prominent in FANCA, FANCG and FANCF cells, indicating that these genes control pADPRT diminution. Our experiments suggest that the pADPRT level is linked with the oxidoreduction reactions seen in FA.

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