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.

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.

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..

Xeroderma Pigmentosum as a Model for Treatment of Bone Marrow Failure in Fanconi Anemia and Aplastic Anemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4235-4235
Author(s):  
W. Clark Lambert ◽  
Santiago A. Centurion
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Fanconi Anemia ◽  
Xeroderma Pigmentosum ◽  
Bone Marrow Failure ◽  
S Phase ◽  
White Female ◽  
Cross Linking

Abstract We have previously shown that the primary cell cycle defect in the inherited, cancer-prone, bone marrow failure associated disease, Fanconi anemia (FA), is not in the G2 phase of the cell cycle, as had been thought for many years, but rather in the S phase. FA cells challenged with the DNA cross-linking agent, psoralen coupled with long wavelength, ultraviolet (UVA) radiation (PUVA), fail to slow their progression through the S phase of the subsequent cell cycle, as do normal cells. FA cells are extremely sensitive to the cytotoxic and clastogenic effects of DNA cross-linkers, such as PUVA, so much so that the diagnosis of FA is based on an assay, the “DEB test”, in which cells are examined for clastogenic and cytotoxic effects of diepoxybutane (DEB), a DNA cross-linking agent. More recently, we have shown that artificially slowing the cell cycle of FA cells exposed to PUVA by subsequent treatment with agents which slow their progression through S phase leads to markedly increased viability and reduced chromosome breakage in vitro. We now show that similar results can be obtained in vivo in patients with another DNA repair deficiency disease, xeroderma pigmentosum (XP), a recessively inherited disorder associated with defective repair of sunlight induced adducts in the DNA of sun-exposed tissues followed by development of numerous mutations causing large numbers of cancers in these same tissues. We treated two patients with XP, a light complected black male and a white female, both 14 years of age, in sun-exposed areas with 5-fluorouracil, an inhibitor of DNA synthesis, daily for three months. In contrast to normal patients, who only show clinical results if an inflammatory response is invoked, marked improvement in the clinical appearance of the skin was seen with no inflammation observed. This effect was confirmed histologically by examining epidermis adjacent to excised lesions in sun-exposed areas and further verified by computerized image analysis. Treatment with agents that slow progression through S phase, such as hydroxyurea, may similarly improve clinical outcomes in patients with FA or others who are developing bone marrow failure.

Clonal chromosomal aberrations in bone marrow cells of Fanconi anemia patients: gains of the chromosomal segment 3q26q29 as an adverse risk factor

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 3872-3874 ◽  
Author(s):  
Holger Tönnies ◽  
Stefanie Huber ◽  
Jörn-Sven Kühl ◽  
Antje Gerlach ◽  
Wolfram Ebell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Risk Factor ◽  
Fanconi Anemia ◽  
Bone Marrow Cells ◽  
Bone Marrow Failure ◽  
Molecular Cytogenetics ◽  
Complementation Group ◽  
Significant Survival ◽  
High Incidence ◽  
Marrow Cells

Abstract Fanconi anemia (FA) is a condition that induces susceptibility to bone marrow failure, myelodysplastic syndrome (MDS), and leukemia. We report on a high incidence of expanding clonal aberrations with partial trisomies and tetrasomies of chromosome 3q in bone marrow cells of 18 of 53 FA patients analyzed, detected by conventional and molecular cytogenetics. To determine the clinical relevance of these findings, we compared the cytogenetic data, the morphologic features of the bone marrow, and the clinical course of these patients with those of 35 FA patients without clonal aberrations of 3q. The 2 groups did not differ significantly with respect to age, sex, or complementation group. There was a significant survival advantage of patients without abnormalities of chromosome 3q. Even more pronounced was the risk assessment of patients with gains of 3q material with respect to the development of morphologic MDS and acute myeloid leukemia (AML). Thus, our data from 18 patients with 3q aberrations reveal that gains of 3q are strongly associated with a poor prognosis and represent an adverse risk factor in FA.

scholarly journals Clinical severity in Fanconi anemia correlates with residual function of FANCB missense variants

2019 ◽  
Author(s):  
Moonjung Jung ◽  
Ramanagouda Ramanagoudr-Bhojappa ◽  
Sylvie van Twest ◽  
Rasim Ozgur Rosti ◽  
Vincent Murphy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Congenital Abnormalities ◽  
Bone Marrow Failure ◽  
Complementation Group ◽  
Clinical Severity ◽  
List Type ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Fancd2 Monoubiquitination

ABSTRACTFanconi anemia (FA) is the most common genetic cause of bone marrow failure, and is caused by inherited pathogenic variants in any of 22 genes. Of these, only FANCB is X-linked. We describe a cohort of 19 children with FANCB variants, from 16 families of the International Fanconi Anemia Registry (IFAR). Those with FANCB deletion or truncation demonstrate earlier than average onset of bone marrow failure, and more severe congenital abnormalities compared to a large series of FA individuals in the published reports. This reflects the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks. For FANCB missense variants, more variable severity is associated with the extent of residual FANCD2 monoubiquitination activity. We used transcript analysis, genetic complementation, and biochemical reconstitution of FANCD2 monoubiquitination to determine the pathogenicity of each variant. Aberrant splicing and transcript destabilization was associated with two missence variants. Individuals carrying missense variants with drastically reduced FANCD2 monoubiquitination in biochemical and/or cell-based assays showed earlier onset of hematologic disease and shorter survival. Conversely, variants with near-normal FANCD2 monoubiquitination were associated with more favorable outcome. Our study reveals a genotype-phenotype correlation within the FA-B complementation group of FA, where severity is linked to the extent of residual FANCD2 monoubiquitination.KEY POINTSX-linked FANCB pathogenic variants predominantly cause acute, early onset bone marrow failure and severe congenital abnormalitiesBiochemical and cell-based assays with patient variants reveal functional properties of FANCB that associate with clinical severity

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.

The Co-Recessive Inheritance Model: A Paradigm for Fanconi Anemia and Other Bone Marrow Failure Syndromes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3760-3760
Author(s):  
W. Clark Lambert ◽  
Monique M. Brown ◽  
Santiago A. Centurion
Keyword(s):  
Bone Marrow ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Normal Population ◽  
Bone Marrow Failure ◽  
Significant Proportion ◽  
Complementation Group ◽  
Recessive Model ◽  
Compound Heterozygous ◽  
Recessive Inheritance

Abstract One of us (WCL) has previously proposed a mathematical model, Co-Recessive Inheritance, for inherited diseases associated with DNA repair deficiencies (Lambert WC, Lambert MW: Mutat. Res., 1985;145:227–234; Lambert WC: Keynote Address, 21st Anniversary Celebration, MRC Cell Mutation Unit, University of Sussex, UK. Mutat. Res., 1992;273:179–102). The model is also applicable to diseases associated with defective cell cycle modulation following specific types of DNA damage, such as Fanconi Anemia, with or without additional defects in DNA repair. The model proposes that in some complementation groups of these diseases defective alleles at more than one locus are required for the disease phenotype to be expressed. It follows from the model (A readily understandable derivation will be presented.) that the carrier frequencies of the genes involved are very much higher than would be predicted based on classical population genetics. This may impact on recent observations of higher than expected co-inheritance of defective alleles of Fanconi Anemia and Bloom Syndrome genes along with BRCA genes in certain populations (e.g., Koren-Michowitz, M, et al.: Am. J. Hematol., 2005;78:203–206), and provides an explanation for the lower than expected incidence of cancer in these individuals. It also provides an explanation for finding biallelic defects in the same DNA repair genes in more than one complementation group of Fanconi Anemia (Howlett NG, et al.: Science, 2002;297:606–609). The Co-Recessive Model predicts that other findings of this nature are to be expected, and provides some guidelines that may be helpful in the process of gene discovery in Fanconi Anemia. Among the more important of these are 1) that the search for defective genes in each complementation group should not cease when one such gene is found, even if one or more patients in the group is homozygous or compound heterozygous for defective alleles of that gene, and 2) that carrier frequencies for some Fanconi Anemia genes may be much higher than would otherwise be anticipated, with a significant proportion of the normal population being carriers. If the latter hypothesis is correct, it follows that the relevance of these rare diseases and their associated genes to disease, including bone marrow failure, in the general population is dramatically greater than has been generally believed.

The Fanconi anemia complementation group C gene product: structural evidence of multifunctionality

Blood ◽  
2001 ◽  
Vol 98 (5) ◽  
pp. 1392-1401 ◽  
Author(s):  
Qishen Pang ◽  
Tracy A. Christianson ◽  
Winifred Keeble ◽  
Jane Diaz ◽  
Gregory R. Faulkner ◽  
...  
Keyword(s):  
Gene Product ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Interferon Γ ◽  
Complementation Group ◽  
Cytokine Signaling ◽  
Cross Linking ◽  
C Cells ◽  
Structural Elements ◽  
Ifn Γ

The Fanconi anemia (FA) group C gene product (FANCC) functions to protect cells from cytotoxic and genotoxic effects of cross-linking agents. FANCC is also required for optimal activation of STAT1 in response to cytokine and growth factors and for suppressing cytokine-induced apoptosis by modulating the activity of double-stranded RNA-dependent protein kinase. Because not all FANCC mutations affect STAT1 activation, the hypothesis was considered that cross-linker resistance function of FANCC depends on structural elements that differ from those required for the cytokine signaling functions of FANCC. Structure-function studies were designed to test this notion. Six separate alanine-substituted mutations were generated in 3 highly conserved motifs of FANCC. All mutants complemented mitomycin C (MMC) hypersensitive phenotype of FA-C cells and corrected aberrant posttranslational activation of FANCD2 in FA-C mutant cells. However, 2 of the mutants, S249A and E251A, failed to correct defective STAT1 activation. FA-C lymphoblasts carrying these 2 mutants demonstrated a defect in recruitment of STAT1 to the interferon γ (IFN-γ) receptor and GST-fusion proteins bearing S249A and E251A mutations were less efficient binding partners for STAT1 in stimulated lymphoblasts. These same mutations failed to complement the characteristic hypersensitive apoptotic responses of FA-C cells to tumor necrosis factor-α (TNF-α) and IFN-γ. Cells bearing a naturally occurring FANCC mutation (322delG) that preserves this conserved region showed normal STAT1 activation but remained hypersensitive to MMC. The conclusion is that a central highly conserved domain of FANCC is required for functional interaction with STAT1 and that structural elements required for STAT1-related functions differ from those required for genotoxic responses to cross-linking agents. Preservation of signaling capacity of cells bearing the del322G mutation may account for the reduced severity and later onset of bone marrow failure associated with this mutation.

scholarly journals Association of clinical severity with FANCB variant type in Fanconi anemia

Blood ◽  
2020 ◽  
Vol 135 (18) ◽  
pp. 1588-1602 ◽  
Author(s):  
Moonjung Jung ◽  
Ramanagouda Ramanagoudr-Bhojappa ◽  
Sylvie van Twest ◽  
Rasim Ozgur Rosti ◽  
Vincent Murphy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Complementation Group ◽  
Clinical Severity ◽  
Missense Variants ◽  
Interstrand Crosslinks ◽  
Pathogenic Variants ◽  
Enzymatic Activation ◽  
Fancd2 Monoubiquitination

Abstract Fanconi anemia (FA) is the most common genetic cause of bone marrow failure and is caused by inherited pathogenic variants in any of 22 genes. Of these, only FANCB is X-linked. We describe a cohort of 19 children with FANCB variants, from 16 families of the International Fanconi Anemia Registry. Those with FANCB deletion or truncation demonstrate earlier-than-average onset of bone marrow failure and more severe congenital abnormalities compared with a large series of FA individuals in published reports. This reflects the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks. For FANCB missense variants, more variable severity is associated with the extent of residual FANCD2 monoubiquitination activity. We used transcript analysis, genetic complementation, and biochemical reconstitution of FANCD2 monoubiquitination to determine the pathogenicity of each variant. Aberrant splicing and transcript destabilization were associated with 2 missense variants. Individuals carrying missense variants with drastically reduced FANCD2 monoubiquitination in biochemical and/or cell-based assays tended to show earlier onset of hematologic disease and shorter survival. Conversely, variants with near-normal FANCD2 monoubiquitination were associated with more favorable outcome. Our study reveals a genotype-phenotype correlation within the FA-B complementation group of FA, where severity is associated with level of residual FANCD2 monoubiquitination.

scholarly journals Classification of Fanconi anemia patients by complementation analysis: evidence for a fifth genetic subtype

Blood ◽  
1995 ◽  
Vol 86 (6) ◽  
pp. 2156-2160 ◽  
Author(s):  
H Joenje ◽  
JR Lo ten Foe ◽  
AB Oostra ◽  
CG van Berkel ◽  
MA Rooimans ◽  
...  
Keyword(s):  
Cell Lines ◽  
Fanconi Anemia ◽  
Clinical Symptoms ◽  
Bone Marrow Failure ◽  
Complementation Group ◽  
Complementation Analysis ◽  
Reference Cell ◽  
Genetic Subtype ◽  
Life Threatening ◽  
Complementation Groups

Fanconi anemia (FA) is an autosomal recessive disease with diverse clinical symptoms, life-threatening progressive panmyelopathy, and cellular hypersensitivity to cross-linking agents. Currently, 4 genetic subtypes or complementation groups (FA-A through FA-D) have been distinguished among 7 unrelated FA patients. We report the use of genetically marked FA lymphoblastoid cell lines representing each of the 4 presently known complementation groups to classify 13 unrelated FA patients through cell fusion and complementation analysis. Twelve cell lines failed to complement cross-linker sensitivity in fusion hybrids with only 1 of the 4 reference cell lines and could thus be unambiguously classified as FA-A (7 patients), FA-C (4 patients), or FA- D (1 patient). One cell line complemented all 4 reference cell lines and therefore represents a new complementation group, designated FA-E. These results imply that at least 5 genes appear to be involved in a pathway that, when defective, causes bone marrow failure in FA patients.

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