A 20-year perspective on the International Fanconi Anemia Registry (IFAR)

Kutler, David I.; Singh, Bhuvanesh; Satagopan, Jaya M.; Batish, Sat Dev; Berwick, Marianne; Giampietro, Philip F.; Hanenberg, Helmut; Auerbach, Arleen D.

doi:10.1182/blood-2002-07-2170

Cited by 676 publications

(703 citation statements)

References 42 publications

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“…17,20,21 Researchers have differentially found that individuals with either FANCG or FANCC mutations are at greater risk of severe cytopenia, whereas those with mutations in either FANCA or FANCG tend to have more somatic anomalies including skin and skeletal anomalies. 17,22 Genes appear to have been used as a proxy for specific mutations in most studies presumably because of the marked heterogeneity of FA with many mutations described within each causative gene and the difficulty in recruiting a patient cohort who are genetically homogeneous. Neveling et al (2009), 23 in a review article, focused on the genotype-phenotype correlations in FA and pointed out the futility in attempting these correlations using individual genes/complementation groups rather than specific mutations.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic consequences in black South African Fanconi anemia patients homozygous for a founder mutation

Feben

Kromberg

Wainwright

et al. 2014

Genetics in Medicine

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Purpose: Fanconi anemia is a genotypically and phenotypically heterogeneous condition, characterized microscopically by chromosomal instability and breakage. Affected individuals manifest growth restriction and congenital physical abnormalities; most progress to hematological disease including bone marrow aplasia. Black South African Fanconi anemia patients share a common causative founder mutation in the Fanconi G gene in 80% of cases (637_643delTACC-GCC). The aim of this study was to investigate the genotype-physical phenotype correlation in a cohort of individuals homozygous for this mutation.Methods: Thirty-five black patients were recruited from tertiary level hematology/oncology clinics in South Africa. Participants were subjected to a comprehensive clinical examination, documenting growth, congenital anomalies, and phenotypic variability.Results: Descriptive statistical analysis showed significant growth abnormalities in many patients and a high frequency (97%) of skin pigmentary anomalies. Subtle anomalies of the eyes, ears, and hands occurred frequently (≥70%). Apart from malformations of the kidney (in 37%) and gastrointestinal tract (in 8.5%), congenital anomalies of other systems including the cardiovascular and central nervous systems, genitalia, and vertebrae were infrequent (<5%). Conclusion:The diagnosis of Fanconi anemia in black South African patients before the onset of hematological symptoms remains a clinical challenge, with the physical phenotype unlikely to be recognized by those without dysmorphology expertise.Genet Med advance online publication 26 December 2013

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Section: Discussionmentioning

confidence: 99%

Phenotypic consequences in black South African Fanconi anemia patients homozygous for a founder mutation

Feben

Kromberg

Wainwright

et al. 2014

Genetics in Medicine

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“…[1][2][3] Fifteen genes, defining 15 complementation groups, have been shown to be involved in FA. 4 One of them, FANCD1, corresponds to the BRCA2 gene, one of the main genes involved in autosomal dominant predisposition to breast and ovarian cancers.…”

Section: Introductionmentioning

confidence: 99%

Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene

et al. 2013

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Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A4G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A4G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A4G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.

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“…The progressive BM failure and the late developing myeloid malignancies account for 90% of the mortality in FA [1]. Aside from cord blood transplantation [2], the only cure for the hematopoietic manifestations of FA is an HLA identical allogeneic BM transplantation from a family member, a therapy available to only about 30% of patients [3].…”

Section: Introductionmentioning

confidence: 99%

“…The identification of these genes raises the potential of using gene transfer technology to express the functional cDNA in autologous stem cells. The BM hypoplasia commonly observed in FA patients [1] and the reduced repopulating ability of stem cells in mice containing a disruption of the murine homologue of an FA gene [29,30] led to the hypothesis that autologous, geneticallycorrected stem cells would have an engraftment and proliferation advantage.…”

Section: Introductionmentioning

confidence: 99%

AMD3100 synergizes with G-CSF to mobilize repopulating stem cells in Fanconi anemia knockout mice

Pulliam

Hobson

Ciccone

et al. 2008

Experimental Hematology

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Fanconi anemia (FA) is a heterogeneous inherited disorder characterized by a progressive bone marrow (BM) failure and susceptibility to myeloid leukemia. Genetic correction using gene transfer technology is one potential therapy. A major hurdle in applying this technology in FA patients is the inability of granulocyte colony-stimulating factor (G-CSF) to mobilize sufficient numbers of hematopoietic stem (HSC)/progenitor cells (HPC) from the BM to the PB. Whether the low number of CD34 + cells is a result of BM hypoplasia or an inability of G-CSF to adequately mobilize FA HSC/HPC remains incompletely understood. Here we use competitive repopulation of lethally irradiated primary and secondary recipients to show that in two murine models of FA, AMD3100 synergizes with G-CSF resulting in a mobilization of HSC, whereas G-CSF alone fails to mobilize stem cells even in the absence of hypoplasia.

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A 20-year perspective on the International Fanconi Anemia Registry (IFAR)

Cited by 676 publications

References 42 publications

Phenotypic consequences in black South African Fanconi anemia patients homozygous for a founder mutation

Phenotypic consequences in black South African Fanconi anemia patients homozygous for a founder mutation

Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene

AMD3100 synergizes with G-CSF to mobilize repopulating stem cells in Fanconi anemia knockout mice

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