Carrier frequency of the IVS4 + 4 A-->T mutation of the Fanconi anemia gene FAC in the Ashkenazi Jewish population

Fanconi anemia (FA) is a genetically and phenotypically heterogeneous autosomal recessive disorder defined by a cellular hypersensitivity to DNA cross-linking agents. One of the FA genes, FAC, has been cloned and the genomic structure of the coding region has been characterized. We have developed amplification refractory mutation system (ARMS) assays for five known mutations in FAC, and have applied these assays to determine the carrier frequency of the IVS4 + 4 A--&gt;T (IVS4) mutation in an Ashkenazi Jewish population. We tested 3,104 Jewish individuals, primarily of Ashkenazi descent, for the two most common FAC mutations, IVS4 and 322delG. Thirty-five IVS4 carriers were identified, for a carrier frequency of 1 in 89 (1.1%; 95% confidence interval 0.79% to 1.56%); no 322delG carriers were found. To determine if the IVS4 mutation was confined to the Ashkenazi Jewish population, we tested 563 Iraqi Jews for IVS4, and no carriers were found. Because the IVS4 mutation has only been found on chromosomes of Ashkenazi Jewish origin and is the only FAC mutation found on these chromosomes, we suggest that a founder effect is responsible for the high frequency of this mutation. With a carrier frequency greater than 1% and simple testing available, the IVS4 mutation merits inclusion in the battery of tests routinely provided to the Jewish population.</jats:p

Hematologic abnormalities in Fanconi anemia: an International Fanconi Anemia Registry study [see comments]

Abstract We analyzed data from 388 subjects with Fanconi anemia reported to the International Fanconi Anemia Registry (IFAR). Of those, 332 developed hematologic abnormalities at a median age of 7 years (range, birth to 31 years). Actuarial risk of developing hematopoietic abnormalities was 98% (95% confidence interval, 93% to 99%) by 40 years of age. Common hematologic abnormalities were thrombocytopenia and pancytopenia. These were often associated with decreased bone marrow (BM) cellularity (75% of cases studied). Clonal cytogenetic abnormalities developed in 23 of 68 persons with BM failure who had adequate studies. Actuarial risk of clonal cytogenetic abnormalities during BM failure was 67% (47% to 87%) by 30 years of age. Fifty-nine subjects developed myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Actuarial risk of MDS or AML was 52% (37% to 67%) by 40 years of age. Risk was higher in persons with than in those without a prior clonal cytogenetic abnormality (3% [0% to 9%] v 35% [0% to 79%]; P = .006). One hundred twenty persons died of hematologic causes including BM failure, MDS or AML and treatment related complications. Actuarial risk of death from hematologic causes was 81% (67% to 90%) by 40 years of age.</jats:p

Hematologic abnormalities in Fanconi anemia: an International Fanconi Anemia Registry study [see comments]

We analyzed data from 388 subjects with Fanconi anemia reported to the International Fanconi Anemia Registry (IFAR). Of those, 332 developed hematologic abnormalities at a median age of 7 years (range, birth to 31 years). Actuarial risk of developing hematopoietic abnormalities was 98% (95% confidence interval, 93% to 99%) by 40 years of age. Common hematologic abnormalities were thrombocytopenia and pancytopenia. These were often associated with decreased bone marrow (BM) cellularity (75% of cases studied). Clonal cytogenetic abnormalities developed in 23 of 68 persons with BM failure who had adequate studies. Actuarial risk of clonal cytogenetic abnormalities during BM failure was 67% (47% to 87%) by 30 years of age. Fifty-nine subjects developed myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Actuarial risk of MDS or AML was 52% (37% to 67%) by 40 years of age. Risk was higher in persons with than in those without a prior clonal cytogenetic abnormality (3% [0% to 9%] v 35% [0% to 79%]; P = .006). One hundred twenty persons died of hematologic causes including BM failure, MDS or AML and treatment related complications. Actuarial risk of death from hematologic causes was 81% (67% to 90%) by 40 years of age.</jats:p

The PISSLRE gene: structure, exon skipping and exclusion as tumor suppressor in breast cancer.

17nonenoneCRAWFORD J; IANZANO L; SAVINO M; WHITMORE M; CLETON-JANSEN AM; SETTASATIAN C; D'APOLITO; M; SESHADRI R; PRONK JC; AUERBACH AD; VERLANDER PC; MATHEW CG; TIPPING AJ; DOGGETT NA; ZELANTE L; CALLEN DF; SAVOIA A.Crawford, J; Ianzano, L; Savino, M; Whitmore, M; CLETON JANSEN, Am; Settasatian, C; D'Apolito, M; Seshadri, R; Pronk, Jc; Auerbach, Ad; Verlander, Pc; Mathew, Cg; Tipping, Aj; Doggett, Na; Zelante, L; Callen, Df; Savoia, Ann