Outcome and experience of implementing spinal muscular atrophy carrier screening on sperm donors.

Spinal muscular atrophy (SMA) carrier screening was performed on 277 active semen donors and new semen donor applicants; five men tested positive as carriers for SMA. The risk for specific medical problems in donor offspring can be significantly reduced by incorporating new genetic tests, such as spinal muscular atrophy carrier screening, into donor screening practices; however, future efforts should focus on communicating the limitations of genetic screening to donor gamete recipients and on the development of guidelines for implementing new genetic tests on donors.

Prevalence of breast and colorectal cancer in Ashkenazi Jewish carriers of Fanconi anemia and Bloom syndrome.

BACKGROUND: Fanconi anemia complementation group C and Bloom syndrome, rare autosomal recessive disorders marked by chromosome instability, are especially prevalent in the Ashkenazi* Jewish community. A single predominant mutation for each has been reported in Ahshkenazi Jews: c.711+4A-->T (IVS4 +4 A-->T) in FACC and BLM(Ash) in Bloom syndrome. Individuals affected by either of these syndromes are characterized by susceptibility for developing malignancies, and we questioned whether heterozygote carriers have a similarly increased risk. OBJECTIVES: To estimate the cancer rate among FACC and BLM(Ash) carriers and their families over three previous generations in unselected Ashkenazi Jewish individuals. METHODS: We studied 42 FACC carriers, 28 BLM(Ash) carriers and 43 controls. The control subjects were Ashkenazi Jews participating in our prenatal genetic screening program who tested negative for FACC and BLM(Ash). All subjects filled out a questionnaire regarding their own and a three-generation family history of cancer. The prevalence rates of cancer among relatives of FACC, BLM(Ash) and controls were computed and compared using the chi-square test. RESULTS: In 463 relatives of FACC carriers, 45 malignancies were reported (9.7%) including 10 breast (2.2%) and 13 colon cancers (2.8%). Among 326 relatives of BLM(Ash) carriers there were 30 malignancies (9.2%) including 7 breast (2.1%) and 4 colon cancers (1.2%). Controls consisted of 503 family members with 63 reported malignancies (12.5%) including 11 breast (2.2%) and 11 colon cancers (2.2%). CONCLUSIONS: We found no significantly increased prevalence of malignancies among carriers in at least three generations compared to the controls.

Coinheritance of BRCA1 and BRCA2 mutations with Fanconi anemia and Bloom syndrome mutations in Ashkenazi Jewish population: possible role in risk modification for cancer development.

Fanconi anemia (FA) and Bloom syndrome (BS) are rare autosomal recessive genetic disorders manifesting in childhood, with a predisposition to cancer development in adolescence and adulthood. Both syndromes are relatively prevalent among the Ashkenazi Jewish population, and, in both syndromes, mutations specific to this population have been identified. Similarly, unique Ashkenazi mutations were found in the genes BRCA1 and BRCA2. These two genes, when mutated, play important roles in familial breast and ovarian carcinogenesis. The genes involved in the pathogenesis of the FA and BS belong to the general class of instability genes. Heterozygosity for the FA gene has no known promalignant potential, while the BS mutation carrier state was associated with an increased frequency of colorectal cancer. The especially frequent carrier state among the Ashkenazi Jewish population coupled with the high prevalence of BRCA1 and BRCA2 in the same population has led us to search for coinheritance affecting the potential for cancer development. One hundred Ashkenazi women with known BRCA1 and BRCA2 mutations were screened for the FA mutation IVS4+4 A-->T and the BS mutation blm(Ash). Our results indicate that there is an increased prevalence of both FA and BS mutation carriers among the population studied compared with the general Ashkenazi population (prevalence of FA mutation 4/100 women [4%] as compared to 35/3104 previously published controls [1.1%], P=0.031, and for BS mutation 3/100 [3.2%] as compared to 36/4001 [0.9%], P=0.058). There was no statistically significant effect of the coinheritance on cancer prevalence, type of cancer, or age of cancer onset. Coinheritance of FA and/or BS mutations seems to be more prevalent among BRCA mutation carriers, but a larger study encompassing more women may help in clarifying this issue.

Bloom syndrome and Fanconi's anemia: rate and ethnic origin of mutation carriers in Israel.

BACKGROUND: The Bloom syndrome gene, BLM, was mapped to 15q26.1 and its product was found to encode a RecQ DNA helicase. The Fanconi's anemia complementation group C gene was mapped to chromosome 9q22.3, but its product function is not sufficiently clear. Both are recessive disorders associated with an elevated predisposition to cancer due to genomic instability. A single predominant mutation of each disorder was reported in Ashkenazi Jews: 2281delATCTGAinsTAGATTC for Bloom syndrome (BLM-ASH) and IVS4 + 4AT for Fanconi's anemia complementation group C. OBJECTIVES: To provide additional verification of the mutation rate of BLM and FACC in unselected Ashkenazi and non-Ashkenazi populations analyzed at the Sheba Medical Center, and to trace the origin of each mutation. METHODS: We used polymerase chain reaction to identify mutations of the relevant genomic fragments, restriction analysis and gel electrophoresis. We then applied the Pronto kit to verify the results in 244 samples and there was an excellent match. RESULTS: A heterozygote frequency of 1:111 for BLM-ASH and 1:92 for FACC was detected in more than 4,000 participants, none of whom reported a family history of the disorders. The Pronto kit confirmed all heterozygotes. Neither of the mutations was detected in 950 anonymous non-Ashkenazi Jews. The distribution pattern of parental origin differed significantly between the two carrier groups, as well as between each one and the general population. CONCLUSIONS: These findings as well as the absence of the mutations in non-Ashkenazi Jews suggest that: a) the mutations originated in the Israelite population that was exiled from Palestine by the Roman Empire in 70 AD and settled in Europe (Ashkenazi), in contrast to those who remained; and b) the difference in origin distribution of the BS and FACC mutations can be explained by either a secondary migration of a subgroup with a subsequent genetic drift, or a separate geographic region of introduction for each mutation.

Growth deficiency and malnutrition in Bloom syndrome.

OBJECTIVES: To describe the growth and nutritional status of a pediatric population with Bloom syndrome. STUDY DESIGN: Longitudinal growth data from 148 patients in the Bloom's Syndrome Registry (85 male, 63 female) were compiled retrospectively from physician and parent records to develop graphed statistics of weight-for-age, height-for-age, fronto-occipital circumference-for-age, and weight-for-height for both sexes with comparisons with the normal population. RESULTS: Term birth measurements confirm that the growth deficiency of Bloom syndrome has prenatal onset. Stunting persists throughout life, and an adolescent growth spurt is not apparent from the smoothed data. Growth continues by at least 1 cm/yr until age 21 years for both sexes. More than half of children with Bloom syndrome are significantly wasted until age 8 years, which is not related to early death or underlying malignancy. The mean body mass index for adults with Bloom syndrome after age 25 years is low normal (n = 22, mean = 20.2 kg/m2). CONCLUSIONS: Children with Bloom syndrome have significant growth retardation and wasting.

The Ashkenazic Jewish Bloom syndrome mutation blmAsh is present in non-Jewish Americans of Spanish ancestry.

Bloom syndrome (BS) is more frequent in the Ashkenazic Jewish population than in any other. There the predominant mutation, referred to as "blmAsh," is a 6-bp deletion and 7-bp insertion at nucleotide position 2281 in the BLM cDNA. Using a convenient PCR assay, we have identified blmAsh on 58 of 60 chromosomes transmitted by Ashkenazic parents to persons with BS. In contrast, in 91 unrelated non-Ashkenazic persons with BS whom we examined, blmAsh was identified only in 5, these coming from Spanish-speaking Christian families from the southwestern United States, Mexico, or El Salvador. These data, along with haplotype analyses, show that blmAsh was independently established through a founder effect in Ashkenazic Jews and in immigrants to formerly Spanish colonies. This striking observation underscores the complexity of Jewish history and demonstrates the importance of migration and genetic drift in the formation of human populations.

Carrier frequency of the Bloom syndrome blmAsh mutation in the Ashkenazi Jewish population.

Bloom syndrome is more common in individuals of Ashkenazi Jewish descent than in any other population, and one particular mutation in the Bloom syndrome gene, blmAsh, is homozygous in nearly all Ashkenazi Jewish persons with Bloom syndrome. We have determined the frequency of blmAsh in 1491 Ashkenazi Jewish persons with no known history of Bloom syndrome and found that 1 in 107 persons was heterozygous. Although not common, genetic screening for Bloom syndrome is feasible in this population.

High frequency of a common Bloom syndrome Ashkenazi mutation among Jews of Polish origin.

Bloom syndrome (BS) is an autosomal recessive disorder characterized by small stature, immunodeficiency, chromosomal instability, and a predisposition to different types of cancer. Although extremely rare in the general population, BS is seen in about 1 in 48,000 Ashkenazi Jews. Mutation analysis of seven Ashkenazi BS probands has shown that all were homozygous for the same mutation in the BLM gene: 2281delATCTGAinsTAGATTC, also known as blmAsh. This finding, along with the increased incidence of BS among Ashkenazi Jews, suggests a founder effect for BS in this population. The purpose of this study was to determine the frequency of blmAsh mutation carriers in a randomly sampled Ashkenazi Jewish population in Israel. The initial study group included 1,613 Ashkenazi Jews who were referred for routine DNA screening tests (cystic fibrosis, Gaucher, Canavan, fragile X). None had a family history of BS. A group of 552 non-Ashkenazi Jews served as controls. Mutation analysis was performed by PCR amplification followed by analysis of a specific BstN1 restriction site, created by the blmAsh mutation. All positive carriers were confirmed by direct sequencing. Sixteen blmAsh carriers were detected among 1,613 Ashkenazi Jews (1 in 101), compared to none among 552 non-Ashkenazi individuals. In this study, Ashkenazi Jews of biparental Polish descent had a significantly higher proportion of the blmAsh mutation (1 in 37) compared to Ashkenazi Jews of non-Polish descent. These results provide further evidence that a founder effect is responsible for the increased incidence of Bloom syndrome among Ashkenazi Jews, particularly those of Polish descent.

Linkage disequilibrium between the FES, D15S127, and BLM loci in Ashkenazi Jews with Bloom syndrome.

Bloom syndrome (BS) is more common in the Ashkenazi Jewish than in any other population. Approximately 1 in 110 Ashkenazi Jews carries blm, the BS mutation. The locus mutated in BS, BLM, maps to chromosome subband 15q26.1, tightly linked to the proto-oncogene FES. We have investigated the basis for the increased frequency of blm in the Ashkenazim by genotyping polymorphic microsatellite loci tightly linked to BLM in affected and unaffected individuals from Ashkenazi Jewish and non-Ashkenazi populations. A striking association of the C3 allele at FES with blm (delta = .422; p = 5.52 x 10(-7)) and of the 145-bp and 147-bp alleles at D15S127 with blm (delta = .392 and delta = .483, respectively; p = 2.8 x 10(-5) and p = 5.4 x 10(-7), respectively) was detected in Ashkenazi Jews with BS. This linkage disequilibrium constitutes strong support for a founder-effect hypothesis: the chromosome in the hypothetical founder who carried blm also carried the C3 allele at FES and either the 145-bp or the 147-bp allele at D15S127.

Purification and properties of the uracil DNA glycosylase from Bloom's syndrome.

Bloom's syndrome uracil DNA glycosylase was highly purified from two non-transformed cell strains derived from individuals from different ethnic groups. Their properties were then compared to two different highly purified normal human uracil DNA glycosylases. A molecular mass of 37 kDa was observed for each of the four human enzymes as defined by gel-filtration column chromatography and by SDS-PAGE. Each of the 37 kDa proteins was identified as a uracil DNA glycosylase by electroelution from the SDS polyacrylamide gel, determination of glycosylase activity by in vitro biochemical assay and identification of the reaction product as free uracil by co-chromatography with authentic uracil. Bloom's syndrome enzymes differed substantially in their isoelectric point and were thermolabile as compared to the normal human enzymes. Bloom's syndrome enzymes displayed a different Km, Vmax and were strikingly insensitive to 5-fluorouracil and 5-bromouracil, pyrimidine analogues which drastically decreased the activity of the normal human enzymes. In particular, each Bloom's syndrome enzyme required 10-100-fold higher concentrations of each analogue to achieve comparable inhibition of enzyme activity. Potential mechanisms are considered through which an altered uracil DNA glycosylase characterizing this cancer-prone human genetic disorder may arise.

Triple autosomal trisomy in a pregnancy at risk for Bloom's syndrome.

Cytogenetic analysis of the products of conception in a pregnancy at risk for Bloom's syndrome (BS) documented the karyotype 49,XX, +2, +8, +11. Autosomal triple trisomy has previously been reported in abortuses but is exceedingly rare. Other interesting but previously unreported observations made during the present study were the following: BS in a Brazilian individual, the first instance of BS diagnosed in South America; transmission of the BS mutation in Jews that are non-Ashkenazi; a medulloblastoma in the propositus, the first malignant brain tumor reported in BS; and, as in all previously examined pregnancies at risk for BS, non-homozygosity for the BS mutation.

Bloom's syndrome in an Iranian Jewish male.

Bloom's syndrome is described in an Iranian Jewish male who subsequently developed myocardial disease. This may represent the first definitely non Ashkenazi Jewish patient in the literature and the only one to develop this complication.

Bloom syndrome: a single complementation group defines patients of diverse ethnic origin.

Patients of diverse ethnic background were recruited in order to examine whether genetic heterogeneity could be demonstrated in Bloom syndrome (BS). Although most cells from BS patients exhibit high sister-chromatid exchange (SCE), lymphoid cells from some patients exhibit dimorphism for high and low SCE. We addressed the issue of dominance or recessivity of the low-SCE BS phenotype. A high-SCE lymphoblast line, HB1, was mutagenized, and a clone, HB10T, carrying the markers ouabain resistance and thioguanine resistance, was isolated to serve as a fusion parent. Two independent low-SCE BS lines were fused with HB10T, and hybrids were selected in HAT medium supplemented with ouabain. The hybrids, which were tetraploid, exhibited the expected phenotypes when exposed to ouabain and thioguanine. In every case, these hybrids had low SCE levels, establishing dominance of the low-SCE phenotype. The same methodology was also used to assess genetic heterogeneity in BS. A complementation analysis was carried out using high-SCE lymphoblast cell lines derived from BS patients. HB10T was fused with five other high-SCE BS lines. No correction of the high SCE characteristic of BS cells was seen in hybrid lines derived from patients of Ashkenazi Jewish, French-Canadian, Mennonite, or Japanese extraction. Thus, a single gene is responsible for the high-SCE phenotype in BS patients of diverse ethnic origin.