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Results for “Haplotypes”

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PubMed1985

Analysis of DNA haplotypes suggests a genetic predisposition to trisomy 21 associated with DNA sequences on chromosome 21.

To test the hypothesis that there is a genetic predisposition to nondisjunction and trisomy 21 associated with DNA sequences on chromosome 21, we used DNA polymorphism haplotypes for chromosomes 21 to examine the distribution of different chromosomes 21 in Down syndrome and control families from the same ethnic group. The chromosomes 21 from 20 Greek families with a Down syndrome child and 27 control Greek families have been examined for DNA polymorphism haplotypes by using four common polymorphic sites adjacent to two closely linked single-copy DNA sequences (namely pW228C and pW236B), which map somewhere near the proximal long arm of chromosome 21. Three haplotypes, +, +---, and - with respective frequencies of 43/108, 24/108, and 23/108, account for the majority of chromosomes 21 in the control families. However, haplotype - was found to be much more commonly associated with chromosomes 21 that underwent nondisjunction in the Down syndrome families (frequency of 21/50; X2 for the two distributions is 9.550; P = 0.023; degrees of freedom, 3). The two populations (control and trisomic families) did not differ in the distribution of haplotypes for two DNA polymorphisms on chromosome 17. The data from this initial study suggest that the chromosome 21, which is marked in Greeks with haplotype - for the four above described polymorphic sites, is found more commonly in chromosomes that participate in nondisjunction than in controls. We propose an increased tendency for nondisjunction due to DNA sequences associated with a subset of chromosomes 21 bearing this haplotype.

Base Sequence↗

PubMed2006

The XRCC1 -77T->C variant: haplotypes, breast cancer risk, response to radiotherapy and the cellular response to DNA damage.

X-ray repair cross-complementing 1 (XRCC1) is required for single-strand break repair in human cells and several polymorphisms in this gene have been implicated in cancer risk and clinical prognostic factors. We examined the frequency of the 5'-untranslated region (5'-UTR) variant -77T-->C (rs 3213235) in 247 French breast cancer (BC) patients, 66 of whom were adverse radiotherapy responders, and 380 controls and determined the haplotypes based on this and the previously genotyped variants Arg194Trp, Arg280His and Arg399Gln. The -77T-->C variant alone showed no significant association with BC risk or therapeutic radiation sensitivity. The H5 haplotype (variant allele codon 280, wild-type allele other positions) was associated with increased BC risk [odds ratio (OR), 1.90; 95% confidence interval (CI), 1.12-3.23] and the H3 haplotype (wild-type allele all four positions) was inversely associated with therapeutic radiation sensitivity compared with the reference group (H1 haplotype, -77C, wild-type allele codons 194, 280, 399) (OR, 0.39; 95% CI, 0.16-0.92). However given that the global tests for association were not significant these results should be interpreted carefully. Lymphoblastoid cell lines heterozygous for the H1/H3 haplotypes had a significantly higher cell survival (P=0.04) after exposure to ionising radiation (IR) than those with the H1/H1 haplotypes, in agreement with the association study. However no haplotype-specific differences in XRCC1 expression or cell cycle progression were noted in the 24 h following IR exposure. These results suggest that the -77T-->C genotype or another variant in linkage disequilibrium influences the cellular response to DNA damage, although the underlying molecular mechanisms remain to be established.

Breast Neoplasms↗

PubMed1988

Study of cis and trans interactions between extended HLA-haplotypes in insulin-dependent diabetes.

From the study of HLA, A, B, C, DR, Bf and C4A, C4B alleles in 287 insulin-dependent diabetes mellitus patients and 108 controls, comparisons were made between 424 diabetic and 216 normal extended haplotypes. In the "cis" situation (haplotype), the highest relative risks (RR) for IDDM were borne by multiloci allelic associations, mainly DR/complement alleles, rather than by DR3 or DR4 considered alone. Susceptibility was strongly associated with two extended haplotypes (Aw30, Cw5, B18, C4BQ0, C4A3, BfF1, DR3 and A2, Cw3, B15, C4Bx, C4A3, BfS, DR4) or their smaller segments. Two haplotypes, S31 associated with DR2 or DR5 and F31 associated with DRw6 or DR7 had a protective effect. In the "trans" situation (opposite haplotype) the large excess of DR3/DR4 heterozygotes was not the only distortion observed. An excess of DR1 (57%) and of C4BQ0 (40%) was noted among non DR3, non DR4 haplotypes in diabetics compared to normal individuals (26% and 23%, respectively, P less than 0.01, 0.05). Homozygotes for DR3 or DR4 were not increased, and other homozygotes were decreased compared to controls. The protective antigens HLA DR2, DR5 and DR7 seemed not to be distributed randomly: their putative protective effect was not observed in the case of combination with DR1 or a B18, DR3 haplotype. DR2 was never found homozygous or combined with DR5. These results suggest that susceptibility to IDDM is generated by both cis and trans interactions between genes or gene products of the HLA region.

Alleles↗

PubMed1994

Molecular characterization of alpha-thalassemia determinants, beta-thalassemia alleles, and beta S haplotypes among Kuwaiti Arabs.

Using amplification, allele-specific oligonucleotide (ASO) hybridization and DNA sequencing we have documented the molecular basis of 64 alpha- and 123 beta-thalassemia (thal) chromosomes, and the haplotypes of 18 beta S chromosomes from patients followed in three hospitals in Kuwait. Of the 30 chromosomes from 15 patients with Hb H disease, 26 (86.7%) carried the polyadenylation (poly A) signal mutation (AATAAA-->AATAAG) in the alpha 2-globin gene, 3 (10%) had the -alpha (3.7 kb) deletion, and 1 (3.3%) had the pentanucleotide deletion in the 5' IVS-I splice junction (alpha-5nt alpha). As many as 12 different beta-thal mutations were identified; 6 Mediterranean alleles [IVS-II-1 (G-->A), IVS-I-6 (T-->C), codon (CD) 39 (C-->T), IVS-I-110 (G-->A), CD 8 (-AA), and IVS-I-1 (G-->A)] were present in 79 (64.2%) of the chromosomes tested. Four East Indian alleles [IVS-I-5 (G-->C), IVS-I 3' end -25 nt deletion, CDs 8/9 (+G), and 619-bp deletion] were found in 31 (25%), and the two Kurdish/Iranian alleles [CD 44 (-C) and CDs 36/37 (-T)] were found in 13 (10.6%) chromosomes. Fourteen beta S chromosomes carried haplotype No. 31 (Saudi Arabia/India); 3 had haplotype No. 19 (Benin), and 1 was a hybrid with haplotype No. 31-specific characteristics in the locus control region hypersensitive site-2 (LCR-HS-2), and haplotype No. 19-specific mutations in the 5' flanking region of the G gamma-promoter. The patient homozygous for haplotype No. 19 was a Jordanian, while the others were Kuwaiti Arabs. The latter appear to be fairly homogeneous in terms of the prevalent alpha-thal determinants and beta S-haplotypes, but there is considerable heterogeneity of their beta-thal alleles. This has implications for genetic counseling and prenatal diagnosis programs.

Anemia, Sickle Cell↗

PubMed1989

Rearrangements and point mutations of P450c21 genes are distinguished by five restriction endonuclease haplotypes identified by a new probing strategy in 57 families with congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is caused by disorders of the P450c21B gene, which, with the P450c21A pseudogene, lies in the HLA locus on chromosome 6. The near identity of nucleotide sequences and endonuclease cleavage sites in these A and B loci makes genetic analysis of this disease difficult. We used a genomic DNA probe that detects the P450c21 genes (A pseudogene, 3.2 kb; B gene, 3.7 kb in Taq I digests) and the 3' flanking DNA not detected with cDNA probes (A pseudogene, 2.4 kb; B gene, 2.5 kb) to examine Southern blots of genomic DNA from 68 patients and 165 unaffected family members in 57 families with CAH. Of 116 CAH-bearing chromosomes, 114 could be sorted into five easily distinguished haplotypes based on blots of DNA digested with Taq I and Bgl II. Haplotype I (76 of 116, 65.6%) was indistinguishable from normal and therefore bore very small lesions, presumably point mutations. Haplotype II (4 of 116, 3.4%) and haplotype III (8 of 116, 6.9%) had deletions and duplications of the P450c21A pseudogene but had structurally intact P450c21B genes presumably bearing point mutations; point mutation thus was the genetic defect in 88 of 116 chromosomes (75.9%). Haplotypes IV and V lack the 3.7-kb Taq I band normally associated with the P450c21B gene. Haplotype IV (13 of 116, 11.2%) retains all other bands, indicating that the P450c21B gene has undergone a gene conversion event, so that it is now also associated with a 3.2-kb band. Haplotype V (13 of 116, 11.2%) lacks the 2.4-kb Taq I fragment and the 12-kb Bgl II fragments normally associated with the P450c21A pseudogene, as well as lacking the 3.7-kb Taq I fragment, indicating deletion of approximately 30 kb of DNA, resulting in a single hybrid P450c21A/B gene. Most (114 of 116, 98%) CAH alleles thus can easily be classified with this new probing strategy, eliminating many ambiguities resulting from probing with cDNA.

Adrenal Hyperplasia, Congenital↗

PubMed2004

CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity.

Reduced adrenal 11 beta-hydroxylation has been associated with an aldosterone synthase (CYP11B2) polymorphism. The 11 beta-hydroxylase gene (CYP11B1) lies close to CYP11B2. We hypothesize that a molecular variant in CYP11B2 is in linkage disequilibrium (LD) with a key quantitative trait in CYP11B1 determining this phenotype. Polymorphisms and inferred haplotypes at CYP11B loci were studied in two independent populations from Europe (n = 100) and South America (n = 99). The latter underwent detailed hormonal studies. LD was estimated by alternative Bayesian methods for inferring the extent of LD when haplotypes at different loci are inferred. Population differences in single nucleotide polymorphisms were modest, indicating the stability of both genes across populations. Using five of nine potentially informative loci at CYP11B sites with allele frequency greater than 0.1, two major contrasting haplotypes, CwtCG and TconvGTA, were found. In both populations the CwtCG haplotype accounted for 44% and the TconvGTA for 32% of subjects. Haplotype distribution did not differ between Europeans and South Americans (chi(2) = 2.81; P = 0.09). In vivo 11 beta-hydroxylase activity, estimated from urinary steroid profiling, was lower in subjects with an increased aldosterone to renin ratio or with the TconvGTA haplotype. These findings indicate that genotypes at the CYP11B locus are in strong LD and that identified haplotypes predict 11 beta-hydroxylase activity.

Base Sequence↗

PubMed2005

Single nucleotide polymorphisms and haplotypes of CYP1A2 in a Japanese population.

In order to identify genetic polymorphisms and haplotype frequencies of CYP1A2 in a Japanese population, the enhancer and promoter regions, all the exons with their surrounding introns, and intron 1 were sequenced from genomic DNA from 250 Japanese subjects. Thirty-three polymorphisms were found, including 13 novel ones: 2 in the enhancer region, 5 in the exons, and 6 in the introns. The most common single nucleotide polymorphism (SNP) was -163C>A (CYP1A2*1F allele) with a 0.628 frequency. In addition to six previously reported non-synonymous SNPs, three novel ones, 125C>G (P42R, CYP1A2*15 allele, MPJ6_1A2032), 1130G>A (R377Q, *16 allele, MPJ6_1A2033), and 1367G>A (R456H, *8 allele, MPJ6_1A2019), were found with frequencies of 0.002, 0.002, and 0.004, respectively. No polymorphism was found in the known nuclear transcriptional factor-binding sites in the enhancer region. Based on linkage disequilibrium analysis, the CYP1A2 gene was analyzed as one haplotype block. Using the 33 detected polymorphisms, 14 haplotypes were unambiguously identified, and 17 haplotypes were inferred by aid of an expectation-maximization-based program. Among them, the second major haplotype CYP1A2*1L is composed of -3860G>A (*1C allele), -2467delT (*1D allele), and -163C>A (*1F allele). Network analysis suggested that relatively rare haplotypes were derived from three major haplotypes, *1A, *1M, and *1N in most cases. Our findings provide fundamental and useful information for genotyping CYP1A2 in the Japanese, and probably Asian populations.

Adrenergic beta-Antagonists↗

PubMed2004

Differences in the contribution of HLA-DR and -DQ haplotypes to susceptibility to adult- and childhood-onset type 1 diabetes in Japanese patients.

To clarify heterogeneity in Japanese adult-onset type 1 diabetes, we analyzed the HLA-DR and -DQ haplotypes, depending on the clinical phenotype, and compared them with those in childhood-onset type 1 diabetes (CO). The patients in a previously reported Ehime Study were divided into subgroups by the mode of onset of diabetes: 68 acute-onset type 1 diabetic patients (AO) and 28 slowly progressive type 1 diabetic patients (SO). HLA haplotypes were compared with those of 80 CO patients and 190 control subjects. Two major susceptible HLA haplotypes in the Japanese, DRB1*0405-DQB1*0401 (DR4) and DRB1*0901-DQB1*0303 (DR9), were significantly increased in the AO and CO groups, but only DR9 was increased in the SO group. AO subjects had a higher frequency of DR9 than CO subjects. Accordingly, the DR9:DR4 frequency increased with increasing age of onset. Another susceptible haplotype, DRB1*0802-DQB1*0302 (DR8), was involved only in the CO group. Analysis of haplotype combinations revealed that DR4 and DR9 had significant dosage effects on the AO and CO groups (P < 0.0001), but only DR9 had such an effect in the SO group (P < 0.03). These results suggest differences in the contribution of HLA class II haplotypes to susceptibility of type 1 diabetes depending on the clinical phenotype and also indicate that HLA class II haplotypes may be associated with the onset age of type 1 diabetes.

Adult↗

PubMed1986

Association of the level of G gamma chain in the fetal hemoglobin of normal adults with specific haplotypes.

The levels of G gamma chain in the fetal hemoglobin of more than 40 Black and Caucasian females were determined with a sensitive high performance liquid chromatography procedure and were correlated with their haplotypes, defined by the presence or absence of 10 different restriction sites. Blood was collected during the 16th and 31st week of pregnancy because of a slightly elevated level of Hb F which facilitated the isolation of this protein from a relatively small sample. Four distinct G gamma levels were observed, each being associated with a specific haplotype. Homozygosity for sub-haplotype A [- + + - + +] is associated with high G gamma values (60-70%); that for sub-haplotype B [- - - - - +] with low levels (25-30%); and that for sub-haplotype C [+ - - - - -] with very low levels (10-15%) (restriction sites listed are Hinc II at epsilon; Xmn I 5' to G gamma; Hind III at G gamma and A gamma; Hinc II at psi beta and 3' to it). Sub-haplotype D [(14)- + - - +] with a rare polymorphism 5' to epsilon is associated with extremely high G gamma values. Hb F levels were low (less than 2.5%) and were independent of the haplotype. It is speculated that, yet unknown, variations in the DNA of gene activity controlling regions are responsible for the differences in G gamma value.

Adolescent↗

PubMed2026

Dissecting the relationship between haplotypes around ATXN2 CAG repeats and the number of CAA interruptions by long-read sequencing.

BACKGROUND: CAG repeat expansions in ATXN2 are implicated as risk factors for several neurological diseases, including spinocerebellar ataxia type 2 (SCA2) when >=33 CAG repeats are present, and amyotrophic lateral sclerosis (ALS) when 27-33 CAG repeats are present. However, how haplotypes around the repeats and CAA interruptions within the repeats are associated with disease phenotypes remains poorly understood. Previous studies on haplotypes around ATXN2 were limited to SNPs very close to the repeats (<5kb) or were based on statistical inference only. METHODS: Here, we used long-read sequencing on the Oxford Nanopore Technologies (ONT) platform to simultaneously infer haplotypes around ATXN2, the number of CAG repeats, and the number of CAA interruptions, along with NYGC ALS Consortium NGS dataset. We further sequenced 41 individuals (EUR = 39) with neurological diseases with intermediate repeats by ONT. RESULTS: We found that haplotypes around ATXN2 and the number of interruptions show ethnicity-specific and ALS-specific distribution. Three CAA interruptions are present at low prevalence (~1%) in control populations in multiple ancestry groups, but high prevalence (~55%) in ALS individuals with intermediate repeats. Furthermore, we examined 159 individuals with ALS (~90% European ancestry) with intermediate ATXN2 repeats and found a unique haplotype in ALS individuals with three CAA interruptions, which can be tagged by an SNV, rs148019457. We also validated that the rs148019457-G allele is only present in haplotypes with three CAA interruptions. CONCLUSIONS: In summary, our study shows that 3 CAA interruptions are rarely seen in healthy controls but are common in those with expanded ATXN2 CAG repeats who have neurological disorders, and that rs148019457 tags a specific haplotype with 3 CAA interruptions within expanded ATXN2 CAG repeats in individuals of European ancestry. These results have implications for the development of precision genomic medicine for neurological disorders, and the tag SNP may help identify those with interruptions from existing population genotyping data.

ATXN2↗

PubMed2026

HLA Allele and Haplotype Frequencies Among Registered Unrelated Donors in the Western Region of Saudi Arabia.

The Saudi stem cell donor registry (SSCDR) has successfully recruited over 92,000 unrelated potential stem cell donors through nationwide campaigns. The Western region of Saudi Arabia is characterized by its unique ethnic diversity, shaped by centuries of immigration and pilgrimage. This study aimed to determine the distribution of HLA alleles and haplotypes among donors from this region. A total of 1112 donors registered with SSCDR were included, all recruited during campaigns conducted in the Western region between 2019 and 2021. Participants provided ancestry information to confirm their city of origin. High-resolution HLA typing for loci A, B, C, DRB1 and DQB1 was performed using sequence-based typing (SBT). Allele and haplotype frequencies were estimated for each subgroup using Arlequin 3.5 software. Distinct haplotype patterns were observed across cities. The most common haplotypes in the 1112 potential stem cell donors in the Western Region of Saudi Arabia were HLA-A*02:01∼C*07:02∼B*07:02∼DRB1*15:01∼DQB1*06:02 and HLA-A*02:01∼C*06:02∼B*50:01∼DRB1*07:01∼DQB1*02:01 in Jeddah; A*23:01∼C*06:02∼B*50:01∼DRB1*07:01∼DQB1*02:01 in Al-Madinah; HLA-A*26:01∼C*07:02∼B*08:01∼DRB1*03:01∼DQB1*02:01, HLA-A*30:01∼C*06:02∼B*13:02∼DRB1*07:01∼DQB1*02:01 and HLA-A*02:01∼C*06:02∼B*50:01∼DRB1*07:01∼DQB1*02:01 in Makkah; HLA-A*02:01∼C*15:02∼B*51:01∼DRB1*13:01∼DQB1*06:03 and HLA-A*02:01∼C*07:02∼B*07:02∼DRB1*15:01∼DQB1*06:02 in Al-Baha; and HLA-A*31:01∼C*15:02∼B*51:01∼DRB1*13:01∼DQB1*06:03 in Taif. HLA data are available in the Allele Frequencies Net Database (AFND: 3854, 3855, 3856, 3857 and 3858) under the population name 'Saudi Western Region'. In western Saudi Arabia, HLA allele and haplotype distributions demonstrate marked city-specific variation. Our research identifies DR7-, DR13- and DR15-based haplotypes as the most prevalent across the region. These findings are critical for optimizing unrelated donor searches for patients lacking compatible familial matches. Understanding these local frequencies allows for more targeted recruitment and better matching probabilities in stem cell registries.

Humans↗

PubMed2004

Association of specific haplotypes of D2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations.

CONTEXT: Dopamine receptor-mediated pathways play critical roles in the mechanism of addiction. However, associations of the D(2) dopamine receptor gene (DRD2) with substance abuse are controversial. OBJECTIVE: To determine whether susceptibility sites resided at DRD2. DESIGN: Haplotype-based case-control analysis of 2 distinct populations using 10 single nucleotide polymorphisms (SNPs) with heroin dependence. SETTING: Universities of Mainz and Bonn, Germany, and 3 local hospitals in southwestern China. Patients Cases and control subjects recruited from China (486 cases, 313 controls) and Germany (471 cases, 192 controls). INTERVENTIONS: Genotyping for 10 SNPs by 5'-exonuclease fluorescence assays. The D' value of linkage disequilibrium and haplotypes were generated by the expectation-maximization algorithm. MAIN OUTCOME MEASURES: Genotype, allele, and haplotype frequencies were compared between cases and controls by chi(2) tests constructed for each population. An additional 32 SNPs randomly distributed in the genome were genotyped for detecting population admixture in the 2 populations. RESULTS: A haplotype block of 25.8 kilobases (kb) was defined by 8 SNPs extending from SNP3 (TaqIB) at the 5' end to SNP10 site (TaqIA) located 10 kb distal to the 3' end of the gene. Within this block, specific haplotype cluster A (carrying TaqIB1 allele) was associated with a high risk of heroin dependence in Chinese patients (P = 1.425 x 10(-22); odds ratio, 52.80; 95% confidence interval, 7.290-382.5 for 8-SNP analysis). A putative recombination "hot spot" was found near SNP6 (intron 6 ins/del G), creating 2 new daughter haplotypes that were associated with a lower risk of heroin dependence in Germans (P = 1.94 x 10(-11) for 8-SNP analysis). There was no evidence of population stratification in either population. CONCLUSIONS: These results strongly support a role of DRD2 as a susceptibility gene with heroin dependence in Chinese patients and was associated with low risk of heroin dependence in Germans.

Adult↗

PubMed1996

Beta-globin gene haplotype in Hb SC disease.

We asked the question, is the haplotype found with the sickle hemoglobin gene associated with different hematological characteristics in patients who were combined heterozygotes for sickle hemoglobin and hemoglobin C (Hb SC disease)? In 73 adults with Hb SC disease, a Benin haplotype chromosome was present in 56%, and Bantu (or Central African Republic; CAR), Senegal, and atypical haplotype chromosomes were found in 25%, 6%, and 12%, respectively. No significant difference were found in hematological characteristics or fetal hemoglobin levels of patients with Benin/C, CAR/C, Senegal/C, and atypical/C haplotypes. There were 71% C I, 18% C II, and 11% other beta(c) haplotypes. Fetal hemoglobin levels are lower in Hb SC disease than in sickle-cell anemia. Perhaps because haplotype has no discernible effect on fetal hemoglobin level in Hb SC disease, it does not modulate its hematological features.

Adult↗

PubMed1996

Fluorescent multiplex microsatellites used to define haplotypes associated with 75 CFTR mutations from the UK on 437 CF chromosomes.

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene contains three highly informative microsatellites: IVS8CA, IVS17bTA, and IVS17bCA. Their analysis improves prenatal/ carrier diagnosis and generates haplotypes from CF chromosomes that are strongly associated with specific mutations. Microsatellite haplotypes were defined for 75 CFTR mutations carried on 437 CF chromosomes (220 for delta F508, 217 for other mutations) from Northern Ireland and three English regions: the North-West, East Anglia, and the South. Fluorescently labelled microsatellites were amplified in a triplex PCR reaction and typed using an ABI 373A fluorescent fragment analyser. These mutations cover all the common and most of the rare CF defects found in the UK, and their corresponding haplotypes and geographic region are tabulated here. Ancient mutations, delta F508, G542X, N1303K, were associated with several related haplotypes due to slippage during replication, whereas other common mutations were associated with the one respective haplotype (e.g., G551D and R560T with 16-7-17, R117H with 16-30-13, 621 + 1G > T with 21-31-13, 3659delC with 16-35-13). This simple, fast, and automated method for fluorescent typing of these haplotypes will help to direct mutation screening for uncharacterised CF chromosomes.

Chromosomes, Human↗

PubMed1999

TP53 mutation and haplotype analysis of two large African American families.

Two large apparently unrelated African American families with a high incidence of breast cancer and other tumors characteristic of Li-Fraumeni breast sarcoma cancer family syndrome were studied. Mutation screening revealed that in both families the affected members carried a germline mutation of the TP53 gene at codon 133 (ATG--> ACG, M133T). In order to determine whether an ancestral haplotype was shared by these two families, polymorphic markers within and flanking the TP53 gene were studied. Haplotype analysis using five markers revealed an identical haplotype shared by the two families. Loss of heterozygosity at the TP53 locus in the probands' tumor tissues from each family was observed; in each case, the retained allele carried the common haplotype. The frequency of this haplotype in the general African American population is <0.003. This unique haplotype, combined with the rare TP53 mutation, suggests that these African American families share a common ancestry. This finding suggests that other African Americans may be carriers of this mutation and thus may be at risk of early-onset breast cancer or other cancers characteristic of the Li-Fraumeni breast sarcoma cancer family syndrome. The finding of recurring mutations in African Americans may facilitate carrier screening and identification in this population.

Alleles↗

PubMed2000

Haplotype and AGG-interspersion analysis of FMR1 (CGG)(n) alleles in the Danish population: implications for multiple mutational pathways towards fragile X alleles.

The AGG interspersion pattern and flanking microsatellite markers and their association with instability of the FMR1 (CGG)(n) repeat, involved in the fragile X syndrome, were analyzed in DNA from filter-paper blood spots randomly collected from the Danish newborn population. Comparison of DXS548-FRAXAC1 haplotype frequencies in the normal population and among fragile X patients suggested strong linkage disequilibrium between normal alleles and haplotype 7-3 and between fragile X alleles and haplotype 2-1 and 6-4. Comparison of the AGG interspersion pattern in 143 alleles, ranging in size from 34-62 CGG, and their associated haplotypes indicates the existence of at least three mutational pathways from normal alleles toward fragile X alleles in the Danish population. Two subgroups of normal alleles, with internal sequences of (CGG)(10)AGG(CGG)(19) and (CGG)(9)AGG(CGG)(12) AGG(CGG)(9), possibly predisposed for expansion, were identified in the data set. When alleles larger than 34 CGG were investigated, comparing the length of 3' uninterrupted CGG triplets (uCGG), we found that alleles associated with haplotype 2-1 and 6-4 contain significantly longer stretches of uCGG than alleles associated with haplotype 7-3. Thus, the data support that (CGG)(n) instability is correlated to the length of uCGG.

Alleles↗

PubMed2005

beta-globin gene cluster haplotypes associated with beta-thalassemia on Corsica island.

In the Corsican population, the incidence of beta-thalassemia traits is reported to be 3.1%. We have investigated the 2 more important beta-thalassemia mutations present in the Corsican population: beta0-39 and beta+IVS1-110. Seven polymorphic sites in the beta-globin gene cluster were analyzed from a sample of 43 non-related beta-thalassemia heterozygotes and of 47 nonrelated healthy individuals, from Central Corsica (Corte). Among the 43 Corsican patients analyzed, the nonsense codon is predominant (88.40%), whereas the beta+IVS1-110 mutation, the most common of beta-thalassemia in the eastern part of the Mediterranean basin, is underrepresented (2.33%). The other individuals did not show positive for the two tested mutations (9.27%). The beta0-39 mutation in the studied population shows a strong association with haplotype II (18.7%) and a weaker association with haplotypes I (2.3%) and VII (2.1%). The strong association of the beta0-39 mutation with haplotype II was also found in Sardinia, suggesting that the mutation on the two islands have the same origin. In the present study all the data concerning frequencies of the mutations and of sequence haplotypes, support the hypothesis of a western Mediterranean origin of the beta0-39 mutation. For the first time, this paper analyzes the association of beta-globin gene cluster haplotypes with the 2 more frequent beta-thalassemia mutations in an isolated population in the centre of Corsica (Corte), which presents certain genetic peculiarities. However, the analysis of beta-haplotypes will be very useful for the genetic epidemiological study in this region.

Codon, Nonsense↗

PubMedDate not supplied

Beta-globin cluster haplotypes in normal individuals and beta(0)39-thalassemia carriers from Sardinia, Italy.

Seven polymorphic sites in the beta-globin cluster in association with specific thalassemia mutations were analyzed in a sample from Sardinia, Italy. In order to verify previous works carried out on normal samples (beta(A)/beta(A)) and family studies on beta-thalassemia homozygotes individuals, the haplotype frequencies in both normal individuals (beta(A)/beta(A)) and beta(0)39-thalassemia carriers (beta(A)/beta0) were studied. In our work chromosomes carrying beta(0)39 mutation are characterized by a prevalence of haplotype II (- + + - + + +) (52%) relative to haplotype I (+- - - - + +) (29%), in contrast, among chromosomes with beta(A) the frequency of haplotype I is much greater than that of haplotype II. These data confirm what was found by other authors. Nevertheless, our results disagree with those of previous studies of Sardinians, both in frequencies values and in the numbers of haplotypes identified. Population analysis performed with samples carrying the beta-thalassemic mutation highlighted the peculiarity of Sardinians with respect to other Mediterranean populations. The Corsican population is most similar to the Sardinian population, confirming previous analyses performed with both classical markers and mitochondrial and genomic DNA.

Adult↗