Haplotype analysis of the BRCA2 9254delATCAT recurrent mutation in breast/ovarian cancer families from Spain

A frame-shift 9254del5 mutation was independently identified in 12 families, eleven of them with Spanish ancestors, in a BRCA2 screening performed in 841 breast and/or ovarian cancer families and in 339 women with breast cancer diagnosed before the age of 40 at different centers in France and Spain. We sought to analyze in detail the haplotype and founder effects of the 9254del5 and to estimate the time of origin of the mutation. Eight polymorphic microsatellite markers and two BRCA2 polymorphisms were used for the haplotype analyses. The markers were located flanking the BRCA2 gene spanning a region of 6.1 cM. Our results suggest that these families shared a common ancestry with BRCA2 9254del5, which is a founder mutation originating in the Northeast Spanish, with an estimated age of 92 (95% CI 56-141) generations.     

Clouston hidrotic ectodermal dysplasia (HED): genetic homogeneity, presence of a founder effect in the French Canadian population and fine genetic mapping

HED is an autosomal dominant skin disorder that is particularly common in the French Canadian population of south-west Quebec. We previously mapped the HED gene to the pericentromeric region of chromosome 13q using linkage analysis in eight French Canadian families. In this study, we extend our genetic analysis to include a multiethnic group of 29 families with 10 polymorphic markers spanning 5.1 cM in the candidate region. Two-point linkage analysis strongly suggests absence of genetic heterogeneity in HED in four families of French, Spanish, African and Malaysian origins. Multipoint linkage analysis in all 29 families generated a peak lod score of 53.5 at D13S1835 with a 1 lod unit support interval spanning 1.8 cM. Recombination mapping placed the HED gene in a 2.4 cM region flanked by D13S1828 proximally and D13S1830 distally. We next show evidence for a strong founder effect in families of French Canadian origin thereby representing the first example of a founder disease in the south-west part of the province of Quebec. Significant association was found between HED in these families and all markers analysed (Fisher's exact test, P < 0.001). Complete allelic association was detected at D13S1828, D13S1827, D13S1835, D13S141 and D13S175 (P(excess) = 1) spanning 1.3 cM. A major haplotype including all 10 associated alleles was present on 65% of affected chromosomes. This haplotype most likely represents the founder haplotype that introduced the HED mutation into the French Canadian population. Luria-Delbrück equations and multipoint likelihood linkage disequilibrium analysis positioned the gene at the D13S1828 locus (likely range estimate: 1.75 cM) and 0.58 cM telomeric to this marker (support interval: 3.27 cM) respectively.     

Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations

The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews. Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora ∼2500 years ago. The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers, and to estimate the age at which the mutation arose. Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5 MB, encompassing the BRCA1 gene locus. Estimation of mutation age was based on a subset of 11 markers spanning a region of ∼5 MB, using a previously developed algorithm applying the maximum likelihood method. Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics. Haplotype analysis indicated that the 185delAG mutation arose 750–1500 years ago. In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) ∼650 years ago, and into the Iraqi–Jewish community ∼450 years ago. The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently. We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews.     

Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families.

The 999del5 mutation is the single, strong BRCA2 founder mutation in Iceland and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. All Icelandic families analysed shared a common core haplotype of about 1.7 cM. The common ancestors for the Icelandic families studied were estimated to trace back to 340-1000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country. Analysis of the Finnish families revealed two distinct haplotypes. A rare one, found in three families in the old settlement region in southwestern Finland, shared a four-marker (0.5 cM) core haplotype with the Icelandic 999del5 haplotype. A distinct approximately 6 cM haplotype was shared by seven 999del5 Finnish families estimated to have a common ancestry 140-300 years ago. These families cluster in two geographical regions in Finland, in the very same area as those with the rare haplotype and also in the most eastern, late settlement region of Finland. The results may indicate a common ancient origin for the 999del5 mutation in Iceland and in Finland, but distinct mutational events cannot be ruled out. The surprising finding of the same mutation in two completely different haplotypes in a sparsely populated area in Finland may suggest gene conversion.     

Haplotype analysis of two recurrent genomic rearrangements in the BRCA1 gene suggests they are founder mutations for the Greek population

Pertesi M, Konstantopoulou I, Yannoukakos D. Haplotype analysis of two recurrent genomic rearrangements in the BRCA1 gene suggests they are founder mutations for the Greek population. The deletions of 4.4 and 3.2 kb identified in exons 24 and 20, respectively, are two of the four most common mutations in the BRCA1 gene in Greek breast cancer patients. They have been reported previously six and three times, respectively, in unrelated Greek families. A total of 11 more families have been identified in the present study. In order to characterize these recurrent mutations as founder mutations, it is necessary to identify the disease‐associated haplotype and prove that it is shared by all the mutation carriers, suggesting that it occurred only once in a common ancestor. Haplotype analysis was performed on 24 mutation carriers and 66 healthy individuals using 10 short tandem repeat markers located within and flanking the BRCA1 gene locus, spanning a 5.9 Mb interval. Results indicate that most of the carriers of the exon 24 deletion share a common core haplotype ‘4‐7‐6‐6‐1‐3’ between markers D17S951 and D17S1299, for a stretch of 2.9 Mb, while the common haplotype for the exon 20 deletion is ‘6‐7‐4‐2‐6‐7‐1‐3’ between markers D17S579 and D17S1299, for a stretch of 3.9 Mb. Both genomic rearrangements in BRCA1 gene are Greek founder mutations, as carriers share the same, for each mutation, disease‐associated haplotype, suggesting the presence of a distinct common ancestor for both mutations.     

Haplotype analysis and ancient origin of the BRCA1 c.4035delA Baltic founder mutation

Uncertainty exists about the origin of BRCA1 c.4035delA mutation which is prevalent in Baltic countries, with the highest frequency being in Lithuania (53% of all BRCA1 mutations), although formal founder mutation analysis by haplotype has not yet been undertaken. In this study we genotyped 78 unrelated BRCA1 c.4035delA mutation carriers families from Lithuania, Latvia, Poland and Russia. The results from the haplotype analyses were used to estimate the age of the mutation. Using maximum likelihood methods we estimated that the mutation arose approximately 1550 years (62 generations of 25 years) ago (ca. 5th century) somewhere in the present territory of Lithuania, in the area inhabited by ancient Baltic tribes at that time. Our results show that this mutation gradually entered the gene pool in the neighboring countries.     

Haplotype analysis reveals that the recurrent BRCA1 deletion of exons 23 and 24 is a Greek founder mutation

A recurrent large genomic rearrangement (LGR) encompassing exons 23 and 24 of the BRCA1 gene has been identified in breast‐ovarian cancer families of Greek origin. Its breakpoints have been determined as c.5406 + 664_*8273del11052 (RefSeq: NM_007294.3) and a diagnostic polymerase chain reaction (PCR) has been set up for rapid screening. In a series of 2,092 high‐risk families completely screened for BRCA1 and BRCA2 germline mutations, we have found the deletion in 35 families (1.68%), representing 7.83% of the mutations identified in both genes and 10.3% of the total BRCA1 mutations. In order to characterize this deletion as a founder mutation, haplotype analysis was conducted in 60 carriers from 35 families, using three BRCA1 intragenic microsatellite markers and four markers surrounding the BRCA1 locus. Our results demonstrate a common shared core disease‐associated haplotype of 2.89Mb. Our calculations estimate that the deletion has originated from a common ancestor 1450 years ago, which most probably inhabited the Asia Minor area. The particular (LGR) is the third mutation of such type that is proven to have a Greek founder effect in the Greek population, illustrating the necessity for LGRs testing in individuals of Greek descent.     

Identification of a founder BRCA1 mutation in the Moroccan population

Breast cancer (BC) is the most frequent cancer among women in Morocco. However, the role of the most prevalent BC‐predisposing genes, BRCA1 and BRCA2, has been largely unexplored. To help define the role of BRCA1 in BC in Morocco, we characterized the first potential BRCA1 founder mutation in this population. Genetic testing of BRCA1 and BRCA2 in BC high‐risk families identified mutation BRCA1 c.5309G>T, p.(Gly1770Val) or G1770V in five independent families from Morocco, suggesting a founder effect. To confirm this hypothesis, haplotype construction was performed using seven intragenic and flanking BRCA1 microsatellite markers. Clinical data were also compiled. Clinical data from carriers of mutation G1770V correspond to data from carriers of BRCA1 pathogenic mutations. Microsatellite analysis showed a common haplotype for the five families in a region comprising 1.54 Mb, confirming G1770V as the first specific founder BRCA1 mutation in the Moroccan population. Our findings contribute to a better understanding of BC genetics in the Moroccan population. Nevertheless, comprehensive studies of mutation G1770V in large series of BC patients from Morocco are needed to assess the real prevalence of this mutation and to improve genetic testing and risk assessment in this population.     

Mutation analysis of the BRCA1 and BRCA2 genes in the Belgian patient population and identification of a Belgian founder mutation BRCA1 IVS5 + 3A > G

Since the identification of the BRCA1 and BRCA2 genes, several hundred different germline mutations in both genes have been reported. Recurrent mutations are rare and mainly due to founder effects. As the mutational spectrum of the BRCA1 and BRCA2 genes in the Belgian patient population is largely unknown, we initiated mutation analysis for the complete coding sequence of both genes in Belgian families with multiple breast and/or ovarian cancer patients and in "sporadic" patients with early onset disease. We completed the analysis in 49 families and in 19 "sporadic" female patients with early onset breast and/or ovarian cancer. In 15 families we identified a mutation (12 mutations in BRCA1 and 3 mutations in BRCA2). In 5 apparently unrelated families the same splice site mutation was identified (BRCA1 IVS5 + 3A > G). Haplotype analysis revealed a common haplotype immediately flanking the mutation in all families suggesting that disease alleles are identical by descent. In none of the 19 sporadic patients was a mutation found.     

Haplotype analysis and age estimation of the 113insR CDKN2A founder mutation in Swedish melanoma families

Germline mutations in the CDKN2A tumor suppressor gene located on 9p21 have been linked to development of melanomas in some families. A germline 3-bp insertion in exon 2 of CDKN2A, leading to an extra arginine at codon 113 (113insR), has been identified in 17 Swedish melanoma families. Analysis of 10 microsatellite markers, spanning approximately 1 Mbp in the 9p21 region, showed that all families share a common allele for at least one of the markers closest to the CDKN2A gene, suggesting that the 113insR mutation is an ancestral founder mutation. Differences in the segregating haplotypes, due to meiotic recombinations and/or mutations in the short-tandem-repeat markers, were analyzed further to estimate the age of the mutation. Statistical analysis using a maximum likelihood approach indicated that the mutation arose 98 generations (90% confidence interval: 52-167 generations), or approximately 2,000 years, ago. Thus, 113insR would be expected to have a more widespread geographic distribution in European and North American regions with ancestral connections to Sweden. Alternatively, CDKN2A may lie in a recombination hot spot region, as suggested by the many meiotic recombinations in this narrow approximately 1-cM region on 9p21.     

Evidence for a common Spinocerebellar ataxia type 7 (SCA7) founder mutation in Scandinavia

Spinocerebellar ataxia type 7 (SCA7) is a neuro-degenerative disorder characterised by progressive cerebellar ataxia and macular degeneration. SCA7 is one of the least common genetically verified autosomal dominant cerebellar ataxias (ADCAs) in the world (4.5 to 11.6%), but in Sweden and Finland SCA7 is the most commonly identified form of ADCA. In an inventory of hereditary ataxias in Scandinavia (Sweden, Norway, Denmark and Finland) we identified 15 SCA7 families, eight in Sweden and seven in Finland, while no cases of SCA7 could be found in Norway or Denmark. We examined whether the relatively high frequency of SCA7 families in Sweden and Finland was the result of a common founder effect. Only two out of 15 families could be connected genealogically. However, an extensive haplotype analysis over a 10.2 cM region surrounding the SCA7 gene locus showed that all 15 families studied shared a common haplotype over at least 1.9 cM. This strongly suggests that all Scandinavian SCA7 families originate from a common founder pre-mutation.     

BRCA2 founder mutation in Slovenian breast cancer families

Linkage analysis has identified BRCA1 and BRCA2 germline mutations as the major cause for cancer predisposition in breast and/or ovarian cancer families. In previous screening efforts on Belgian families we had a BRCA1/2 gene mutation detection rate of 25%.(1) Here we report the results of a BRCA mutation screening in seven high-risk breast/ovarian cancer families from Slovenia. We found a single but highly recurrent BRCA2 splice site mutation (IVS16-2A>G) in three breast cancer-only families. This cancer-linked mutation could not be identified in three families with ovarian cancer, suggesting that the mutation predisposes at least predominantly to breast cancer. All mutation carriers shared a common disease associated haplotype indicating a founder effect. This mutation most probably occurred in a single ancestor and seems essentially confined to the Slovene population.     

Frequent mutation in North African patients with MUTYH‐associated polyposis

Lefevre JH, Colas C, Coulet F, Baert‐Desurmont S, Mongin C, Tiret E, Frebourg T, Soubrier F, Parc Y. Frequent mutation in North African patients with MUTYH‐associated polyposis. MUTYH‐associated polyposis (MAP) has been characterized as an autosomal recessive disease predisposing to a variable number of colorectal adenomas with a high risk of cancer. Numerous studies have indicated that two missense mutations (Y179C and G396D) account for about 80% of MUTYH allelic variants in Europeans. Ethnic and geographic differences in the mutation spectrum have been observed. The aim of this study was to report mutations in patients from North Africa, determine the incidence of the c.1227_1228dup mutation in our cohort of MUTYH patients and to evaluate the existence of a founder effect. Within a group of 36 families with MAP, 11 were shown to have a homozygous c.1227_1228dup mutation. These families came from Algeria (n = 5), Tunisia (n = 4), Morocco (n = 1) and Portugal (n = 1). Probands belonging to families of North African origin showed a significantly higher frequency of c.1227_1228dup (78.6% vs 4.5%, p < 0.0001). Haplotype analyses were performed using 10 microsatellite markers surrounding the MUTYH gene spanning a region of 4.4 cM. We identified a common haplotype of at least 1.3 cM in all families suggesting a founder effect for this mutation.     

The M53I mutation in CDKN2A is a founder mutation that predominates in melanoma patients with Scottish ancestry

Germline mutations in the tumor suppressor gene CDKN2A have been shown to predispose to cutaneous malignant melanoma. The M53I mutation is the most common CDKN2A mutation identified in Scottish melanoma patients and is also found in a small number of families in other countries. The aim of this study was to determine whether the occurrence of this mutation is due to a common ancestor originating from Scotland, and if so, to estimate how long ago the mutation arose. We examined 18 families carrying the M53I mutation: six from Scotland, five from Canada, four from Australia, and three from America. Haplotypes derived from segregation of seven informative microsatellite markers flanking CDKN2A were constructed in each family. Our findings show that 14 of 18 families carry a common ancestral haplotype on which the mutation arose approximately 88 generations ago (1-LOD-unit support interval 44-198 generations). This haplotype is very rare in controls, which supports the idea that it is a common founder mutation haplotype. The four M53I families that do not share the consensus haplotype may in fact have arisen from the same founder, but this is potentially obscured by presumed replication slippage for some of the microsatellite markers tested.     

Reconstructing the Genealogy of a BRCA1 Founder Mutation by Phylogenetic Analysis

Estimating the age of founder mutations may contribute to improve our knowledge of population genetics and evolutionary history of diseases. Previous haplotype analysis suggested that the BRCA1*1499insA mutation was a founder allele, probably originated in Tuscany (Italy). Here, we collected additional pedigrees carrying this mutation, and applied a phylogenetic method for estimating mutation age. A chromosome segment of about 25 cM, including 37 short tandem repeats (STRs) on both sides of the BRCA1 gene (DeCode map), was typed in 50 subjects (28 mutation carriers) from 14 unrelated families. The time to the most recent common ancestor (MRCA) of the mutation carriers was estimated by the length of the shared haplotype between all possible pairs of individuals. A function relating the length of the shared haplotype to the time to the MRCA was obtained by a computer simulation. This approach gives results comparable with those of other existing mutation‐dating methods, but does not depend explicitly on population‐specific parameters such as allele frequencies, provides narrower confidence intervals (CI), and allows one to build an extended genealogical tree of all mutation carriers. The 1499insA mutation shared by the investigated subjects was estimated to be present in an individual living about 30 generations ago (95% CL 22‐56), or 750 years (95% CL 550‐1,400).     

Fine mapping the candidate region for peripheral neuropathy with or without agenesis of the corpus callosum in the French Canadian population

Peripheral neuropathy with or without agenesis of the corpus callosum (ACCPN [MIM 2180000]) is an autosomal recessive disease characterised by progressive sensorimotor neuropathy, mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum. The ACCPN gene was mapped in 1996 to a 4 cM region on chromosome 15. We have since collected additional French Canadian (FC) families and typed a total of 11 polymorphic markers spanning approximately 18 cM on chromosome 15. Through the use of haplotype analysis we have confirmed the presence of a founder haplotype in the FC population, and identified critical recombinants which reduce the ACCPN candidate interval to a approximately 2 cM or 1000 Kb region flanked by markers D15S1040 and ACTC. Linkage disequilibrium analysis supports the haplotype data, and suggests that the ACCPN gene lies nearest to marker D15S1232.     

中国乳腺癌患者BRCA1基因的频发突变5589del8

目的研究在中国大陆乳腺癌人群中是否存在BRCAI／2基因突变的“热点”。方法研究对象为来自全国4个乳腺癌医疗中心的177例家族性和早发性乳腺癌患者和426例散发性乳腺癌患者,根据前期研究中已发现的BRCAI／2基因突变位点,应用变性高效液相色谱分析和DNA测序技术对这些患者进行已知位点的突变检测。结果在前期研究的70例家族性和早发性乳腺癌患者和本研究的177例患者（共247例）中,共发现3例BRCAl5589del8突变的携带者,在426例散发性乳腺癌患者中也发现了2例BRCAl5589del8突变的携带者。单倍型分析的结果显示这5例患者具有相近甚至相同的单倍型。结论BRCAl5589del8突变是中国人群中BRCAl基因的频发突变,它是否是中国人群中的“始祖突变”仍需进一步研究证实。     

C73R is a hotspot mutation in the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria

Congenital erythropoietic porphyria (CEP) results from profoundly deficient activity of the fourth enzyme of the haeme biosynthetic pathway, uroporphyrinogen III synthase (UROIIIS). CEP is a rare, recessively inherited disorder, and mutations in the UROIIIS gene detected in CEP patients are heterogeneous. The notable exception to this rule is a single missense mutation, designated C73R, which represents over 40% of all mutant UROIIIS alleles. In this study, we investigated three separate families with CEP from different ethnic backgrounds. We performed haplotype analysis using two microsatellite markers that closely flank the UROIIIS gene on chromosome 10q24, spanning a region of 4 cM on the GB4 linkage panel. Haplotype analysis revealed the occurrence of C73R on different haplotypes in four out of four disease chromosomes studied. The results are consistent with the hypothesis that C73R is a hotspot mutation for CEP, and does not represent wide dispersion of a single ancestral mutant C73R allele.     

Expansion of CTG repeat in myotonin protein kinase gene on Alu(ins)-HinfI-I background in a myotonic dystrophy patient from India. Mutations in brief no. 210. Online

To determine the founder of Indian myotonic dystrophy mutation, we have studied the expansion of CTG repeats in myotonin protein kinase gene and two intragenic linked loci Alu(ins) / Alu(del) and G/T intron 9 HinfI polymorphism in ten unrelated DM patients from eastern India. Out of these ten patients, reconstruction of haplotype was possible for five patients unambiguously. In the other five cases, haplotype for the normal allele was assumed to be the most common haplotype found in normal individuals from Indian populations. Such analysis showed that in nine cases, the expansion of CTG repeats took place on Alu(ins)-HinfI-2 background indicating common founder with other DM mutation published. However, in one case we observed a different haplotype [Alu(ins)-HinfI-1] which could be a new mutation or due to admixture.     

Expansion of CTG repeat in myotonin protein kinase gene on Alu(ins)‐Hinf1‐1 background in a myotonic dystrophy patient from India

To determine the founder of Indian myotonic dystrophy mutation, we have studied the expansion of CTG repeats in myotonin protein kinase gene and two intragenic linked loci Alu(ins) / Alu(del) and G/T intron 9 Hinf1 polymorphism in ten unrelated DM patients from eastern India. Out of these ten patients, reconstruction of haplotype was possible for five patients unambiguously. In the other five cases, haplotype for the normal allele was assumed to be the most common haplotype found in normal individuals from Indian populations. Such analysis showed that in nine cases, the expansion of CTG repeats took place on Alu(ins)‐Hinf1‐2 background indicating common founder with other DM mutation published. However, in one case we observed a different haplotype [Alu(ins)‐Hinf1‐1] which could be a new mutation or due to admixture. © 1998 Wiley‐Liss, Inc.