Study of large inbred Friedreich ataxia families reveals a recombination between D9S15 and the disease locus

Friedreich ataxia is a neurodegenerative disorder with autosomal recessive inheritance. Precise linkage mapping of the Friedreich ataxia locus (FRDA) in 9q13-q21 should lead to the isolation of the defective gene by positional cloning. The two closest DNA markers, D9S5 and D9S15, show very tight linkage to FRDA, making difficult the ordering of the three loci. We present a linkage study of three large Friedreich ataxia families of Tunisian origin, with several multiallelic markers around D9S5 and D9S15. Haplotype data were used to investigate genetic homogeneity of the disease in these geographically related families. A meiotic recombination was found in a nonaffected individual, which excludes a 150-kb segment, including D9S15, as a possible location for the Friedreich ataxia gene and which should orient the search in the D9S5 region.     

Fine mapping of the SLEB2 locus involved in susceptibility to systemic lupus erythematosus

We have previously reported linkage of systemic lupus erythematosus to chromosome 2q37 in multicase families from Iceland and Sweden. This locus (SLEB2) was identified by linkage to the markers D2S125 and D2S140. In the present study we have analyzed additional microsatellite markers and SNPs covering a region of 30 cM around D2S125 in an extended set of Nordic families (Icelandic, Swedish, and Norwegian). Two-point linkage analysis in these families gave a maximum lod score at the position of markers D2S2585 and D2S2985 (Z = 4.51, PIC = 0.65), by applying a "model-free" pseudo-marker linkage analysis. Based on multipoint linkage analysis in the Nordic families, the most likely location of the SLEB2 locus is estimated to be in the interval between D2S125 and the position of markers D2S2585 and D2S2985, with a peak multipoint lod score of Z = 6.03, assuming a dominant pseudo-marker model. Linkage disequilibrium (LD) analysis was performed using the data from the multicase families and 89 single-case families of Swedish origin, using the same set of markers. The LD analysis showed evidence for association in the single-case and multicase families with locus GAAT3C11 (P < 0.0003), and weak evidence for association was obtained for several markers located telomeric to D2S125 in the multicase families. Thirteen Mexican families were analyzed separately and found not to have linkage to this region. Our results support the presence of the SLEB2 locus at 2q37.     

Evidence for locus heterogeneity in human autosomal dominant split hand/split foot malformation.

Split hand/split foot (SHSF; also known as ectrodactyly) is a human developmental disorder characterized by missing central digits and other distal limb malformations. An association between SHSF and cytogenetically visible rearrangements of chromosome 7 at bands q21-q22 provides compelling evidence for the location of a causative gene at this location, and the locus has been designated SHFD1. In the present study, marker loci were localized to the SHFD1 critical region through the analysis of somatic cell hybrids derived from individuals with SHSF and cytogenetic abnormalities involving the 7q21-q22 region. Combined genetic and physical data suggest that the order of markers in the SHFD1 critical region is cen-D7S492-D7S527-(D7S479-D7S491)-SHFD1-++ +D7S554-D7S518-qter. Dinucleotide repeat polymorphisms at three of these loci were used to test for linkage of SHSF to this region in a large pedigree that demonstrates autosomal dominant SHSF. Evidence against linkage of the SHSF gene to 7q21-q22 was obtained in this pedigree. Therefore, combined molecular and genetic data provide evidence for locus heterogeneity in autosomal dominant SHSF. We propose the name SHSF2 for this second locus.     

Power comparisons of the transmission/disequilibrium test and sib-transmission/disequilibrium-test statistics.

Brachydactyly type B (BDB), an autosomal dominant disorder, is the most severe of the brachydactylies and is characterized by hypoplasia or absence of the terminal portions of the index to little fingers, usually with absence of the nails. The thumbs may be of normal length but are often flattened and occasionally are bifid. The feet are similarly but less severely affected. We have performed a genomewide linkage analysis of three families with BDB, two English and one Portugese. The two English families show linkage to the same region on chromosome 9 (combined multipoint maximum LOD score 8.69 with marker D9S257). The 16-cM disease interval is defined by recombinations with markers D9S1680 and D9S1786. These two families share an identical disease haplotype over 18 markers, inclusive of D9S278-D9S280. This provides strong evidence that the English families have the same ancestral mutation, which reduces the disease interval to <12.7 cM between markers D9S257 and D9S1851 in chromosome band 9q22. In the Portuguese family, we excluded linkage to this region, a result indicating that BDB is genetically heterogeneous. Reflecting this, there were atypical clinical features in this family, with shortening of the thumbs and absence or hypoplasia of the nails of the thumb and hallux. These results enable a refined classification of BDB and identify a novel locus for digit morphogenesis in 9q22.     

Genomewide Linkage Analysis of Stature in Multiple Populations Reveals Several Regions with Evidence of Linkage to Adult Height

Genomewide linkage analysis has been extremely successful at identification of the genetic variation underlying single-gene disorders. However, linkage analysis has been less successful for common human diseases and other complex traits in which multiple genetic and environmental factors interact to influence disease risk. We hypothesized that a highly heritable complex trait, in which the contribution of environmental factors was relatively limited, might be more amenable to linkage analysis. We therefore chose to study stature (adult height), for which heritability is approximately 75%-90% (Phillips and Matheny 1990; Carmichael and McGue 1995; Preece 1996; Silventoinen et al. 2000). We reanalyzed genomewide scans from four populations for which genotype and height data were available, using a variance-components method implemented in GENEHUNTER 2.0 (Pratt et al. 2000). The populations consisted of 408 individuals in 58 families from the Botnia region of Finland, 753 individuals in 183 families from other parts of Finland, 746 individuals in 179 families from Southern Sweden, and 420 individuals in 63 families from the Saguenay-Lac-St.-Jean region of Quebec. Four regions showed evidence of linkage to stature: 6q24-25, multipoint LOD score 3.85 at marker D6S1007 in Botnia (genomewide P<.06), 7q31.3-36 (LOD 3.40 at marker D7S2195 in Sweden, P<.02), 12p11.2-q14 (LOD 3.35 at markers D12S10990-D12S398 in Finland, P<.05) and 13q32-33 (LOD 3.56 at markers D13S779-D13S797 in Finland, P<.05). In a companion article (Perola et al. 2001 [in this issue]), strong supporting evidence is obtained for linkage to the region on chromosome 7. These studies suggest that highly heritable complex traits such as stature may be genetically tractable and provide insight into the genetic architecture of complex traits.     

A major locus for myoclonus-dystonia maps to chromosome 7q in eight families

Myoclonus-dystonia (M-D) is an autosomal dominant disorder characterized by myoclonic and dystonic muscle contractions that are often responsive to alcohol. The dopamine D2 receptor gene (DRD2) on chromosome 11q has been implicated in one family with this syndrome, and linkage to a 28-cM region on 7q has been reported in another. We performed genetic studies, using eight additional families with M-D, to assess these two loci. No evidence for linkage was found for 11q markers. However, all eight of these families showed linkage to chromosome 7 markers, with a combined multipoint LOD score of 11.71. Recombination events in the families define the disease gene within a 14-cM interval flanked by D7S2212 and D7S821. These data provide evidence for a major locus for M-D on chromosome 7q21.     

An autosomal recessive nonsyndromic-hearing-loss locus identified by DNA pooling using two inbred Bedouin kindreds.

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most common form of severe inherited childhood deafness. We present the linkage analysis of two inbred Bedouin kindreds from Israel that are affected with ARNSHL. A rapid genomewide screen for markers linked to the disease was performed by using pooled DNA samples. This screen revealed evidence for linkage with markers D9S922 and D9S301 on chromosome 9q. Genotyping of individuals from both kindreds confirmed linkage to chromosome 9q and a maximum combined LOD score of 26.2 (recombination fraction [theta] .025) with marker D9S927. The disease locus was mapped to a 1.6-cM region of chromosome 9ql3-q2l, between markers D9S15 and D9S927. The disease segregates with a common haplotype in the two kindreds, at markers D9S927, D9S175, and D9S284 in the linked interval, supporting the hypothesis that both kindreds inherited the deafness gene from a common ancestor. Although this nonsyndromic-hearing-loss (NSHL) locus maps to the same cytogenetic interval as DFNB7, it does not overlap the currently defined DFNB7 interval and may represent (1) a novel form of NSHL in close proximity to DFNB7 or (2) a relocalization of the DFNB7 interval to a region telomeric to its reported location. This study further demonstrates that DNA pooling is an effective means of quickly identifying regions of linkage in inbred families with heterogeneous autosomal recessive disorders.     

Mapping of facioscapulohumeral muscular dystrophy gene to chromosome 4q35-qter by multipoint linkage analysis and in situ hybridization

We have recently assigned the facioscapulohumeral muscular dystrophy (FSHD) gene to chromome 4 by linkage to the microsatellite marker Mfd 22 (locus D4S171). We now report that D4S139, a VNTR locus, is much more closely linked to FSHD. Two-point linkage analysis between FSHD and D4S139 in nine informative families showed a maximum combined lod score (Zmax) of 17.28 at a recombination fraction theta of 0.027. Multipoint linkage analysis between FSHD and the loci D4S139 and D4S171 resulted in a peak lod score of 20.21 at 2.7 cM from D4S139. Due to the small number of recombinants found with D4S139, the position of the FSHD gene relative to that of D4S139 could not be established with certainty. D4S139 was mapped to chromosome 4q35-qter by in situ hybridization, thus firmly establishing the location of the FSHD gene in the subtelomeric region of chromosome 4q. One small family yielded a negative lod score for D4S139. In the other families no significant evidence for genetic heterogeneity was obtained. Studies of additional markers and new families will improve the map of the FSHD region, reveal possible genetic heterogeneity, and allow better diagnostic reliability.     

Linkage analysis narrows the critical region for oculodentodigital dysplasia to chromosome 6q22-q23.

Oculodentodigital dysplasia (ODDD) is an autosomal dominant condition with high penetrance and variable expressivity. The anomalies of the craniofacial region, eyes, teeth, and limbs indicate abnormal morphogenesis during early fetal development. Neurologic abnormalities occur later in life and appear to be secondary to white matter degeneration and basal ganglia changes. In familial cases, the dysmorphic and/or neurodegenerative components of the phenotype can be more severe and/or present at a younger age in subsequent generations, suggesting genetic anticipation. These clinical features suggest that the ODDD gene is pleiotropic with important functions throughout pre- and postnatal development. We have performed two-point linkage analysis with seven ODDD families and 19 microsatellite markers on chromosome 6q spanning a genetic distance of approximately 11 cM in males and 20 cM in females. We have refined the location of the ODDD gene between DNA markers D6S266/D6S261 (centromeric) and D6S1639 (telomeric), an interval of 1.01 (male) to 2.87 (female) cM. The strongest linkage was to DNA marker D6S433 (Zmax = 8.96, thetamax = 0.001). Families show significant linkage to chromosome 6q22-q23 and no evidence for genetic heterogeneity.     

High-resolution physical mapping of four microsatellite repeat markers near the RYR1 locus on chromosome 19q13.1 and apparent exclusion of the MHS locus from this region in two malignant hyperthermia susceptible families.

Malignant hyperthermia susceptibility (MHS) is a potentially lethal, hereditary disorder of skeletal muscle that may be triggered by inhalation anesthetics and depolarizing muscle relaxants. Defects in the gene encoding the ryanodine receptor (RYR1) localized on human chromosome 19q13.1 have been proposed to be responsible for MHS. Using a chromosome 19-specific human/hamster somatic cell hybrid mapping panel, we were able to determine that four closely linked microsatellite repeat markers bracket RYR1 with the order 19cen-D19S75-D19S191-RYR1-(D19S47, D19S190)-19ter. Application of the four markers to genetic studies of MHS showed recombination between the markers and MHS in two families, with linkage analysis apparently excluding the MHS locus from the RYR1 region of 19q13.1. These results therefore support the recent observations of genetic heterogeneity in MHS.     

Genetic heterogeneity in families with hereditary multiple exostoses

We have carried out a linkage analysis on 11 families segregating gene(s) for hereditary multiple exostoses (EXT). Four highly informative, short tandem-repeat (STR) markers that have been physically mapped to an interval surrounding the Langer-Giedion chromosomal region (8q24.11-q24.13) were used in a multipoint linkage analysis. Significant evidence for linkage of EXT with genetic heterogeneity was found. A model of heterogeneity with linkage of the disease gene to the STR markers in 70% of the families (with a 95% confidence interval of 26%–96%) produced a maximum LOD score of 8.11, with the most likely position of EXT between D8S85 and D8S199. Thus there are at least two genes that are capable of causing hereditary multiple exostoses, one in the Langer-Giedion region and one at another, unlinked location.     

Osteoarthritis-susceptibility locus on chromosome 11q, detected by linkage.

We present a two-stage genomewide scan for osteoarthritis-susceptibility loci, using 481 families that each contain at least one affected sibling pair. The first stage, with 272 microsatellite markers and 297 families, involved a sparse map covering 23 chromosomes at intervals of approximately 15 cM. Sixteen markers that showed evidence of linkage at nominal P相似文献   

Mapping of facioscapulohumeral muscular dystrophy gene to chromosome 4q35-qter by multipoint linkage analysis and in situ hybridization

We have recently assigned the facioscapulohumeral muscular dystrophy (FSHD) gene to chromosome 4 by linkage to the microsatellite marker Mfd 22 (locus D4S171). We now report that D4S139, a VNTR locus, is much more closely linked to FSHD. Two-point linkage analysis between FSHD and D4S139 in nine informative families showed a maximum combined lod score (Z_max) of 17.28 at a recombination fraction θ of 0.027. Multipoint linkage analysis between FSHD and the loci D4S139 and D4S171 resulted in a peak lod score of 20.21 at 2.7 cM from D4S139. Due to the small number of recombinants found with D4S139, the position of the FSHD gene relative to that of D4S139 could not be established with certainty. D4S139 was mapped to chromosome 4q35-qter by in situ hybridization, thus firmly establishing the location of the FSHD gene in the subtelomeric region of chromosome 4q. One small family yielded a negative lod score for D4S139. In the other families no significant evidence for genetic heterogeneity was obtained. Studies of additional markers and new families will improve the map of the FSHD region, reveal possible genetic heterogeneity, and allow better diagnostic reliability.     

Regional mapping of facioscapulohumeral muscular dystrophy gene on 4q35: Combined analysis of an international consortium

Members of an international consortium for linkage analysis of the facioscapulohumeral muscular dystrophy (FSHD) gene have pooled data for joint analyses, in an attempt to determine the precise location of the FSHD gene and the order of four DNA markers on 4q35 region. Six laboratories determined a total of 3,078 genotypes in 65 families, consisting of a total of 504 affected subjects and 559 unaffected subjects. For each marker, a mean of 648 meioses were informative. D4S139 and D4S163 were identified as the closest linked markers to the FSHD locus, with 99% upper confidence intervals of recombination fractions of .08 and .10, respectively. We have used the CRI-MAP program to construct the most likely order of cen-D4S171-F11-D4S163-D4S139-FSHD-tel, with favorable odds of 10(8)-10(114) over all other orders except that in which F11 and D4S171 are reversed, for which the odds ratio was 191:1. With this order, the genetic map of this region extends 25.5 cM in males and 13.8 cM in females (averaging 19.5 cM for sexes combined); the sex difference was statistically significant (P = .0013). Comparison between families for the two-point and multipoint lod scores involving FSHD showed no evidence for heterogeneity of this disorder. However, after the completion of this analysis, one large family which might show heterogeneity was identified. In view of this and the fact that all of the linked markers reside on the same side of the FSHD locus, the clinical application of these markers is not recommended at this time.     

Sublocalization of an Ataxia-Telangiectasia Gene Distal to D11S384 by Ancestral Haplotyping In Costa Rican Families

In an effort to localize a gene for ataxia-telangiectasia (A-T), we have genotyped 27 affected Costa Rican families, with 13 markers, in the chromosome 11q22-23 region. Significant linkage disequilibrium was detected for 9/13 markers between D11S1816 and D11S1391. Recombination events observed in these pedigrees places A-T between D11S1819 and D11S1960. One ancestral haplotype is common to 24/54 affected chromosomes and roughly two-thirds of the families. Inferred (ancestral) recombination events involving this common haplotype in earlier generations suggest that A-T is distal to D11S384 and proximal to D11S1960. Several other common haplotypes were identified, consistent with multiple mutations in a single gene. When considered together with all other evidence, this study further sublocalizes the major A-T locus to ≈200 kb, between markers S384 and S535.     

Analysis of the prostate cancer-susceptibility locus HPC20 in 172 families affected by prostate cancer

A recent study of hereditary prostate cancer has provided evidence for a prostate cancer-susceptibility locus, HPC20, which maps to 20q13. To assess further the potential contribution of this locus to prostate cancer susceptibility, we studied 172 unrelated families affected by prostate cancer, using 17 polymorphic markers across a 98.5-cM segment of chromosome 20 that contains the candidate region. Parametric analysis, allowing for heterogeneity, resulted in an overall HLOD score of 0.09 (P=.39) at D20S171, under the assumption of linkage in 6% of families. Mode-of-inheritance-free analysis of the entire data set resulted in a maximal Zlr score of 0.76 (LOD 0.13; P=.22) at the same location. The strongest evidence for linkage was seen in the subset of 16 black families (LOD 0.86; Zlr=1.99; P=.023) between markers D20S893 and D20S120, near the putative location of HPC20. Although some positive results were observed, our linkage study does not provide statistically significant support for the existence of a prostate cancer-susceptibility locus HPC20 at 20q13.     

Genetic and physical map of the interferon region on chromosome 9p.

A region of chromosome 9, surrounding the interferon-beta (IFNB1) locus and the interferon-alpha (IFNA) gene cluster on 9p13-p22, has been shown to be frequently deleted or rearranged in a number of human cancers, including leukemia, glioma, non-small-cell lung carcinoma, and melanoma. To assist in better defining the precise region(s) of 9p implicated in each of these malignancies, a combined genetic and physical map of this region was generated using the available 9p markers IFNB1, IFNA, D9S3, and D9S19, along with a newly described locus, D9S126. The relative order and distances between these loci were determined by multipoint linkage analysis of CEPH (Centre d'Etude du Polymorphisme Humain) pedigree DNAs, pulsed-field gel electrophoresis, and fluorescence in situ hybridization. All three mapping approaches gave concordant results and, in the case of multipoint linkage analysis, the following gene order was supported for these and other closely linked chromosome 9 markers present in the CEPH database: pter-D9S33-IFNB1/IFNA-D9S126-D9S3-D9S19 -D9S9/D9S15-ASSP3-qter. This map serves to extend preexisting chromosome 9 maps (which focus primarily on 9q) and also reassigns D9S3 and D9S19 to more proximal locations on 9p.     

Genetic and physical mapping on chromosome 4 narrows the localization of the gene for facioscapulohumeral muscular dystrophy (FSHD).

We have used a combination of classical RFLPs and PCR-based polymorphisms including CA repeats and single-strand conformation polymorphisms to generate a fine-structure genetic map of the distal long arm of chromosome 4q. This map is now genetically linked to the pre-existing anchor map of 4pter-4q31 and generates, for the first time, a complete linkage map of this chromosome. The map consists of 32 anchor loci placed with odds of greater than 1,000:1. The high-resolution map in the cytogenetic region surrounding 4q35 provides the order 4cen-D4S171-F11-D4S187-D4S163-D4S139-4q ter. When we used somatic cell hybrids from a t(X;4)(p21;q35) translocation, these five markers fell into three groups consistent with the genetic map-D4S171 and F11 in 4pter-4q35, D4S163 and D4S139 in 4q35-4qter, and D4S187 as a junction fragment between these two regions. These markers are in tight linkage to the gene for facioscapulo-humeral muscular dystrophy (FSHD) mapped to this region by several collaborating investigators and provide a framework for further detailed analysis of this region.     

Fine localization of the Nijmegen breakage syndrome gene to 8q21: evidence for a common founder haplotype.

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, a birdlike face, growth retardation, immunodeficiency, lack of secondary sex characteristics in females, and increased incidence of lymphoid cancers. NBS cells display a phenotype similar to that of cells from ataxia-telangiectasia patients, including chromosomal instability, radiation sensitivity, and aberrant cell-cycle-checkpoint control following exposure to ionizing radiation. A recent study reported genetic linkage of NBS to human chromosome 8q21, with strong linkage disequilibrium detected at marker D8S1811 in eastern European NBS families. We collected a geographically diverse group of NBS families and tested them for linkage, using an expanded panel of markers at 8q21. In this article, we report linkage of NBS to 8q21 in 6/7 of these families, with a maximum LOD score of 3.58. Significant linkage disequilibrium was detected for 8/13 markers tested in the 8q21 region, including D8S1811. In order to further localize the gene for NBS, we generated a radiation-hybrid map of markers at 8q21 and constructed haplotypes based on this map. Examination of disease haplotypes segregating in 11 NBS pedigrees revealed recombination events that place the NBS gene between D8S1757 and D8S270. A common founder haplotype was present on 15/18 disease chromosomes from 9/11 NBS families. Inferred (ancestral) recombination events involving this common haplotype suggest that NBS can be localized further, to an interval flanked by markers D8S273 and D8S88.     

Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping.

Familial hemophagocytic lymphohistiocytosis (FHL), also known as familial erythrophagocytic lymphohistiocytosis and familial histiocytic reticulosis, is a rare autosomal recessive disorder of early childhood characterized by excessive immune activation. Linkage of the disease gene to an approximately 7.8-cM region between markers D9S1867 and D9S1790 at 9q21.3-22 was identified by homozygosity mapping in four inbred FHL families of Pakistani descent with a combined maximum multipoint LOD score of 6.05. This is the first genetic locus to be described in FHL. However, homozygosity by descent across this interval could not be demonstrated in an additional affected kindred of Arab origin, whose maximum multipoint LOD score was -0.12. The combined sample revealed significant evidence for linkage to 9q markers (LOD score with heterogeneity, 5.00). Identification of the gene(s) involved in the pathogenesis of FHL will contribute to an understanding of the control of T-lymphocyte and macrophage activation, which is central to homeostasis in the immune system.