Maximum Two-point LOD Score Research Articles

Confirmation of linkage of hereditary partial lipodystrophy to chromosome 1q21‐22

Familial lipodystrophy is a genetically heterogeneous set of disorders characterized by a total or partial absence of subcutaneous fat, diabetes mellitus or impaired glucose tolerance, hyperlipidemia, and hypermetabolism [Senior and Gellis, 1964]. One subtype, familial partial lipodystrophy Dunnigan (FPLD), is a rare autosomal dominant trait that results in an gradual loss of subcutaneous fat in the lower trunk and limbs, Type V hyperlipoproteinemia, hypertriglyceridemia, and insulin-resistant diabetes. Previous reports of this condition have been limited to case reports or very small families. Recently, Peters et al. reported on linkage of five families of Western European descent to a 5.3 cM region on chromosome 1q21-22 between the flanking markers D1S305 and D1S1600 [Peters et al., 1998: Nat Genet 18:292–295]. We performed linkage and haplotype analysis using highly polymorphic, microsatellite markers on a large, multigeneration Caucasian kindred of German ancestry. The maximum two-point lod score achieved was 4.96 at θmax = 0 for marker D1S2721. Multipoint analysis gave an overall maximum lod score of 6.27 near marker D1S2721. The results of the haplotype analysis support the minimal candidate region as reported by Peters et al. Am. J. Med. Genet. 82:161–165, 1999. © 1999 Wiley-Liss, Inc.

Hereditary Isolated Renal Magnesium Loss Maps to Chromosome 11q23

Hypomagnesemia due to isolated renal magnesium loss has previously been demonstrated in two presumably unrelated Dutch families with autosomal dominant mode of inheritance. Patients with magnesium deficiency may suffer from tetany and convulsions, but the patients with hereditary renal magnesium wasting can also be clinically nonsymptomatic. In a genomewide linkage study, we first excluded a possible candidate region, on chromosome 9q, that encompasses the gene for intestinal hypomagnesemia with secondary hypocalcemia and, subsequently, found linkage to markers on chromosome 11q23. Detailed haplotype analyses identified a common haplotype segregating in both families, suggesting both their relationship through a common ancestor and the existence of a single, hypomagnesemia-causing mutation within them. The maximum two-point LOD score (Zmax) was found for marker D11S4127 (Zmax=6.41 at a recombination fraction of. 00), whereas a multipoint analysis gave a Zmax of 8.24 between markers D11S4142 and D11S4171. Key recombination events define a 5. 6-cM region between these two markers on chromosome 11q23. We conclude that this region encompasses a gene, involved in renal magnesium handling, that is mutated in our patients and is different from the gene involved in intestinal magnesium handling.

Stargardt disease: linkage to the ABCR gene region on 1p21-p22 in Scandinavian families.

Stargardt disease (STGD) or fundus flavimaculatus (FFM) is one of the most frequent causes of macular degeneration in childhood. The disease is inherited as an autosomal recessive trait and the corresponding gene has been localized to chromosome 1p21-22 and subsequently identified as the ATP-binding cassette transporter (ABCR) gene. To characterize Finnish and Swedish STGD families genetically, with special reference to chromosome region 1p21-22. We performed genetic linkage and haplotype analyses in five families of Finnish and Swedish origin with members affected by STGD or FFM. Evidence for linkage between STGD and the ABCR gene region on chromosome 1p was found with a maximum cumulative two-point lod score for marker D1S188 (Z=4.04, theta=0.001). The affected individuals of all families, including the offspring of a consanguineous family, were found heterozygous for haplotypes spanning the ABCR gene. The results support genetic homogeneity for a STGD/FFM gene defect on chromosome 1p21-22. A variety of haplotypes tightly linked to the ABCR gene region were found among affected individuals which indicate the presence of several independent STGD mutations in the Scandinavian population.

A New Graves Disease–Susceptibility Locus Maps To Chromosome 20q11.2

The autoimmune thyroid diseases (AITDs) include two related disorders, Graves disease (GD) and Hashimoto thyroiditis, in which perturbations of immune regulation result in an immune attack on the thyroid gland. The AITDs are multifactorial and develop in genetically susceptible individuals. However, the genes responsible for this susceptibility remain unknown. Recently, we initiated a whole-genome linkage study of patients with AITD, in order to identify their susceptibility genes. We studied a data set of 53 multiplex, multigenerational AITD families (323 individuals), using highly polymorphic and densely spaced microsatellite markers (intermarker distance <10 cM). Linkage analysis was performed by use of two-point and multipoint parametric methods (classic LOD-score analysis). While studying chromosome 20, we found a locus on chromosome 20q11.2 that was strongly linked to GD. A maximum two-point LOD score of 3.2 was obtained at marker D20S195, assuming a recessive mode of inheritance and a penetrance of.3. The maximum nonparametric LOD score was 2.4 (P=.00043); this score also was obtained at marker D20S195. Multipoint linkage analysis yielded a maximum LOD score of 3.5 for a 6-cM interval between markers D20S195 and D20S107. There was no evidence for heterogeneity in our sample. In our view, these results indicate strong evidence for linkage and suggest the presence of a major GD-susceptibility gene on chromosome 20q11.2.

The Gene for Human Fibronectin Glomerulopathy Maps to 1q32, in the Region of the Regulation of Complement Activation Gene Cluster

Fibronectin glomerulopathy (GFND) is a newly recognized autosomal dominant disease of the kidney that results in albuminuria, microscopic hematuria, hypertension, renal tubular acidosis type IV, and end-stage renal disease in the 2d to 6th decade of life. The disease is characterized histologically by massive deposits of fibronectin (Fn) present in the subendothelial spaces of renal glomerular capillaries. The cause of human GFND is unknown. In order to localize a candidate gene for GFND, we performed linkage analysis of a large, 193-member pedigree containing 13 affected individuals. Since we had previously excluded the genes for Fn and uteroglobin as candidate genes for GFND, a total-genome search for linkage was performed. Examination of 306 microsatellite markers resulted in a maximum two-point LOD score of 4.17 at a recombination fraction of. 00 for marker D1S249, and a maximum multipoint LOD score of 4.41 for neighboring marker D1S2782. By detection of recombination events, a critical genetic interval of 4.1 cM was identified, which was flanked by markers D1S2872 and D1S2891. These findings confirm that GFND is a distinct disease entity among the fibrillary glomerulopathies. Gene identification will provide insights into the molecular interactions of Fn in GFND, as well as in genetically unaltered conditions.

Autosomal dominant distal spinal muscular atrophy type V (dSMA-V) and Charcot-Marie-Tooth disease type 2D (CMT2D) segregate within a single large kindred and map to a refined region on chromosome 7p15.

Two separate disorders, autosomal dominant distal spinal muscular atrophy type V (dSMA-V) characterized by marked bilateral weakness in the hands and atrophy of thenar eminence and the first interosseous muscle, and Charcot-Marie-Tooth disease type 2D (CMT2D) characterized by sensory deficits in addition to the upper limb weakness and wasting, have been independently linked to chromosome 7p. We identified a multigenerational Mongolian kindred with 17 members affected with either dSMA-V or CMT2D and mapped both syndromes to the same region on chromosome 7p15. A maximum two-point lod score of 4.74 at recombination fraction zero was obtained with marker D7S474. Tight linkage without recombination was also detected with markers D7S526 and D7S632. A multipoint lod score of 6.07 suggested that the gene is located between markers D7S526 and D7S474. A single conserved haplotype was associated with dSMA-V and CMT2D. Based on informative recombination events, the disease locus was placed between markers D7S516 and D7S1514 within the 7p15 band. Data obtained from this study suggest that a single gene is responsible for both syndromes, dSMA-V and CMT2D, and extend our knowledge of the candidate region.

Genetic linkage of Meleda disease to chromosome 8qter.

Meleda disease (mal de Meleda) MIM *248300 is an autosomal recessive disorder, clinically characterised by transgressive palmoplantar keratoderma, hyperhidrosis and perioral erythema. It was first described on the Adriatic island of Meleda, where it was relatively common. The prevalence in the general population is estimated to be 1 in 100,000. Linkage analysis of two large consanguineous families from Algeria, including 10 affected individuals, showed strong evidence for localisation of Meleda disease to chromosome 8qter with a maximum two-point lod score for D8S1751 of 8.21 at theta = 0. Analysis of homozygosity regions and recombination events places the gene in a region of at least 3 cM, telomeric to D8S1727. A common haplotype was observed in the two families, suggesting a founder effect.

The Autosomal Recessive Kenny–Caffey Syndrome Locus Maps to Chromosome 1q42–q43

Kenny–Caffey syndrome (KCS) is an osteosclerotic bone dysplasia with associated hypocalcemia and ocular abnormalities. Both autosomal dominant (MIM127000) and autosomal recessive (MIM244460) inheritance patterns have been described. Using eight consanguineous Kuwaiti kindreds, a genome-wide search for linkage to the gene causing the autosomal recessive form of KCS was performed with polymorphic short tandem repeat markers. Significant linkage to a locus situated at chromosome 1q42 → q43 with a maximal two-point lod score of 13.30 with marker D1S2649 was obtained. Haplotype analysis of flanking markers identified recombination events defining the KCS locus to a region between markers D1S2800 on the centromeric boundary and D1S2850 on the telomeric boundary, an approximately 4-cM interval. All affected individuals in these unrelated kindreds were homozygous for identical alleles at markers D1S2649 and D1S235, suggesting a single ancestral mutation underlying the disease in these families. Haploinsufficiency at 22q11, reported in another consanguineous KCS kindred, was not documented in these families.

Support for a Chromosome 18p Locus Conferring Susceptibility to Functional Psychoses in Families with Schizophrenia, by Association and Linkage Analysis

The action of antipsychotic drugs on dopamine receptors suggests that dopaminergic signal transmission may play a role in the development of schizophrenia. We tested eight candidate genes (coding for dopamine receptors, the dopamine transporter, and G-proteins) in 59 families from Germany and Israel, for association. A P value of .00055 (.0044 when corrected for the no. of markers tested) was obtained for the intronic CA-repeat marker G-olfalpha on chromosome 18p. The value decreased to .000088 (.0007) when nine sibs with recurrent unipolar depressive disorder were included. Linkage analysis using SSLP markers densely spaced around G-olfalpha yielded a maximum two-point LOD score of 3.1 for a marker 0.5 cM distal to G-olfalpha. Multipoint analysis under the assumption of heterogeneity supported this linkage-whether the affected pheotype was defined narrowly or broadly-as did nonparametric linkage (NPL). In 12 families with exclusively maternal transmission of the disease, the NPL value also supported linkage to this marker. In order to test for association/linkage disequilibrium in the presence of linkage, the sample was restricted to independent offspring. When this sample was combined with 65 additional simplex families (each of them comprising one schizophrenic offspring and his or her parents), the 124-bp allele of G-olfalpha was transmitted 47 times and was not transmitted 21 times (P=.009). These results suggest the existence, on chromosome 18p, of a potential susceptibility locus for functional psychoses.

Evidence for a prostate cancer susceptibility locus on the X chromosome.

Over 200,000 new prostate cancer cases are diagnosed in the United States each year, accounting for more than 35% of all cancer cases affecting men, and resulting in 40,000 deaths annually. Attempts to characterize genes predisposing to prostate cancer have been hampered by a high phenocopy rate, the late age of onset of the disease and, in the absence of distinguishing clinical features, the inability to stratify patients into subgroups relative to suspected genetic locus heterogeneity. We previously performed a genome-wide search for hereditary prostate cancer (HPC) genes, finding evidence of a prostate cancer susceptibility locus on chromosome 1 (termed HPC1; ref. 2). Here we present evidence for the location of a second prostate cancer susceptibility gene, which by heterogeneity estimates accounts for approximately 16% of HPC cases. This HPC locus resides on the X chromosome (Xq27-28), a finding consistent with results of previous population-based studies suggesting an X-linked mode of HPC inheritance. Linkage to Xq27-28 was observed in a combined study population of 360 prostate cancer families collected at four independent sites in North America, Finland and Sweden. A maximum two-point lod score of 4.60 was observed at DXS1113, theta=0.26, in the combined data set. Parametric multipoint and non-parametric analyses provided results consistent with the two-point analysis. Significant evidence for genetic locus heterogeneity was observed, with similar estimates of the proportion of linked families in each separate family collection. Genetic mapping of the locus represents an important initial step in the identification of an X-linked gene implicated in the aetiology of HPC.

Genomewide Search for Dehydrated Hereditary Stomatocytosis (Hereditary Xerocytosis): Mapping of Locus to Chromosome 16 (16q23-qter)

Dehydrated hereditary stomatocytosis, also known as "hereditary xerocytosis," is caused by a red blood cell-membrane defect characterized by stomatocytic morphology, increased mean corpuscular hemoglobin concentration, decreased osmotic fragility, increased permeability to the univalent cations Na+ and K+, and an increased proportion of phosphatidylcholine in the membrane. The clinical presentation is heterogeneous, ranging from mild to moderate hemolytic anemia associated with scleral icterus, splenomegaly, and choletithiasis. Iron overload may develop later in life. The disease is transmitted as an autosomal dominant trait. We recruited a large three-generation Irish family affected with DHS and comprising 23 members, of whom 14 were affected and 9 were healthy. Two additional, small families also were included in the study. The DNA samples from the family members were used in a genomewide search to identify, by linkage analysis, the DHS locus. After the exclusion of a portion of the human genome, we obtained conclusive evidence for linkage of DHS to microsatellite markers on the long arm of chromosome 16 (16q23-q24). A maximum two-point LOD score of 6.62 at recombination fraction .00 was obtained with marker D16S520. There are no recombination events defining the telomeric limit of the region, which therefore is quite large. No candidate genes map to this area.

Mitochondrial Neurogastrointestinal Encephalomyopathy Syndrome Maps to Chromosome 22q13.32-qter

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is a rare, multisystem disorder characterized clinically by ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility, leukoencephalopathy, thin body habitus, and myopathy. Laboratory studies reveal defects of oxidative-phosphorylation and multiple mtDNA deletions frequently in skeletal muscle. We studied four ethnically distinct families affected with this apparently autosomal recessive disorder. Probands from each family were shown, by Southern blot, to have multiple mtDNA deletions in skeletal muscle. We mapped the MNGIE locus to 22q13.32-qter, distal to D22S1161, with a maximum two-point LOD score of 6.80 at locus D22S526. Cosegregation of MNGIE with a single chromosomal region in families with diverse ethnic backgrounds suggests that we have mapped an important locus for this disorder. We found no evidence to implicate three candidate genes in this region, by using direct sequence analysis for DNA helicase II and by assaying enzyme activities for arylsulfatase A and carnitine palmitoyltransferase.

Predisposing Gene for Early-Onset Prostate Cancer, Localized on Chromosome 1q42.2-43

There is genetic predisposition associated with >=10% of all cancer of the prostate (CaP). By means of a genomewide search on a selection of 47 French and German families, parametric and nonparametric linkage (NPL) analysis allowed identification of a locus, on chromosome 1q42.2-43, carrying a putative predisposing gene for CaP (PCaP). The primary localization was confirmed with several markers, by use of three different genetic models. We obtained a maximum two-point LOD score of 2.7 with marker D1S2785. Multipoint parametric and NPL analysis yielded maximum HLOD and NPL scores of 2.2 and 3.1, respectively, with an associated P value of . 001. Homogeneity analysis with multipoint LOD scores gave an estimate of the proportion of families with linkage to this locus of 50%, with a likelihood ratio of 157/1 in favor of heterogeneity. Furthermore, the 9/47 families with early-onset CaP at age <60 years gave multipoint LOD and NPL scores of 3.31 and 3.32, respectively, with P = .001.

The Bjornstad Syndrome (Sensorineural Hearing Loss and Pili Torti) Disease Gene Maps to Chromosome 2q34-36

We report that the Bjornstad syndrome gene maps to chromosome 2q34-36. The clinical association of sensorineural hearing loss with pili torti (broken, twisted hairs) was described >30 years ago by Bjornstad; subsequently, several small families have been studied. We evaluated a large kindred with Bjornstad syndrome in which eight members inherited pili torti and prelingual sensorineural hearing loss as autosomal recessive traits. A genomewide search using polymorphic loci demonstrated linkage between the disease gene segregating in this kindred and D2S434 (maximum two-point LOD score = 4.98 at theta = 0). Haplotype analysis of recombination events located the disease gene in a 3-cM region between loci D2S1371 and D2S163. We speculate that intermediate filament and intermediate filament-associated proteins are good candidate genes for causing Bjornstad syndrome.

Autozygosity Mapping, to Chromosome 11q25, of a Rare Autosomal Recessive Syndrome Causing Histiocytosis, Joint Contractures, and Sensorineural Deafness

We describe a highly consanguineous family, originating from Pakistan, displaying histiocytosis, joint contractures, and sensorineural deafness. The form of histiocytosis exhibited by this family does not fit readily into any of the recognized classes of this disease. It appears to represent a novel form of familial histiocytosis demonstrating autosomal recessive inheritance. Using autozygosity mapping, we have identified a homozygous region of approximately 1 cM at chromosome 11q25, in affected individuals. A maximum two-point LOD score of 3.42 (recombination fraction straight theta = .00) was obtained with marker D11S968. This is the first genetic locus to be described that is involved in the molecular pathogenesis of histiocytosis.

A Locus for Autosomal Recessive Congenital Microphthalmia Maps to Chromosome 14q32

Congenital microphthalmia (CMIC) (OMIM 309700) may occur in isolation or in association with a variety of systemic malformations. Isolated CMIC may be inherited as an autosomal dominant, an autosomal recessive, or an X-linked trait. On the basis of a whole-genome linkage analysis, we have mapped the first locus for isolated CMIC, in a five-generation consanguineous family with autosomal recessive inheritance, to chromosome 14q32. All affected individuals in this family have bilateral CMIC. Linkage analysis gave a maximum two-point LOD score of 3.55 for the marker D14S65. Surrounding this marker is a region of homozygosity of 7.3 cM, between the markers D14S987 and D14S267, within which the disease gene is predicted to lie. The genes for several eye-specific transcription factors are located on human chromosome 14q and in the syntenic region of mouse chromosome 12. However, both CHX10 (14q24.3), mutations of which give rise to CMIC in mouse models, and OTX2 (14q21-22) can be excluded as candidates for autosomal recessive congenital microphthalmia (arCMIC), since they map outside the critical disease region defined by recombination events. This suggests that arCMIC is caused by defects in a novel developmental gene that may be important or even essential in eye development.

A Susceptibility Locus for Bipolar Affective Disorder on Chromosome 4q35

Bipolar affective disorder (BAD) affects approximately 1% of the population and shows strong heritability. To identify potential BAD susceptibility loci, we undertook a 15-cM genome screen, using 214 microsatellite markers on the 35 most informative individuals of a large, statistically powerful pedigree. Data were analyzed by parametric two-point linkage methods under several diagnostic models. LOD scores >1.00 were obtained for 21 markers, with four of these >2.00 for at least one model. The remaining 52 individuals in the family were genotyped with these four markers, and LOD scores remained positive for three markers. A more intensive screen was undertaken in these regions, with the most positive results being obtained for chromosome 4q35. Using a dominant model of inheritance with 90% maximum age-specific penetrance and including bipolar I, II, schizoaffective/mania, and unipolar individuals as affected, we obtained a maximum two-point LOD score of 2.20 (theta = .15) at D4S1652 and a maximum three-point LOD score of 3.19 between D4S408 and D4S2924. Nonparametric analyses further supported the presence of a locus on chromosome 4q35. A maximum score of 2.62 (P=.01) was obtained between D4S1652 and D4S171 by use of the GENEHUNTER program, and a maximum score of 3.57 (P=.0002) was obtained at D4S2924 using the affected pedigree member method. Analysis of a further 10 pedigrees suggests the presence of this locus in at least one additional family, indicating a possible predisposing locus and not a pedigree-specific mutation. Our results suggest the presence of a novel BAD susceptibility locus on chromosome 4q35.

Gene Localization for an Autosomal Dominant Familial Periodic Fever to 12p13

We report gene localization in a family with a benign autosomal dominant familial periodic fever (FPF) syndrome characterized by recurrent fever associated with abdominal pain. The clinical features are similar to the disorder previously described as familial Hibernian fever, and they differ from familial Mediterranean fever (FMF) in that FPF episodes usually do not respond to colchicine and FPF is not associated with amyloidosis. Frequent recombination with the marker D16S2622, <1 Mb from FMF, at 16p13.3, excluded allelism between these clinically similar conditions. Subsequently, a semiautomated genome search detected linkage of FMF to a cluster of markers at 12p13, with a multipoint LOD score of 6.14 at D12S356. If penetrance of 90% is assumed, the FPF gene maps to a 19-cM interval between D12S314 and D12S364; however, if complete penetrance is assumed, then FPF maps to a 9-cM region between D12S314 and D12S1695. This interval includes the dentatorubropallidoluysian atrophy locus, which, with FPF, gave a maximum two-point LOD score of 3.7 at a recombination fraction of 0. This is the first of the periodic-fever genes, other than FMF, to be mapped. Positional candidate genes may now be selected for mutation analysis to determine the molecular basis for FPF. Together with the recent identification of the defective gene in FMF, identification of a gene for FPF might provide new insights into the regulation of inflammatory responses.

Chromosomal localization of two genes underlying late-infantile neuronal ceroid lipofuscinosis.

Classical late-infantile neuronal ceroid lipofuscinosis (LINCL; CLN2) is an inherited neurodegenerative disorder of childhood characterized by seizures, loss of vision, and progressive motor and mental deterioration. The hallmark of this disease is the accumulation of enlarged, secondary lysosomes packed with curvilinear bodies in cells of affected individuals. The biochemical basis of LINCL remains unknown and there is no treatment effective in delaying the progression of this fatal disorder. During a genome-wide search using a set of highly polymorphic markers and 15 affected individuals from 7 multi-affected families, we obtained evidence for linkage of the LINCL gene CLN2 with markers on chromosome 11p15.5. We then genotyped patients and all available family members, including 8 single-affected families, for markers spanning 15 cM of 11p15.5. We obtained a maximum two-point LOD score of 6.16 at 0 = 0.00 at the marker locus D11S2362. Multipoint analysis yielded a maximum LOD score of 6.90 localized to the same marker. Using haplotype analysis, we localized CLN2 to a minimum candidate region of 11 cM flanked by marker loci D11S4046 on the telomeric side and D11S1996 on the centromeric side. Additionally, we present data suggesting that the gene underlying a variant LINCL subtype found in Costa Rica maps to the region defined by the CLN6 locus on chromosome 15q21-23. The mapping of these two LINCL loci provides a genetic basis for understanding the clinical heterogeneity observed in this group of diseases.

Localization of the gene for familial partial lipodystrophy (Dunnigan variety) to chromosome 1q21-22.

Obesity is strongly implicated in the pathophysiology of insulin resistance, diabetes mellitus and dyslipidemia. The mechanisms, however, by which obesity causes these complications are not known. The study of single-gene disorders affecting adipose tissue may elucidate some of the mechanisms involved in these processes. Familial partial lipodystrophy, Dunnigan variety, (FPLD, OMIM 308980) is an autosomal-dominant condition characterized by marked loss of subcutaneous adipose tissue affecting the trunk and extremities but with excess fat deposition in the head and neck areas. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus, dyslipidemia and acanthosis nigricans. The genetic basis of FPLD is unknown. We carried out a genome-wide scan with a set of highly polymorphic short tandem-repeats (STR) in individuals from five well-characterized pedigrees and mapped the FPLD locus to chromosome 1q21-22. The maximum two-point lod score obtained with a highly polymorphic microsatellite at D1S2624 at theta(max)=0 was 5.84. Multipoint-linkage analysis yielded a peak lod score of 8.25 between D1S305 and D1S1600. There was no evidence for genetic heterogeneity (alpha=1) in the pedigrees.