Peutz-Jeghers Syndrome: Confirmation of Linkage to Chromosome 19p13.3 and Identification of a Potential Second Locus, on 19q13.4

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease with variable expression and incomplete penetrance, characterized by mucocutaneous pigmentation and hamartomatous polyposis. Patients with PJS have increased frequency of gastrointestinal and extraintestinal malignancies (ovaries, testes, and breast). In order to map the locus (or loci) associated with PJS, we performed a genomewide linkage analysis, using DNA polymorphisms in six families (two from Spain, two from India, one from the United States, and one from Portugal) comprising a total of 93 individuals, including 39 affected and 48 unaffected individuals and 6 individuals with unknown status. During this study, localization of a PJS gene to 19p13.3 (around marker D19S886) had been reported elsewhere. For our families, marker D19S886 yielded a maximum LOD score of 4.74 at a recombination fraction (theta) of .045; multipoint linkage analysis resulted in a LOD score of 7.51 for the interval between D19S886 and 19 pter. However, markers on 19q13.4 also showed significant evidence for linkage. For example, D19S880 resulted in a maximum LOD score of 3.8 at theta = .13. Most of this positive linkage was contributed by a single family, PJS07. These results confirm the mapping of a common PJS locus on 19p13.3 but also suggest the existence, in a minority of families, of a potential second PJS locus, on 19q13.4. Positional cloning and characterization of the PJS mutations will clarify the genetics of the syndrome and the implication of the gene(s) in the predisposition to neoplasias.     

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.     

A gene for autosomal recessive limb-girdle muscular dystrophy in Manitoba Hutterites maps to chromosome region 9q31-q33: evidence for another limb-girdle muscular dystrophy locus.

Characterized by proximal muscle weakness and wasting, limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of clinical disorders. Previous reports have documented either autosomal dominant or autosomal recessive modes of inheritance, with genetic linkage studies providing evidence for the existence of at least 12 distinct loci. Gene products have been identified for five genes responsible for autosomal recessive forms of the disorder. We performed a genome scan using pooled DNA from a large Hutterite kindred in which the affected members display a mild form of autosomal recessive LGMD. A total of 200 markers were used to screen pools of DNA from patients and their siblings. Linkage between the LGMD locus and D9S302 (maximum LOD score 5.99 at recombination fraction .03) was established. Since this marker resides within the chromosomal region known to harbor the gene causing Fukuyama congenital muscular dystrophy (FCMD), we expanded our investigations, to include additional markers in chromosome region 9q31-q34.1. Haplotype analysis revealed five recombinations that place the LGMD locus distal to the FCMD locus. The LGMD locus maps close to D9S934 (maximum multipoint LOD score 7.61) in a region that is estimated to be approximately 4.4 Mb (Genetic Location Database composite map). On the basis of an inferred ancestral recombination, the gene may lie in a 300-kb region between D9S302 and D9S934. Our results provide compelling evidence that yet another gene is involved in LGMD; we suggest that it be named "LGMD2H."     

Localization of a gene for benign adult familial myoclonic epilepsy to chromosome 8q23.3-q24.1.

Benign adult familial myoclonic epilepsy is an autosomal dominant idiopathic epileptic syndrome characterized by adult-onset tremulous finger movement, myoclonus, epileptic seizures, and nonprogressive course. It was recently recognized in Japanese families. In this study, we report that the gene locus is assigned to the distal long arm of chromosome 8, by linkage analysis in a large Japanese kindred with a maximum two-point LOD score of 4.31 for D8S555 at recombination fraction of 0 (maximum multipoint LOD score of 5.42 for the interval between D8S555 and D8S1779). Analyses of recombinations place the locus within an 8-cM interval, between D8S1784 and D8S1694, in which three markers, D8S1830, D8S555, and D8S1779, show no recombination with the phenotypes. Although three other epilepsy-related loci on chromosome 8q have been recognized-one on chromosome 8q13-21 (familial febrile convulsion) and two others on chromosome 8q24 (KCNQ3 and childhood absence epilepsy)-the locus assigned here is distinct from these three epilepsy-related loci. This study establishes the presence of a new epilepsy-related locus on 8q23.3-q24.11.     

A new locus for autosomal dominant stargardt-like disease maps to chromosome 4

Stargardt disease (STGD) is the most common hereditary macular dystrophy and is characterized by decreased central vision, atrophy of the macula and underlying retinal-pigment epithelium, and frequent presence of prominent flecks in the posterior pole of the retina. STGD is most commonly inherited as an autosomal recessive trait, but many families have been described in which features of the disease are transmitted in an autosomal dominant manner. A recessive locus has been identified on chromosome 1p (STGD1), and dominant loci have been mapped to both chromosome 13q (STGD2) and chromosome 6q (STGD3). In this study, we describe a kindred with an autosomal dominant Stargardt-like phenotype. A genomewide search demonstrated linkage to a locus on chromosome 4p, with a maximum LOD score of 5.12 at a recombination fraction of.00, for marker D4S403. Analysis of extended haplotypes localized the disease gene to an approximately 12-cM interval between loci D4S1582 and D4S2397. Therefore, this kindred establishes a new dominant Stargardt-like locus, STGD4.     

Linkage of a gene for macular corneal dystrophy to chromosome 16.

Autosomal recessive macular corneal dystrophy (MCD) is a heterogeneous disorder leading to visual impairment. Sixteen American and Icelandic families (11 type I and 5 type II) were analyzed for linkage, by use of 208 polymorphic microsatellite markers. A significant maximum LOD score Zmax of 7.82 at a maximum recombination fraction (thetamax) of .06 was found with the 16q22 locus D16S518 for MCD type I. In addition, a peak LOD score of 2.50 at a recombination fraction of .00 was obtained for the MCD type II families, by use of the identical marker. These findings raise the possibility that MCD type II may be due to the same genetic locus that is involved in MCD type I.     

Mapping of a new locus for autosomal recessive demyelinating Charcot-Marie-Tooth disease to 19q13.1-13.3 in a large consanguineous Lebanese family: exclusion of MAG as a candidate gene

Autosomal recessive Charcot-Marie-Tooth disease (CMT) type 4 (CMT4) is a complex group of demyelinating hereditary motor and sensory neuropathies presenting genetic heterogeneity. Five different subtypes that correspond to six different chromosomal locations have been described. We hereby report a large inbred Lebanese family affected with autosomal recessive CMT4, in whom we have excluded linkage to the already-known loci. The results of a genomewide search demonstrated linkage to a locus on chromosome 19q13.1-13.3, over an 8.5-cM interval between markers D19S220 and D19S412. A maximum pairwise LOD score of 5.37 for marker D19S420, at recombination fraction [theta].00, and a multipoint LOD score of 10.3 for marker D19S881, at straight theta = .00, strongly supported linkage to this locus. Clinical features and the results of histopathologic studies confirm that the disease affecting this family constitutes a previously unknown demyelinating autosomal recessive CMT subtype known as "CMT4F." The myelin-associated glycoprotein (MAG) gene, located on 19q13.1 and specifically expressed in the CNS and the peripheral nervous system, was ruled out as being the gene responsible for this form of CMT.     

Homozygosity and linkage-disequilibrium mapping of the syndrome of congenital hypoparathyroidism, growth and mental retardation, and dysmorphism to a 1-cM interval on chromosome 1q42-43.

The syndrome of hypoparathyroidism associated with growth retardation, developmental delay, and dysmorphism (HRD) is a newly described, autosomal recessive, congenital disorder with severe, often fatal consequences. Since the syndrome is very rare, with all parents of affected individuals being consanguineous, it is presumed to be caused by homozygous inheritance of a single recessive mutation from a common ancestor. To localize the HRD gene, we performed a genomewide screen using DNA pooling and homozygosity mapping for apparently unlinked kindreds. Analysis of a panel of 359 highly polymorphic markers revealed linkage to D1S235. The maximum LOD score obtained was 4.11 at a recombination fraction of 0. Analysis of three additional markers-GGAA6F06, D1S2678, and D1S179-in a 2-cM interval around D1S235 resulted in LOD scores >3. Analysis of additional chromosome 1 markers revealed evidence of genetic linkage disequilibrium and place the HRD locus within an approximately 1-cM interval defined by D1S1540 and D1S2678 on chromosome 1q42-43.     

A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3.

Hereditary spastic paraplegia is a genetically and phenotypically heterogeneous disorder. Both pure and complicated forms have been described, with autosomal dominant, autosomal recessive, and X-linked inheritance. Various loci (SPG1-SPG6) associated with this disorder have been mapped. Here, we report linkage analysis of a large consanguineous family affected with autosomal recessive spastic paraplegia with age at onset of 25-42 years. Linkage analysis of this family excluded all previously described spastic paraplegia loci. A genomewide linkage analysis showed evidence of linkage to chromosome 16q24.3, with markers D16S413 (maximum LOD score 3.37 at recombination fraction [theta] of .00) and D16S303 (maximum LOD score 3.74 at straight theta=.00). Multipoint analysis localized the disease gene in the most telomeric region, with a LOD score of 4.2. These data indicate the presence of a new locus linked to pure recessive spastic paraplegia, on chromosome 16q24.3, within a candidate region of 6 cM.     

Dominant intermediate Charcot-Marie-Tooth neuropathy maps to chromosome 19p12-p13.2

The hereditary disorders of peripheral nerve form one of the most common groups of human genetic diseases, collectively called Charcot-Marie-Tooth (CMT) neuropathy. Using linkage analysis we have identified a new locus for a form of CMT that we have called "dominant intermediate CMT" (DI-CMT). A genomewide screen using 383 microsatellite markers showed strong linkage to the short arm of chromosome 19 (maximum LOD score 4.3, with a recombination fraction (straight theta) of 0, at D19S221 and maximum LOD score 5.28, straight theta=0, at D19S226). Haplotype analysis performed with 14 additional markers placed the DI-CMT locus within a 16.8-cM region flanked by the markers D19S586 and D19S546. Multipoint linkage analysis suggested the most likely location at D19S226 (maximum multipoint LOD score 6.77), within a 10-cM confidence interval. This study establishes the presence of a locus for DI-CMT on chromosome 19p12-p13.2.     

Localization of the Gene for Thiamine-Responsive Megaloblastic Anemia Syndrome, on the Long Arm of Chromosome 1, by Homozygosity Mapping

Thiamine-responsive megaloblastic anemia, also known as "TRMA" or "Rogers syndrome," is an early-onset autosomal recessive disorder defined by the occurrence of megaloblastic anemia, diabetes mellitus, and sensorineural deafness, responding in varying degrees to thiamine treatment. On the basis of a linkage analysis of affected families of Alaskan and of Italian origin, we found, using homozygosity mapping, that the TRMA-syndrome gene maps to a region on chromosome 1q23.2-23.3 (maximum LOD score of 3.7 for D1S1679). By use of additional consanguineous kindreds of Israeli-Arab origin, the putative disease-gene interval also has been confirmed and narrowed, suggesting genetic homogeneity. Linkage analysis generated the highest combined LOD-score value, 8.1 at a recombination fraction of 0, with marker D1S2799. Haplotype analysis and recombination events narrowed the TRMA locus to a 16-cM region between markers D1S194 and D1S2786. Several heterozygote parents had diabetes mellitus, deafness, or megaloblastic anemia, which raised the possibility that mutations at this locus predispose carriers in general to these manifestations. Characterization of the metabolic defect of TRMA may shed light on the role of thiamine deficiency in such common diseases.     

Localization of the fourth locus (GLC1E) for adult-onset primary open-angle glaucoma to the 10p15-p14 region.

One of the major causes of blindness is primary open-angle glaucoma, which affects millions of elderly people worldwide. Genetic studies have so far mapped three loci for the adult-onset form of this condition to the 2cen-q13, 3q21-q24, and 8q23 regions. Herein, we report the localization of a fourth locus, to the 10p15-p14 region, in one large British family with a classical form of normal-tension open-angle glaucoma. Of the 42 meioses genotyped in this pedigree, 39 subjects (16 affected) inherited a haplotype compatible with their prior clinical designation, whereas the remaining 3 were classified as unknown. Although a maximum LOD score of 10.00 at a recombination fraction of straight theta=.00 was obtained with D10S1216, 21 other markers provided significant values, varying between 3.77 and 9.70. When only the affected meioses of this kindred were analyzed, LOD scores remained statistically significant, ranging from 3.16 (D10S527) to 3.57 (D10S506). Two critical recombinational events in the affected subjects positioned this new locus to a region of approximately 21 cM, flanked by D10S1729 and D10S1664. However, an additional recombination in a 59-year-old unaffected female suggests that this locus resides between D10S585 (or D10S1172) and D10S1664, within a genetic distance of 5-11 cM. However, the latter minimum region must be taken cautiously, because the incomplete penetrance has previously been documented for this group of eye conditions. A partial list of genes that positionally are considered as candidates includes NET1, PRKCT, ITIH2, IL2RA, IL15RA, IT1H2, hGATA3, the mRNA for open reading frame KIAA0019, and the gene for D123 protein.     

A new locus for generalized epilepsy with febrile seizures plus maps to chromosome 2

Generalized epilepsy with febrile seizures plus (GEFS+) is a recently recognized but relatively common form of inherited childhood-onset epilepsy with heterogeneous epilepsy phenotypes. We genotyped 41 family members, including 21 affected individuals, to localize the gene causing epilepsy in a large family segregating an autosomal dominant form of GEFS+. A genomewide search examining 197 markers identified linkage of GEFS+ to chromosome 2, on the basis of an initial positive LOD score for marker D2S294 (Z=4.4, recombination fraction [straight theta] = 0). A total of 24 markers were tested on chromosome 2q, to define the smallest candidate region for GEFS+. The highest two-point LOD score (Zmax=5.29; straight theta=0) was obtained with marker D2S324. Critical recombination events mapped the GEFS+ gene to a 29-cM region flanked by markers D2S156 and D2S311, with the idiopathic generalized epilepsy locus thereby assigned to chromosome 2q23-q31. The existence of the heterogeneous epilepsy phenotypes in this kindred suggests that seizure predisposition determined by the GEFS+ gene on chromosome 2q could be modified by other genes and/or by environmental factors, to produce the different seizure types observed.     

Novel locus for autosomal dominant hereditary spastic paraplegia, on chromosome 8q.

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of disorders characterized by insidiously progressive spastic weakness in the legs. Genetic loci for autosomal dominant HSP exist on chromosomes 2p, 14q, and 15q. These loci are excluded in 45% of autosomal dominant HSP kindreds, indicating the presence of additional loci for autosomal dominant HSP. We analyzed a Caucasian kindred with autosomal dominant HSP and identified tight linkage between the disorder and microsatellite markers on chromosome 8q (maximum two-point LOD score 5.51 at recombination fraction 0). Our results clearly establish the existence of a locus for autosomal dominant HSP on chromosome 8q23-24. Currently this locus spans 6.2 cM between D8S1804 and D8S1774 and includes several potential candidate genes. Identifying this novel HSP locus on chromosome 8q23-24 will facilitate discovery of this HSP gene, improve genetic counseling for families with linkage to this locus, and extend our ability to correlate clinical features with different HSP loci.     

Autosomal dominant distal myopathy: linkage to chromosome 14.

We have studied a family segregating a form of autosomal dominant distal myopathy (MIM 160500) and containing nine living affected individuals. The myopathy in this family is closest in clinical phenotype to that first described by Gowers in 1902. A search for linkage was conducted using microsatellite, VNTR, and RFLP markers. In total, 92 markers on all 22 autosomes were run. Positive linkage was obtained with 14 of 15 markers tested on chromosome 14, with little indication of linkage elsewhere in the genome. Maximum two-point LOD scores of 2.60 at recombination fraction .00 were obtained for the markers MYH7 and D14S64--the family structure precludes a two-point LOD score > or = 3. Recombinations with D14S72 and D14S49 indicate that this distal myopathy locus, MPD1, should lie between these markers. A multipoint analysis assuming 100% penetrance and using the markers D14S72, D14S50, MYH7, D14S64, D14S54, and D14S49 gave a LOD score of exactly 3 at MYH7. Analysis at a penetrance of 80% gave a LOD score of 2.8 at this marker. This probable localization of a gene for distal myopathy, MPD1, on chromosome 14 should allow other investigators studying distal myopathy families to test this region for linkage in other types of the disease, to confirm linkage or to demonstrate the likely genetic heterogeneity.     

Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2

Birt-Hogg-Dubé syndrome (BHD), an inherited autosomal genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal neoplasia, lung cysts, and spontaneous pneumothorax. To identify the BHD locus, we recruited families with cutaneous lesions and associated phenotypic features of the BHD syndrome. We performed a genomewide scan in one large kindred with BHD and, by linkage analysis, localized the gene locus to the pericentromeric region of chromosome 17p, with a LOD score of 4.98 at D17S740 (recombination fraction 0). Two-point linkage analysis of eight additional families with BHD produced a maximum LOD score of 16.06 at D17S2196. Haplotype analysis identified critical recombinants and defined the minimal region of nonrecombination as being within a <4-cM distance between D17S1857 and D17S805. One additional family, which had histologically proved fibrofolliculomas, did not show evidence of linkage to chromosome 17p, suggesting genetic heterogeneity for BHD. The BHD locus lies within chromosomal band 17p11.2, a genomic region that, because of the presence of low-copy-number repeat elements, is unstable and that is associated with a number of diseases. Identification of the gene for BHD may reveal a new genetic locus responsible for renal neoplasia and for lung and hair-follicle developmental defects.     

Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q

Pyoderma gangrenosum, cystic acne, and aseptic arthritis are clinically distinct disorders within the broad class of inflammatory diseases. Although this triad of symptoms is rarely observed in a single patient, a three-generation kindred with autosomal-dominant transmission of these three disorders has been reported as "PAPA syndrome" (MIM 604416). We report mapping of a disease locus for familial pyoderma gangrenosum-acne-arthritis to the long arm of chromosome 15 (maximum two-point LOD score, 5.83; recombination fraction [straight theta] 0 at locus D15S206). Under the assumption of complete penetrance, haplotype analysis of recombination events defined a disease interval of 10 cM, between D15S1023 and D15S979. Successful identification of a single disease locus for this syndrome suggests that these clinically distinct disorders may share a genetic etiology. These data further indicate the role of genes outside the major histocompatibility locus in inflammatory disease.     

A gene for arthrogryposis multiplex congenita neuropathic type is linked to D5S394 on chromosome 5qter.

Arthrogryposis multiplex congenita (AMC) is a heterogeneous-symptom complex characterized by joint contractures at birth that involve more than one part of the body. We performed a genetic-linkage study of one large Israeli-Arab inbred kindred showing autosomal recessive inheritance of AMC neuropathic type that had been recently investigated by our group. After analysis of approximately 80% of the genome, D5S1456, which showed no increased homozygosity, showed increased genotype sharing in affected individuals. Linkage analysis in all family members revealed linkage between AMC and D5S1456 on chromosome 5qter (maximum LOD score 5.3 at recombination fraction .001). Analysis of additional markers in this region places the gene causing AMC in this family between D5S1456 and D5S498.