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.     

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.     

A new locus for autosomal dominant dilated cardiomyopathy identified on chromosome 6q12-q16

Dilated cardiomyopathy (DCM) is a heart-muscle disease characterized by ventricular dilatation and impaired heart contraction and is heterogeneous both clinically and genetically. To date, 12 candidate disease loci have been described for autosomal dominant DCM. We report the identification of a new locus on chromosome 6q12-16 in a French family with 9 individuals affected by the pure form of autosomal dominant DCM. This locus was found by using a genomewide search after exclusion of all reported disease loci and genes for DCM. The maximum pairwise LOD score was 3.52 at recombination fraction 0.0 for markers D6S1644 and D6S1694. Haplotype construction delineated a region of 16.4 cM between markers D6S1627 and D6S1716. This locus does not overlap with two other disease loci that have been described in nonpure forms of DCM and have been mapped on 6q23-24 and 6q23. The phospholamban, malic enzyme 1-soluble, and laminin-alpha4 genes were excluded as candidate genes, using single-strand conformation polymorphism or linkage analysis.     

A new locus for autosomal dominant pure spastic paraplegia, on chromosome 2q24-q34

Hereditary spastic paraplegia (HSP) comprises a group of clinically and genetically heterogeneous disorders causing progressive spasticity and weakness of the lower limbs. We report a large family of French descent with autosomal dominant pure HSP. We excluded genetic linkage to the known loci causing HSP and performed a genomewide search. We found evidence for linkage of the disorder to polymorphic markers on chromosome 2q24-q34: a maximum LOD score of 3. 03 was obtained for marker D2S2318. By comparison with families having linkage to the major locus of pure autosomal dominant HSP (SPG4 on chromosome 2p), there were significantly more patients without Babinski signs, with increased reflexes in the upper limbs, and with severe functional handicaps.     

A new susceptibility locus for autosomal dominant pancreatic cancer maps to chromosome 4q32-34

Pancreatic cancer is the fifth leading cause of cancer death in the United States. Nearly every person diagnosed with pancreatic cancer will die from it, usually in <6 mo. Familial clustering of pancreatic cancers is commonly recognized, with an autosomal dominant inheritance pattern in approximately 10% of all cases. However, the late age at disease onset and rapid demise of affected individuals markedly hamper collection of biological samples. We report a genetic linkage scan of family X with an autosomal dominant pancreatic cancer with early onset and high penetrance. For the study of this family, we have developed an endoscopic surveillance program that allows the early detection of cancer and its precursor, before family members have died of the disease. In a genomewide screening of 373 microsatellite markers, we found significant linkage (maximum LOD score 4.56 in two-point analysis and 5.36 in three-point analysis) on chromosome 4q32-34, providing evidence for a major locus for pancreatic cancer.     

Mapping of locus for autosomal dominant retinitis pigmentosa on chromosome 6q23

Retinitis pigmentosa (RP) is a genetically heterogeneous group of retinal degenerative disorders resulting in severe visual loss and blindness that have remained incurable till date. We report the mapping of the disease locus in a 3-generation family of Indian origin with autosomal dominant RP (ADRP). Diagnosis of RP and recruitment was made after a complete clinical evaluation of all members. Manifestations of the disease included night blindness with blurred central vision in some cases, loss of peripheral vision, and diffuse degeneration of the retinal pigment epithelium. Linkage analysis using microsatellite markers was carried out on 34 members (14 affected). After testing for linkage to known retinal dystrophy loci as well as a subsequent genome-wide analysis, we detected linkage to markers on chromosome 6q23: D6S262 at 130 cM, D6S457 (130 cM) and D6S1656 (131 cM) gave significant 2-point LOD scores of 3.0–3.8. Multipoint LOD scores of ≥3.0 were obtained for markers between 121 and 130 cM. Haplotype analysis with several markers in the same region on chromosome 6 shows a disease-cosegregating region of about 25 Mb between 109 and 135 Mb. There are no known RP genes in this interval, which contains >100 genes. This study provides evidence for a novel ADRP locus on chromosome 6q23.     

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.     

A locus for autosomal dominant colobomatous microphthalmia maps to chromosome 15q12-q15

Congenital microphthalmia is a common developmental ocular disorder characterized by shortened axial length. Isolated microphthalmia is clinically and genetically heterogeneous and may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Here, we studied a five-generation family of Sephardic Jewish origin that included 38 members, of whom 7 have either unilateral or bilateral microphthalmia of variable severity inherited as an autosomal dominant trait with incomplete penetrance. After exclusion of several candidate loci, we performed a genome-scan study and demonstrated linkage to chromosome 15q12-q15. Positive LOD scores were obtained with a maximum at the D15S1007 locus (maximum LOD score 3.77, at recombination fraction 0.00). Haplotype analyses supported the location of the disease-causing gene in a 13.8-cM interval between loci D15S1002 and D15S1040.     

A locus for autosomal dominant "pure" hereditary spastic paraplegia maps to chromosome 19q13

Genetic loci for autosomal dominant pure hereditary spastic paraplegia (ADPHSP) have been mapped to chromosomes 2p, 8q, 12q, 14q, and 15q. We undertook a genomewide linkage screen of a large family with ADPHSP, for which linkage at all previously identified ADPHSP loci was excluded. Analysis of markers on chromosome 19q gave a peak pairwise LOD score of 3.72 at D19S420, allowing assignment of a novel ADPHSP locus (which we have termed "SPG12") to this region. Haplotype construction and analysis of recombination events narrowed the SPG12 locus to a 16.1-cM region between markers D19S868 and D19S902.     

A locus for an autosomal dominant form of progressive renal failure and hypertension at chromosome 1q21

Linkage studies were performed in a large family with an autosomal dominant phenotype characterized by nephropathy and hypertension. In this family of Iraqi Jewish origin, the nephropathy develops into progressive renal failure. By performing a genomewide linkage search, we localized the disease gene to chromosome 1q21; the highest LOD score was obtained for the marker at locus D1S305, which yielded a maximum LOD score of 4.71 at a recombination fraction of 0. Recombination mapping defined an interval of approximately 11.6 cM, between the markers at loci D1S2696 and D1S2635, that contains the disease gene. Localization of the disease-causing gene in this family represents a necessary step toward isolation of the defective gene and toward a deeper understanding of the mechanisms of hypertension and progressive renal failure.     

A locus for autosomal dominant reflex epilepsy precipitated by hot water maps at chromosome 10q21.3-q22.3

Hot water epilepsy (HWE) is a form of reflex or sensory epilepsy wherein seizures are precipitated by an unusual stimulus, the contact of hot water over the head and body. Genome-wide linkage analysis of a large family with ten affected members, provided evidence of linkage (Z _max = 3.17 at θ = 0 for D10S412) to chromosome 10q21. Analysis of five additional HWE families, for markers on chromosome 10, further strengthened the evidence of linkage to the same chromosomal region with three out of five families showing concordance for the disease haplotype and providing a two-point LOD score of 4.86 at θ = 0 and 60% penetrance for D10S412. The centromere-proximal and -distal boundaries of the critical genetic interval of about 15 Mb at 10q21.3-q22.3 were defined by D10S581 and D10S201, respectively. Sequence analysis of a group of functional candidate genes, the ion channels KCNMA1, VDAC2 and solute carriers SLC25A16, SLC29A3 revealed no potentially pathogenic mutation. We propose to carry out further analysis of positional candidate genes from this region to identify the gene responsible for this unusual neurobehavioral phenotype.     

Identification of a new autosomal dominant limb-girdle muscular dystrophy locus on chromosome 7.

We report the identification of a new locus for autosomal dominant limb-girdle muscular dystrophy (LGMD1) on 7q. Two of five families (1047 and 1701) demonstrate evidence in favor of linkage to this region. The maximum two-point LOD score for family 1047 was 3.76 for D7S427, and that for family 1701 was 2.63 for D7S3058. Flanking markers place the LGMD1 locus between D7S2423 and D7S427, with multipoint analysis slightly favoring the 9-cM interval spanned by D7S2546 and D7S2423. Three of five families appear to be unlinked to this new locus on chromosome 7, thus establishing further heterogeneity within the LGMD1 diagnostic classification.     

A new locus (RP31) for autosomal dominant retinitis pigmentosa maps to chromosome 9p

Retinitis pigmentosa (RP) is a debilitating disease of the retina affecting ∼1.5 million people worldwide. RP shows remarkable heterogeneity both clinically and genetically, with more than 40 genetic loci implicated, 12 of which account for the autosomal dominant form (adRP) of inheritance. We have recently identified a French Canadian family that presents with early onset adRP. After exclusion of all known loci for adRP, a genome-wide search established firm linkage with a marker from the short arm of chromosome 9 (LOD score of 6.3 at recombination fraction θ=0). The linked region is flanked by markers D9S285 and D9S1874, corresponding to a genetic distance of 31 cM, in the region 9p22-p13.     

A new locus for autosomal dominant familial exudative vitreoretinopathy maps to chromosome 11p12-13

We report a new locus for familial exudative vitreoretinopathy (FEVR), on chromosome 11p12-13 in a large autosomal dominant pedigree. Statistically significant linkage was achieved across a 14-cM interval flanked by markers GATA34E08 and D11S4102, with a maximum multipoint LOD score of 6.6 at D11S2010. FEVR is a disease characterized by the failure of development of peripheral retinal blood vessels, and it is difficult to diagnose clinically because of the wide spectrum of fundus abnormalities associated with it. The identification of a new locus is important for genetic counseling and potentiates further studies aimed toward the identification of a gene with an important role in angiogenesis within neuroepithelial tissues. Such a gene may also have a role in the genetic predisposition to retinopathy of prematurity, a sporadic disorder with many clinical similarities to FEVR.     

Genetic and physical mapping of the locus for autosomal dominant renal Fanconi syndrome, on chromosome 15q15.3

Autosomal dominant renal Fanconi syndrome is a genetic model for the study of proximal renal tubular transport pathology. We were able to map the locus for this disease to human chromosome 15q15.3 by genotyping a central Wisconsin pedigree with 10 affected individuals. After a whole-genome scan with highly polymorphic simple sequence repeat markers, a maximum LOD score of 3.01 was calculated for marker D15S659 on chromosome 15q15.3. Linkage and haplotype analysis for an additional 24 markers flanking D15S659 narrowed the interval to approximately 3 cM, with the two highest single-point LOD scores observed being 4.44 and 4.68 (for D15S182 and D15S537, respectively). Subsequently, a complete bacterial artificial chromosome contig was constructed, from the High Throughput Genomic Sequence Database, for the region bounded by D15S182 and D15S143. The identification of the gene and gene product altered in autosomal dominant renal Fanconi syndrome will allow the study of the physiology of proximal renal tubular transport.     

A new locus on chromosome 12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant form of hypertension

Pseudohypoaldosteronism type II (PHA2) is a rare autosomal dominant form of volume-dependent low-renin hypertension characterized by hyperkalemia and hyperchloremic acidosis but also by a normal glomerular filtration rate. These features, together with the correction of blood pressure and metabolic abnormalities by small doses of thiazide diuretics, suggest a primary renal tubular defect. Two loci have previously been mapped at low resolution to chromosome 1q31-42 (PHA2A) and 17p11-q21 (PHA2B). We have now analyzed a new, large French pedigree, in which 12 affected members over three generations confirmed the autosomal dominant inheritance. Affected subjects had hypertension together with long-term hyperkalemia (range 5.2-6.2 mmol/liter), hyperchloremia (range: 100-109 mmol/liter), normal plasma creatinine (range: 63-129 mmol/liter) and low renin levels. Genetic linkage was excluded for both PHA2A and PHA2B loci (all LOD scores Z<-3.2 at recombination fraction [theta] 0), as well as for the thiazide-sensitive sodium-chloride cotransporter gene. A genome-wide scan using 383 microsatellite markers showed a strong linkage with the chromosome 12p13 region (maximum LOD score Z=6.18, straight theta=0, at D12S99). Haplotype analysis using 10 additional polymorphic markers led to a minimum 13-cM interval flanked by D12S1652 and D12S336, thus defining a new PHA2C locus. Analysis of two obvious candidate genes (SCNN1A and GNb3) located within the interval showed no deleterious mutation. In conclusion, we hereby demonstrate further genetic heterogeneity of this Mendelian form of hypertension and identify a new PHA2C locus, the most compelling and precise linkage interval described to date.     

A gene for fluctuating, progressive autosomal dominant nonsyndromic hearing loss, DFNA16, maps to chromosome 2q23-24.3.

The sixteenth gene to cause autosomal dominant nonsyndromic hearing loss (ADNSHL), DFNA16, maps to chromosome 2q23-24.3 and is tightly linked to markers in the D2S2380-D2S335 interval. DFNA16 is unique in that it results in the only form of ADNSHL in which the phenotype includes rapidly progressing and fluctuating hearing loss that appears to respond to steroid therapy. This observation suggests that it may be possible to stabilize hearing through medical intervention, once the biophysiology of deafness due to DFNA16 is clarified. Especially intriguing is the localization of several voltage-gated sodium-channel genes to the DFNA16 interval. These cationic channels are excellent positional and functional DFNA16 candidate genes.     

A novel locus for disseminated superficial actinic porokeratosis maps to chromosome 16q24.1-24.3

Disseminated superficial actinic porokeratosis (DSAP) is an uncommon autosomal dominant keratinization disorder with genetic heterogeneity characterized by multiple superficial keratotic lesions surrounded by a slightly raised keratotic border. Thus far, there have been three susceptible loci determined for DSAP and one locus for disseminated superficial porokeratosis (DSP), i.e. 12q23.2-24.1, 15q25.1-26.1, 1p31.3-p31.1 and 18p11.3. Moreover, the locus for porokeratosis palmaris plantaris et disseminata (PPPD) was mapped to 12q24.1-24.2, which overlapped with the first DSAP locus. Following the exclusion of these known loci in a four-generation Chinese DSAP family, we performed a genome-wide linkage analysis and identified a new locus on chromosome 16q24.1-24.3. The maximum two-point LOD score of 3.73 was obtained with the marker D16S3074 at a recombination fraction θ of 0.00. Haplotype analysis defined the critical 17.4-cM region for DSAP between D16S3091 and D16S413. This is regarded to be the forth locus for DSAP (DSAP4). ATP2C1 was sequenced as a candidate gene, however, no mutation was found. Further investigation for the genetic basis of DSAP is under way.