Confirmation of linkage of Duane's syndrome and refinement of the disease locus to an 8.8-cM interval on chromosome 2q31

Duane's syndrome is a congenital abnormality of eye movement, which may be inherited as an autosomal dominant trait but usually occurs sporadically. Genetic mapping in a Mexican family has recently identified a locus for Duane's syndrome within a 17.8-cM region of chromosome 2q31. The region was flanked by the microsatellite markers D2S2330 and D2S364. We performed linkage and haplotype analysis in a four-generation UK family with autosomal dominant transmission of Duane's syndrome. Linkage to 2q31 was confirmed with a maximum logarithm of differences (lod) score of 3.3 at theta = 0. The genetic interval was reduced to an 8.8-cM region between markers D2S326 and D2S364 that includes the candidate homeobox D gene cluster.     

X chromosome-inactivation patterns confirm the late timing of monoamniotic-MZ twinning.

Autosomal dominant brachydactyly type B (BDB) is characterized by nail aplasia with rudimentary or absent distal and middle phalanges. We describe two unrelated families with BDB. One family is English; the other family is Canadian but of English ancestry. We assigned the BDB locus in the Canadian family to an 18-cM interval on 9q, using linkage analysis (LOD score 3.5 at recombination fraction [theta] 0, for marker D9S938). Markers across this interval also cosegregated with the BDB phenotype in the English family (LOD score 2.1 at straight theta=0, for marker D9S277). Within this defined interval is a smaller (7.5-cM) region that contains 10 contiguous markers whose disease-associated haplotype is shared by the two families. This latter result suggests a common founder among families of English descent that are affected with BDB.     

The gene for spinal cerebellar ataxia 3 (SCA3) is located in a region of approximately 3 cM on chromosome 14q24.3-q32.2.

SCA3, the gene for spinal cerebellar ataxia 3, was recently mapped to a 15-cM interval between D14S67 and D14S81 on chromosome 14q, by linkage analysis in two families of French ancestry. The SCA3 candidate region has now been refined by linkage analysis with four new microsatellite markers (D14S256, D14S291, D14S280, and AFM343vf1) in the same two families, in which 19 additional individuals were genotyped, and in a third French family. Combined two-point linkage analyses show that the new markers, D14S280 and AFM343vf1, are tightly linked to the SCA3 locus, with maximal lod scores, at recombination fraction, (theta) = .00, of 7.05 and 13.70, respectively. Combined multipoint and recombinant haplotype analyses localize the SCA3 locus to a 3-cM interval flanked by D14S291 and D14S81. The same allele for D14S280 segregates with the disease locus in the three kindreds. This allele is frequent in the French population, however, and linkage disequilibrium is not clearly established. The SCA3 locus remains within the 29-cM region on 14q24.3-q32.2 containing the gene for the Machado-Joseph disease, which is clinically related to the phenotype determined by SCA3, but it cannot yet be concluded that both diseases result from alterations of the same gene.     

Localization of the gene causing keratolytic winter erythema to chromosome 8p22-p23, and evidence for a founder effect in South African Afrikaans-speakers.

Keratolytic winter erythema (KWE), also known as "Oudtshoorn skin disease," or "erythrokeratolysis hiemalis," is an autosomal dominant skin disorder of unknown etiology characterized by a cyclical erythema, hyperkeratosis, and recurrent and intermittent peeling of the palms and soles, particularly during winter. Initially KWE was believed to be unique to South Africa, but recently a large pedigree of German origin has been identified. The disorder occurs with a prevalence of 1/7,000 in the South African Afrikaans-speaking Caucasoid population, and this high frequency has been attributed to founder effect. After a number of candidate regions were excluded from linkage to KWE in both the German family and several South African families, a genomewide analysis was embarked on. Linkage to the microsatellite marker D8S550 on chromosome 8p22-p23 was initially observed, with a maximum LOD score (Z(max)) of 9.2 at a maximum recombination fraction (theta(max)) of .0 in the German family. Linkage was also demonstrated in five of the larger South African families, with Z(max) = 7.4 at theta(max) = .02. When haplotypes were constructed, 11 of 14 South African KWE families had the complete "ancestral" haplotype, and 3 demonstrated conservation of parts of this haplotype, supporting the hypothesis of founder effect. The chromosome segregating with the disease in the German family demonstrated a different haplotype, suggesting that these chromosomes do not have a common origin. Recombination events place the KWE gene in a 6-cM interval between D8S550 and D8S552. If it is assumed that there was a single South African founder, a proposed ancestral recombinant suggests that the gene is most likely in a 1-cM interval between D8S550 and D8S265.     

Refinement of the locus for autosomal dominant cerebellar ataxia type II to chromosome 3p21.1–14.1

We have previously mapped the gene for autosomal dominant cerebellar ataxia type II (ADCAII) to chromosome 3p12-p21.1 in a region of 33 cM by using four families of different geographic origin. In this study, we analysed the families with nine additional simple tandem repeat markers located in the ADCAII candidate region. An extensive clinical evaluation was also performed in the Belgian family CA-1 on two probably affected and seven at-risk individuals by means of ophthalmological examination and magnetic resonance imaging. Based on informative recombinants, we were able to reduce the ADCAII candidate region to the 12-cM region between D3S1300 and D3S1285. Furthermore, haplotype analysis among the families suggested that the most likely location of the ADCAII gene is within the 6.2-cM interval between D3S3698 and D3S1285. Because of the documented anticipation in ADCAII families, we also analysed family CA-1 with six polymorphic triplet repeat markers located on chromosome 3. None of these markers showed expanded alleles. Received: 16 August 1996 / Revised: 7 October 1996     

Identification of a locus on chromosome 14q for idiopathic basal ganglia calcification (Fahr disease).

Idiopathic basal ganglia calcification (IBGC) is a neurodegenerative syndrome that is associated with a variety of movement disorders and neurobehavioral and cognitive manifestations. Despite numerous clinical, pathological, and biochemical investigations, its etiology remains unknown. We have identified a multigenerational family with dominantly inherited IBGC and, in 24 members of this family, performed a whole-genome scan using polymorphic microsatellite markers to identify the first chromosomal locus for this disorder (IBGC1). A maximum two-point LOD score of 3.37 was obtained at marker D14S1014, and a maximum multipoint LOD score of 4.95 was obtained between D14S75 and D14S306. The minimal haplotype shared by affected patients extended over a 17.1-cM region bounded by D14S70 and D14S66, which is potentially further narrowed to a 13.3-cM region by a recombination observed in a patient with probable affected status. The age at onset appeared to be decreasing by an average of >20 years with each transmission, which is consistent with genetic anticipation.     

Localization of the gene for congenital dyserythropoietic anemia type I to a <1-cM interval on chromosome 15q15.1-15.3.

Congenital dyserythropoietic anemias (CDA) are a rare group of red-blood-cell disorders of unknown etiology that are characterized by ineffective erythropoiesis, pathognomonic cytopathology of the nucleated red blood cells in the bone marrow, and secondary hemochromatosis. In CDA type I, bone-marrow electron microscopy reveals characteristic findings in erythroid precursors, including spongy heterochromatin and enlarged nuclear pores. Since the genetic basis of CDA type I is not evident, we used homozygosity and linkage mapping to localize the genetic defect responsible for CDA type I in 25 Bedouins from four large consanguineous families. We report the linkage of this disease to markers on chromosome 15 located at q15. 1-q15.3. Fourteen markers within a 12-cM interval were typed in the relevant family members. Nine of the markers yielded maximum LOD scores of 1.625-12.928 at a recombination fraction of .00. Linkage disequilibrium was found only with marker D15S779. Haplotype analysis revealed eight different carrier haplotypes and highlighted the existence of a founder haplotype. Identification of historical crossover events further narrowed the gene location to between D15S779 and D15S778. The data suggest localization of the CDA type I gene within a 0.5-cM interval. The founder mutation probably occurred >/= 400 years ago. Sequence analysis of the coding region of protein 4.2, the only known erythroid-specific gene in the locus, did not reveal any change in the CDA type I patients. Future analysis of this locus may lead to the identification of a gene essential to normal erythropoiesis.     

Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease in which motor neurons in the brain and spinal cord degenerate by largely unknown mechanisms. ALS is familial (FALS) in 10% of cases, and the inheritance is usually dominant, with variable penetrance. Mutations in copper/zinc super oxide dismutase (SOD1) are found in 20% of familial and 3% of sporadic ALS cases. Five families with ALS and frontotemporal dementia (ALS-FTD) are linked to 9q21, whereas one family with pure ALS is linked to 18q21. We identified two large European families with ALS without SOD1 mutations or linkage to known FALS loci and conducted a genomewide linkage screen using 400 microsatellite markers. In both families, two-point LOD scores >1 and a haplotype segregating with disease were demonstrated only across regions of chromosome 16. Subsequent fine mapping in family 1 gave a maximum two-point LOD score of 3.62 at D16S3137 and a three-point LOD score of 3.85 for markers D16S415 and D16S3137. Haplotype analysis revealed no recombination > approximately 30 cM, (flanking markers at D16S3075 and D16S3112). The maximum two-point LOD score for family 2 was 1.84 at D16S415, and the three-point LOD score was 2.10 for markers D16S419 and D16S415. Definite recombination occurred in several individuals, which narrowed the shared haplotype in affected individuals to a 10.1-cM region (flanking markers: D16S3396 and D16S3112). The region shared by both families on chromosome 16q12 corresponds to approximately 4.5 Mb on the Marshfield map. Bioinformatic analysis of the region has identified 18 known genes and 70 predicted genes in this region, and sequencing of candidate genes has now begun.     

A novel form of "central pouchlike" cataract, with sutural opacities, maps to chromosome 15q21-22

Congenital cataract is a clinically and genetically highly heterogeneous eye disorder, with autosomal dominant inheritance being most common. We investigated a large seven-generation family with 74 individuals affected by autosomal dominant congenital cataract (ADCC). The phenotype in this family can be described as "central pouchlike" cataract with sutural opacities, and it differs from the other mapped cataracts. We performed linkage analysis with microsatellite markers in this family and excluded the known candidate genes. A genomewide search revealed linkage to markers on chromosome 15, with a maximum two-point LOD score of 5.98 at straight theta=0 with marker D15S117. Multipoint analysis also gave a maximum LOD score of 5.98 at D15S117. Multipoint and haplotype analysis narrowed the cataract locus to a 10-cM region between markers D15S209 and D15S1036, closely linked to marker D15S117 in q21-q22 region of chromosome 15. This is the first report of a gene for a clinically new type of ADCC at 15q21-22 locus.     

Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I

Hereditary sensory neuropathy type I (HSN I) is an axonal form of autosomal-dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. Unrecognized, these can result in delayed wound healing and osteomyelitis, necessitating distal amputations. To elucidate the genetic basis of an HSN I subtype in a family in which mutations in the few known HSN I genes had been excluded, we employed massive parallel exon sequencing of the 14.3 Mb disease interval on chromosome 14q. We detected a missense mutation (c.1065C>A, p.Asn355Lys) in atlastin-1 (ATL1), a gene that is known to be mutated in early-onset hereditary spastic paraplegia SPG3A and that encodes the large dynamin-related GTPase atlastin-1. The mutant protein exhibited reduced GTPase activity and prominently disrupted ER network morphology when expressed in COS7 cells, strongly supporting pathogenicity. An expanded screen in 115 additional HSN I patients identified two further dominant ATL1 mutations (c.196G>C [p.Glu66Gln] and c.976 delG [p.Val326TrpfsX8]). This study highlights an unexpected major role for atlastin-1 in the function of sensory neurons and identifies HSN I and SPG3A as allelic disorders.     

Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies): Genetic analysis of three unrelated SCA2 families

Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders that are clinically and genetically heterogeneous. We report here a genetic linkage study, with five chromosome 12q markers, of three Martinican families with ADCA type I, for which the spinocerebellar ataxia 1 (SCA1) locus was excluded. Linkage to the SCA2 locus was demonstrated with a maximal lod score of 6.64 at = 0.00 with marker D12S354. Recombinational events observed by haplotype reconstruction demonstrated that the SCA2 locus is located in an approximately 7-cM interval flanked by D 12S 105 and D12S79. Using thez _max-l method, multipoint analysis further reduced the candidate interval for SCA2 to a region of 5 cM. Two families shared a common haplotype at loci spanning 7 cM, which suggests a founder effect, whereas a different haplotype segregated with the disease in the third family. Finally, a mean anticipation of 12 ± 14 years was found in parent-child couples, with no parental sex effect, suggesting that the disease might be caused by an expanded and unstable triplet repeat.     

Mapping of the Gene for Machado-Joseph Disease within a 3.6-cM Interval Flanked by D14S291/D14S280 and D14S81, on the Basis of Studies of Linkage and Linkage Disequilibrium in 24 Japanese Families

The gene locus of Machado-Joseph disease (MJD) has recently been mapped within a 29-cM subregion of 14q chromosome. We did a linkage study of 24 multigenerational MJD Japanese pedigrees, in an attempt to narrow the candidate region of this gene. Pairwise and multipoint linkage analysis, together with haplotype segregation analysis, led to the conclusion that the MJD gene is located at the 6.8-cM interval between D14S256 and D14S81 (Z_max = 24.78, multipoint linkage analysis). D14S291 and D14S280, located at the center of this interval, showed no obligate recombination with the MJD gene (Z_max = 5.93 for D14S291 and 9.99 for D14S280). A weak, but significant, linkage disequilibrium of MJD gene was noted with D14S81 (P < .05) but not with D14S291 or D14S280. These results suggest that a 3.6-cM interval flanked by D14S291/D14S280 and D14S81 is the most likely location of the MJD gene and that it is closest to D14S81.     

Mapping of gene loci for nephronophthisis type 4 and Senior-Løken syndrome, to chromosome 1p36

For nephronophthisis (NPHP), the primary genetic cause of chronic renal failure in young adults, three loci have been mapped. To identify a new locus for NPHP, we here report on total-genome linkage analysis in seven families with NPHP, in whom we had excluded linkage to all three known NPHP loci. LOD scores >1 were obtained at nine loci, which were then fine mapped at 1-cM intervals. Extensive total-genome haplotype analysis revealed homozygosity in one family, in the region of the PCLN1 gene. Subsequent mutational analysis in this gene revealed PCLN1 mutations, thereby allowing exclusion of this family as a phenocopy. Multipoint linkage analysis for the remaining six families with NPHP together yielded a maximum LOD score (Z_max) of 8.9 (at D1S253). We thus identified a new locus, NPHP4, for nephronophthisis. Markers D1S2660 and D1S2642 are flanking NPHP4 at a 2.9-cM critical interval. In one family with NPHP4, extensive genealogical studies were conducted, revealing consanguinity during the 17th century. On the basis of haplotype sharing by descent, we obtained a multipoint Z_max of 5.8 for D1S253 in this kindred alone. In addition, we were able to localize to the NPHP4 locus a new locus for Senior-Løken syndrome, an NPHP variant associated with retinitis pigmentosa.     

Fine Mapping of the Gene for Carbohydrate-Deficient Glycoprotein Syndrome, Type I (CDG1): Linkage Disequilibrium and Founder Effect in Scandinavian Families

Carbohydrate-deficient glycoprotein syndrome type I (CDG I) is characterized clinically by severe nervous system involvement and biochemically by defects in the carbohydrate residues in a number of serum glycoproteins. The CDG1 gene was recently localized by us to a 13-cM interval in chromosome region 16p13. In this study 44 CDG I families from nine countries were analyzed with available markers in a region ranging from marker D16S495 to D16S497, and haplotype and linkage disequilibrium analyses were performed. One specific haplotype was found to be markedly overrepresented in CDG I patients from a geographically distinct region in Scandinavia, strongly indicating that CDG I families in this region share the same ancestral CDG1 mutation. Furthermore, analysis of the extent of the common haplotype in these families indicates that the CDG1 gene is located in the region defined by markers D16S513–AFMa284wd5–D16S768–D16S406–D16S502. The critical CDG1 region, in strong linkage disequilibrium with markers AFMa284wd5, D16S768, and D16S406, thus constitutes less than 1 Mb of DNA and less than 1 cM in the very distal part of the CDG1 region defined by us previously.     

Mapping of Charcot-Marie-Tooth Disease Type 1C to Chromosome 16p Identifies a Novel Locus for Demyelinating Neuropathies

Charcot-Marie-Tooth (CMT) neuropathy represents a genetically heterogeneous group of diseases affecting the peripheral nervous system. We report genetic mapping of the disease to chromosome 16p13.1-p12.3, in two families with autosomal dominant CMT type 1C (CMT1C). Affected individuals in these families manifest characteristic CMT symptoms, including high-arched feet, distal muscle weakness and atrophy, depressed deep-tendon reflexes, sensory impairment, slow nerve conduction velocities, and nerve demyelination. A maximal combined LOD score of 14.25 was obtained with marker D16S500. The combined haplotype analysis in these two families localizes the CMT1C gene within a 9-cM interval flanked by markers D16S519 and D16S764. The disease-linked haplotypes in these two pedigrees are not conserved, suggesting that the gene mutation underlying the disease in each family arose independently. The epithelial membrane protein 2 gene (EMP2), which maps to chromosome 16p13.2, was evaluated as a candidate gene for CMT1C.     

Mapping of a gene determining familial partial epilepsy with variable foci to chromosome 22q11-q12

We identified two large French-Canadian families segregating a familial partial epilepsy syndrome with variable foci (FPEVF) characterized by mostly nocturnal seizures arising from frontal, temporal, and occasionally occipital epileptic foci. There is no evidence for structural brain damage or permanent neurological dysfunction. The syndrome is inherited as an autosomal dominant trait with incomplete penetrance. We mapped the disease locus to a 3. 8-cM interval on chromosome 22q11-q12, between markers D22S1144 and D22S685. Using the most conservative diagnostic scheme, the maximum cumulative LOD score was 6.53 at recombination fraction (straight theta) 0 with D22S689. The LOD score in the larger family was 5.34 at straight theta=0 with the same marker. The two families share an identical linked haplotype for >/=10 cM, including the candidate interval, indicating a recent founder effect. A severe phenotype in one of the probands may be caused by homozygosity for the causative mutation, as suggested by extensive homozygosity for the linked haplotype and a bilineal family history of epilepsy. An Australian family with a similar phenotype was not found to link to chromosome 22, indicating genetic heterogeneity of FPEVF.     

Autosomal Dominant Postaxial Polydactyly, Nail Dystrophy, and Dental Abnormalities Map to Chromosome 4p16, in the Region Containing the Ellis–van Creveld Syndrome Locus

We have studied a four-generation family with features of Weyers acrofacial dysostosis, in which the proband has a more severe phenotype, resembling Ellis-van Creveld syndrome. Weyers acrofacial dysostosis is an autosomal dominant condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar condition, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease. Linkage and haplotype analysis determined that the disease locus in this pedigree resides on chromosome 4p16, distal to the genetic marker D4S3007 and within a 17-cM region flanking the genetic locus D4S2366. This region includes the Ellis-van Creveld syndrome locus, which previously was reported to map within a 3-cM region between genetic markers D4S2957 and D4S827. Either the genes for the condition in our family and for Ellis-van Creveld syndrome are near one another or these two conditions are allelic with mutations in the same gene. These data also raise the possibility that Weyers acrofacial dysostosis is the heterozygous expression of a mutation that, in homozygous form, causes the autosomal recessive disorder Ellis-van Creveld syndrome.     

Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by developmental arrest in the sensory and autonomic nervous systems and by Ashkenazi Jewish ancestry. We previously had mapped the defective gene (DYS) to an 11-cM segment of chromosome 9q31-33, flanked by D9S53 and D9S105. By using 11 new polymorphic loci, we now have narrowed the location of DYS to <0.5 cM between the markers 43B1GAGT and 157A3. Two markers in this interval, 164D1 and D9S1677, show no recombination with the disease. Haplotype analysis confirmed this candidate region and revealed a major haplotype shared by 435 of 441 FD chromosomes, indicating a striking founder effect. Three other haplotypes, found on the remaining 6 FD chromosomes, might represent independent mutations. The frequency of the major FD haplotype in the Ashkenazim (5 in 324 control chromosomes) was consistent with the estimated DYS carrier frequency of 1 in 32, and none of the four haplotypes associated with FD was observed on 492 non-FD chromosomes from obligatory carriers. It is now possible to provide accurate genetic testing both for families with FD and for carriers, on the basis of close flanking markers and the capacity to identify >98% of FD chromosomes by their haplotype.