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Alterations of the gamma-aminobutyric acid (GABA) signaling system has been strongly linked to the pathophysiology of autism spectrum disorder (ASD). Genetic associations of common variants in GABA receptor subunits, in particular GABRA4 on chromosome 4p12, with ASD have been replicated by several studies. Moreover, molecular investigations have identified altered transcriptional and translational levels of this gene and protein in brains of ASD individuals. Since the genotyped common variants are likely not the functional variants contributing to the molecular consequences or underlying ASD phenotype, this study aims to examine rare sequence variants in GABRA4, including those outside the protein coding regions of the gene. We comprehensively re-sequenced the entire protein coding and noncoding portions of the gene and putative regulatory sequences in 82 ASD individuals and 55 developmentally typical pediatric controls, all homozygous for the most significant previously associated ASD risk allele (G/G at rs1912960). We identified only a single common, coding variant, and no association of any single marker or set of variants with ASD. Functional annotation of noncoding variants identified several rare variants in putative regulatory sites. Finally, a rare variant unique to ASD cases, in an evolutionary conserved site of the 3'UTR, shows a trend toward decreasing gene expression. Hence, GABRA4 rare variants in noncoding DNA may be variants of modest physiological effects in ASD etiology.

Misregulation of the methyl-CpG-binding protein 2 (MECP2) gene has been found to cause a myriad of neurological disorders including autism, mental retardation, seizures, learning disabilities, and Rett syndrome. We hypothesized that mutations in other members of the methyl-CpG-binding domain (MBD) family may also cause autistic features in individuals. We evaluated 226 autistic individuals for alterations in the four genes most homologous to MECP2: MBD1, MBD2, MBD3, and MBD4. A total of 46 alterations were identified in the four genes, including ten missense changes and two deletions that alter coding sequence. Several are either unique to our autistic population or cosegregate with affected individuals within a family, suggesting a possible relation of these variations to disease etiology. Variants include a R23M alteration in two affected half brothers which falls within the MBD domain of the MBD3 protein, as well as a frameshift in MBD4 that is predicted to truncate almost half of the protein. These results suggest that rare cases of autism may be influenced by mutations in members of the dynamic MBD protein family.

Autism is characterized as one of the pervasive developmental disorders, a spectrum of often severe behavioral and cognitive disturbances of early development. The high heritability of autism has driven multiple efforts to identify genetic variation that increases autism susceptibility. Numerous studies have suggested that variation in peripheral and central metabolism of serotonin (5-hydroxytryptamine) may play a role in the pathophysiology of autism. We screened 403 autism families for 45 single nucleotide polymorphisms in ten serotonin pathway candidate genes. Although genome-wide linkage scans in autism have provided support for linkage to various loci located within the serotonin pathway, our study does not provide strong evidence for linkage to any specific gene within the pathway. The most significant association (p = 0.0002; p = 0.02 after correcting for multiple comparisons) was found at rs1150220 (HTR3A) located on chromosome 11 ( approximately 113 Mb). To test specifically for multilocus effects, multifactor dimensionality reduction was employed, and a significant two-way interaction (p value = 0.01) was found between rs10830962, near MTNR1B (chromosome11; 92,338,075 bp), and rs1007631, near SLC7A5 (chromosome16; 86,413,596 bp). These data suggest that variation within genes on the serotonin pathway, particularly HTR3A, may have modest effects on autism risk.

The complex inheritance involved in multiple sclerosis (MS) risk has been extensively investigated, but our understanding of MS genetics remains rudimentary. In this study, we explore 51 single nucleotide polymorphisms (SNPs) in 36 candidate genes from the inflammatory pathway and test for gene-gene interactions using complementary case-control, discordant sibling pair, and trio family study designs. We used a sample of 421 carefully diagnosed MS cases and 96 unrelated, healthy controls; discordant sibling pairs from 146 multiplex families; and 275 trio families. We used multifactor dimensionality reduction to explore gene-gene interactions. Based on our analyses, we have identified several statistically significant models including both main effect models and two-locus, three-locus, and four-locus epistasis models that predict MS disease risk with between approximately 61% and 85% accuracy. These results suggest that significant epistasis, or gene-gene interactions, may exist even in the absence of statistically significant individual main effects.

Autism is a neurodevelopmental disorder of complex genetics, characterized by impairment in social interaction and communication, as well as repetitive behavior. Multiple lines of evidence, including alterations in levels of GABA and GABA receptors in autistic patients, indicate that the GABAergic system, which is responsible for synaptic inhibition in the adult brain, may be involved in autism. Previous studies in our lab indicated association of noncoding single nucleotide polymorphisms (SNPs) within a GABA receptor subunit gene on chromosome 4, GABRA4, and interaction between SNPs in GABRA4 and GABRB1 (also on chromosome 4), within Caucasian autism patients. Studies of genetic variation in African-American autism families are rare. Analysis of 557 Caucasian and an independent population of 54 African-American families with 35 SNPs within GABRB1 and GABRA4 strengthened the evidence for involvement of GABRA4 in autism risk in Caucasians (rs17599165, p=0.0015; rs1912960, p=0.0073; and rs17599416, p=0.0040) and gave evidence of significant association in African-Americans (rs2280073, p=0.0287 and rs16859788, p=0.0253). The GABRA4 and GABRB1 interaction was also confirmed in the Caucasian dataset (most significant pair, rs1912960 and rs2351299; p=0.004). Analysis of the subset of families with a positive history of seizure activity in at least one autism patient revealed no association to GABRA4; however, three SNPs within GABRB1 showed significant allelic association; rs2351299 (p=0.0163), rs4482737 (p=0.0339), and rs3832300 (p=0.0253). These results confirmed our earlier findings, indicating GABRA4 and GABRB1 as genes contributing to autism susceptibility, extending the effect to multiple ethnic groups and suggesting seizures as a stratifying phenotype.

Previous linkage studies have suggested that chromosome 12 may harbor susceptibility genes for late-onset Alzheimer disease (LOAD). No risk genes on chromosome 12 have been conclusively identified yet. We have reported that the linkage evidence for LOAD in a 12q region was significantly increased in autopsy-confirmed families particularly for those showing no linkage to alpha-T catenin gene, a LOAD candidate gene on chromosome 10 [LOD score increased from 0.1 in the autopsy-confirmed subset to 4.19 in the unlinked subset (optimal subset); p<0.0001 for the increase in LOD score], indicating a one-LOD support interval spanning 6 Mb. To further investigate this finding and to identify potential candidate LOAD risk genes for follow-up analysis, we analyzed 99 single nucleotide polymorphisms in this region, for the overall sample, the autopsy-confirmed subset, and the optimal subset, respectively, for comparison. We saw no significant association (p<0.01) in the overall sample. In the autopsy-confirmed subset, the best finding was obtained in the activation transcription factor 7 (ATF7) gene (single-locus association, p=0.002; haplotype association global, p=0.007). In the optimal subset, the best finding was obtained in the hypothetical protein FLJ20436 (FLJ20436) gene (single-locus association, p=0.0026). These results suggest that subset and covariate analyses may be one approach to help identify novel susceptibility genes on chromosome 12q for LOAD.

Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous diseases characterized by neuronal degeneration that is maximal at the distal ends of the longest axons of the central nervous system. The most common cause of autosomal dominant HSP is mutation of a novel gene encoding spastin, a protein whose function is still being elucidated. One clue concerning spastin function is its intracellular localization. Here, we describe a novel anti-spastin antiserum designed to a unique epitope contained within all splicing isoforms. The antiserum exhibits specific immunostaining of recombinant spastin in intact, fixed cells. Using this reagent, we find that endogenous spastin is located at the centrosome in a variety of cell types at all points in the cell cycle. This localization is resistant to microtubule disruption, suggesting that spastin may be an integral centrosomal protein. In addition to the centrosome, spastin also localizes at discrete focal regions along the axons of primary cultured neurons. These data lend additional support to the emerging hypothesis that spastin plays a role in microtubule dynamics, with a crucial role in microtubule organization.

Several recent case-control studies have examined the association between single nucleotide polymorphisms (SNPs) in the promoter region of the apolipoprotein E gene (APOE) and risk of Alzheimer disease (AD), with conflicting results. We assessed the relation between five APOE region SNPs and risk of AD in both case-control and family-based analyses. We observed a statistically significant association with the +5361T allele in the overall case-control analysis (P value=0.04) after adjusting for the known effect of the APOE-4 allele. Further analysis revealed this association to be limited to carriers of the APOE-4 allele. Age-stratified analyses in the patients with age at onset of 80 years or greater and age-matched controls showed that the -219T allele (P value=0.009) and the +113C allele (P value=0.03) are associated with increased risk of AD. Despite these findings, haplotype and family-based association analyses were unable to provide evidence that the APOE region SNPs influenced risk of AD independent of the APOE-4 allele. In addition to risk, we tested for association between the SNPs and age at onset of AD, but found no association in the case-control or family based analyses. In conclusion, SNPs +5361, or a SNP in strong linkage disequilibrium, may confer some additional risk for developing AD beyond the risk due to APOE-4; however, the effect independent of APOE-4 is likely to be small.

Apolipoprotein E (APOE) is a confirmed risk factor for Alzheimer disease. APOE is also involved in several other neurodegenerative disorders, including Parkinson disease and multiple sclerosis. Previous studies of amyotrophic lateral sclerosis (Lou Gehrig disease, ALS) have investigated the effect of APOE on the risk of developing ALS, age at onset, site of onset, and duration of the disease. The results have been inconsistent, possibly due to small sample sizes and complete reliance on case-control data. No family-based association studies were performed. To address these limitations, we investigated the relationship between APOE functional polymorphisms and age at onset of ALS in a large set of 508 families. We treated age at onset as a quantitative trait and performed family-based association analysis using the TDTQ5 method. APOE-2 is protective against earlier onset (P =0.001) with an average age at onset of APOE-2 carriers approximately 3 years later than that of non-APOE-2 carriers. Similar to our previous report, we did not find APOE associated with ALS risk. Our findings suggest that APOE may express its strongest effect through age at onset rather than on risk.

Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disease characterized by wide variability in phenotypic expression, both within and among families. The most-common cause of autosomal dominant HSP is mutation of the gene encoding spastin, a protein of uncertain function. We report the existence of intragenic polymorphisms of spastin that modify the HSP phenotype. One (S44L) is a previously described recessively acting allele and the second is a novel allele affecting the adjacent amino acid residue (P45Q). In 4 HSP families in which either L44 or Q45 segregates independently of a missense or splicing mutation in the AAA domain of spastin, L44 and Q45 are each associated with a striking decrease in age at onset in the presence of the AAA domain mutations. Using a bioinformatics approach, we found that the highly conserved S44 is predicted to be phosphorylated by a number of family members of the proline-directed serine/threonine cyclin-dependent kinases (Cdks). Cdk1 and Cdk5 showed no kinase activity toward synthetic spastin peptide in an in vitro kinase assay, suggesting that this serine residue may be phosphorylated by a different Cdk. Our identification of S44L and P45Q as modifiers of the HSP phenotype suggests a role for spastin phosphorylation by Cdks in the neurodegeneration of the most-common form of HSP.

We and others have previously detected association of the Tau H1 haplotype on chromosome 17 with risk of idiopathic Parkinson disease (PD). The H1 haplotype appears to have a fundamental importance in neurodegeneration, as multiple studies have shown it is also associated with an increased risk for progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration syndromes, and primary progressive aphasia. Therefore, to divide the H1 haplotype into sub-haplotypes that could be more significantly associated with the risk of developing PD, and to delimit the genes lying in the H1 haplotype, we analyzed 34 single nucleotide polymorphisms (SNPs) spanning over 3.15 megabases in the region containing Tau. These SNPs are located in or flank the corticotropin-releasing hormone receptor 1, presenilin homolog 2, Tau, Saitohin, and KIAA1267 genes. Analysis of linkage disequilibrium (LD) using these 34 SNPs suggests that the H1 haplotype extends over about 1.3 megabases, making it the largest region of LD reported to date. Of the 29 SNPs lying in this region of LD, 5 were identified as "haplotype tagging" SNPs (htSNPs), capturing 96% of the sample's haplotype diversity. Association analysis with these htSNPs revealed a new H1 sub-haplotype that is significantly associated with PD ( P<0.02). These results define the genes and regulatory regions included in this region of LD, containing an important susceptibility allele contributing to increased risk of neurodegeneration.

Multiple sclerosis (MS) is a demyelinating autoimmune disease with a strong yet complex genetic component. To date only the HLA-DR locus, and specifically the HLA-DR15 allele, has been identified and confirmed as influencing the risk of developing MS. Genomic screens on several datasets have been performed and have identified several chromosomal regions with interesting results, but none have yet been confirmed. We tested seven of the most-promising regions (on chromosomes 1p, 2p, 3p, 3q, 5q, 19q, and Xp) identified from several genomic screens in a dataset of 98 multiplex MS families from the United States and 90 multiplex MS families from France. The results did not confirm linkage to 2p, 3q, 5q, or Xp in the overall dataset, or in subsets defined by geographic origin or HLA-DR15 status. Regions on 1p34, 3p14, and 19q13 produced lod scores >0.90 in at least one subset of the data, suggesting that these regions should be examined in more detail.

As part of an on-going genomic screen of unlinked Charcot-Marie-Tooth disease type 2 (CMT2) families, we identified 11 regions in the genome with lod scores > or = 1.0. One of these regions was near the recently identified CMTDI1 locus on 19q. We show evidence of linkage of DUK 1118 to this region and our data reduce the minimum candidate interval for CMTDI1 to the 9-cM interval spanned by D19S586 and D19S432. We also demonstrate that five additional CMT2 families are unlinked to 19q markers, providing further evidence of CMT2 heterogeneity.

Multiple sclerosis (MS) is an autoimmune neurological disorder with a complex etiology. Sibling risk, twin, and adoption studies have demonstrated that genes play a vital role in susceptibility to MS. Numerous association and linkage studies have implicated the major histocompatibility complex (MHC) as one component of the genetic etiology, but additional loci remain to be identified. Genomic screens have suggested over 50 regions that might harbor these genes, but there has been little agreement between studies. The one region suggested by all four screens resides within chromosome 19q13. Allelic associations with several markers in this region have also been described. This region has now been examined in detail in an expanded dataset of MS families from the United States. Genetic linkage and association were tested with multiple markers in this region using both parametric and non-parametric analyses. Additional support for an MS susceptibility locus was observed, primarily in families with the MS-associated HLA-DR2 allele. While consistent, this effect appears to be modest with a maximum lambda(s) = 1.47, probably representing no more than 10% of the overall genetic effect in MS.

We evaluated seven families segregating pure, autosomal dominant familial spastic paraplegia (SPG) for linkage to four recently identified SPG loci on chromosomes 2q (1), 8q (2), 12q (3), and 19q (4). These families were previously shown to be unlinked to SPG loci on chromosomes 2p, 14q, and 15q. Two families demonstrated linkage to the new loci. One family (family 3) showed significant evidence for linkage to chromosome 12q, peaking at D12S1691 (maximum lod = 3.22). Haplotype analysis of family 3 did not identify any recombinants among affected individuals in the 12q candidate region. Family 5 yielded a peak lod score of 2.02 at marker D19S868 and excluded linkage to other known SPG loci. Haplotype analysis of family 5 revealed several cross-overs in affected individuals, thereby potentially narrowing the SPG12 candidate region to a 5-cM region between markers D19S868 and D19S220. Three of the families definitively excluded all four loci examined, providing evidence for further genetic heterogeneity of pure, autosomal dominant SPG. In conclusion, these data confirm the presence of SPG10 (chromosome 12), potentially reduce the minimum candidate region for SPG12 (chromosome 19q), and suggest there is at least one additional autosomal dominant SPG locus.

Autistic disorder (AD) is a developmental disorder affecting social interactions, communication, and behavior. AD is a disease of complex genetic architecture. It is postulated that several genes contribute to the underlying etiology of AD. Chromosome 15 is of particular interest due to numerous reports of AD in the presence of chromosomal abnormalities, located mainly in the 15q11-q13 region. There are also a number of plausible candidate genes in this area, including the gamma-aminobutyric acidA (GABA(A)) receptor gene complex. We have undertaken a study of this region of chromosome 15 in a data set of 63 multiplex families (with 2 or more AD affected individuals per family). We found evidence in support of linkage to the 15q11-q13 region, as well as evidence of increased recombination in this region. These findings provide further support for the involvement of chromosome 15q11-q13 in the genetic etiology of AD.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. A complex genetic etiology is thought to underlie susceptibility to this disease. The present study was designed to analyze whether differences in genes that encode myelin proteins influence susceptibility to MS. We performed linkage analysis of MS to markers in chromosomal regions that include the genes encoding myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMGP), and myelin oligodendrocyte glycoprotein (MOG) in a well-characterized population of 65 multiplex MS families consisting of 399 total individuals, 169 affected with MS and 102 affected sibpairs. Physical mapping data permitted placement of MAG and PLP genes on the Genethon genetic map; all other genes were mapped on the Genethon genetic map by linkage analysis. For each gene, at least one marker within the gene and/or two tightly linked flanking markers were analyzed. Marker data analysis employed a combination of genetic trait model-dependent (parametric) and model-independent linkage methods. Results indicate that MAG, MBP, OMGP, and PLP genes do not have a significant genetic effect on susceptibility to MS in this population. As MOG resides within the MHC, a potential role of the MOG gene could not be excluded.

The apolipoprotein E (APOE)-4 allele is a major risk factor for late-onset Alzheimer disease (AD), but it does not account for all the genetic variation in late-onset AD; thus, other genetic markers must be examined. Previous studies suggest an HLA-A2 allele association with risk and earlier onset age of AD. Because these effects may be additive to those of APOE-4, we studied HLA-A2 and APOE-4 frequencies in AD patients and cognitively intact controls. A total of 712 unrelated Caucasian subjects included 479 patients with AD (435 sporadic, 44 familial) and 233 controls. Patients (mean+/-SD age 73.9+/-7.9 years, range 42-93 years) had probable AD, according to standard diagnostic criteria; controls (mean+/-SD age 70.4+/-8.5 years, range 37-92 years) were cognitively intact. APOE and HLA-A2 typing used polymerase chain reaction to indicate the number of APOE-4 alleles present as well as the presence (A1/A2, A2/A2 genotypes) or absence (A1/A1 genotype) of HLA-A2. A two-way analysis of variance was used to assess the effect of the HLA-A2 allele on age at onset of dementia. No association between HLA-A2 and APOE-4 was found, and the presence of HLA-A2 allele did not increase AD risk. There was also no evidence for an association between HLA-A2 and earlier onset age of AD. Examination age, sex, family history of AD, and recruitment site had no influence on these results. In conclusion, the HLA-A2 allele did not influence AD risk or onset age in this study population. A2 heterozygosity, and population differences, including stratification sub-structures, and other undetermined factors could contribute to discrepant findings among studies.

Charcot-Marie-Tooth disease type 4A (CMT4A) is a severe, autosomal recessive peripheral neuropathy linked to chromosome 8q13-q21. We have previously constructed a YAC contig across the CMT4A region and narrowed the disease-flanking interval to approximately three megabases. Subsequently, we constructed a PAC/BAC contig made of 44 clones and mapped 44 new and 30 previous STSs, ESTs, and polymorphic makers to the region. Using 13 polymorphic markers, we have now identified an ancestral haplotype segregating in three families, indicating a common founder mutation. Two ancestral recombination events in this haplotype significantly reduce the minimal candidate region to a minimal trailing path of five PAC/BAC clones, which will now allow direct investigation of candidate genes for CMT4A.

Autosomal recessive familial amyotrophic lateral sclerosis (RFALS) is a rare form of ALS that usually presents at an early age with slow progression of symptoms. RFALS is clinically and genetically heterogeneous and the locus of RFALS type 3 was mapped to 2q33 (ALS2) in a single family. We now report linkage of a more-common form of RFALS to chromosome 15q15-q22 markers (ALS5) and show further genetic locus heterogeneity in RFALS. ALS5 is the locus for most families with RFALS and appears to be present in both North African and European populations.

Tuberous sclerosis complex (TSC) is an autosomal dominant multi-system disorder with two known disease loci on chromosomes 9q34 (TSC1) and 16p13.3 (TSC2). TSC has a prevalence of approximately 1 in 5,000-6,000, exhibits incomplete penetrance, and occurs in all racial groups. Our laboratory has undertaken the complete mutation analysis of the TSC2 gene in 42 TSC families using single-strand conformation polymorphism analysis and reverse transcription-polymerase chain reaction. Of the total of 42 families, 16 show evidence of linkage to the chromosome 16 TSC2 locus and 26 are either sporadic or too small to establish chromosome linkage. The TSC2 gene spans at least 45 kilobases of genomic DNA, has 41 known exons, and codes for a 5,474-base pair transcript. After complete gene analysis, 16 TSC2 mutations have been identified, including DNA insertions, deletions, splice site mutations, and amino acid substitutions. The majority of putative TSC2 mutations were found in sporadic rather than TSC2-linked families. We have also detected 15 polymorphisms which occur in the TSC2 gene.

The low-density lipoprotein receptor-related protein gene (LRP1) is often mentioned as a candidate gene for Alzheimer disease (AD) because of its role as a receptor for apolipoprotein E (apoE), a major genetic risk factor for late-onset familial and sporadic AD. A recent association study of a tetranucleotide repeat polymorphism located 5' to the LRP1 gene detected an increase in the 87 base pair allele in AD cases compared to unaffected controls. Additionally, an independent study involving a genomic screen for genes associated with late-onset AD identified a region as a possible location of a late-onset AD gene on chromosome 12p between D12S373 and D12S390, about 10 cM proximal to LRP1. We examined 144 late-onset multiplex AD families, 436 sporadic AD cases, and 240 controls and found no evidence of linkage or association of LRP1 and AD. Our data indicate that genetic variation of the LRP1 gene is not a major risk factor in the etiology of AD.

Amyotrophic lateral sclerosis (ALS) is a neuro-degenerative disorder with both sporadic and familial forms. Approximately 20% of autosomal dominant ALS is caused by mutations in the Cu/Zn superoxide dismutase (SOD1) gene. The causes of the remaining forms of ALS are unknown. The apolipoprotein E (APOE) gene is a known genetic risk factor for Alzheimer disease (AD), another neuro-degenerative disease. The APOE-4 allele increases risk and decreases age at onset in AD. Studies examining ALS and APOE have failed to show a significant effect of APOE on overall risk in ALS. Studies examining the effect of APOE-4 on site of onset in ALS (bulbar or limb) have been contradictory, with some studies showing an APOE association with bulbar onset and others showing no effect. Sample size was limited in these previous reports, particularly with respect to the number of bulbar onset cases (n = 33, 34 and 53). The present study examines a large collaborative data set of ALS patients (n = 363; 95 with bulbar onset) and age-matched neurologically normal controls. The results for these data showed no significant differences in the percentage of subjects with the APOE-4/4 and APOE-4/X genotypes (X = APOE-2 or APOE-3) when comparing cases and controls in both the overall data set or in the data set stratified by site of onset. Similarly, logistic regression analysis in the overall and stratified data set while controlling for sex showed no increase or decrease in risk of ALS associated with the APOE-4 allele. In addition, there were no significant differences in age at onset between patients with APOE-X/X, and APOE-4/4 or APOE-4/X genotypes, overall or stratified by site of onset. We conclude based on these data that the APOE gene is not a major genetic risk factor for site of onset in ALS.

We examined 11 Caucasian pedigrees with autosomal dominant 'uncomplicated' familial spastic paraplegia (SPG) for linkage to the previously identified loci on chromosomes 2p, 14q and 15q. Chromosome 15q was excluded for all families. Five families showed evidence for linkage to chromosome 2p, one to chromosome 14q, and five families remained indeterminate. Homogeneity analysis of combined chromosome 2p and 14q data gave no evidence for a fourth as yet unidentified SPG locus. Recombination events reduced the chromosome 2p minimum candidate region (MCR) to a 3 cM interval between D2S352 and D2S367 and supported the previously reported 7 cM MCR for chromosome 14q. Age of onset (AO) was highly variable, indicating that subtypes of SPG are more appropriately defined on a genetic basis than by AO. Comparison of AO in parent-child pairs was suggestive of anticipation, with a median difference of 9.0 years (p<0.0001).

The Charcot-Marie-Tooth (CMT) neuropathies are a group of disorders exhibiting neurophysical, pathological and genetic heterogeneity. CMT2 is a diagnostic subtype of this group of disorders characterized by variable expression and age-of-onset and normal or slightly diminished nerve conduction velocities. Previously, linkage and heterogeneity had been reported in CMT2 with linked families localizing to chromosome 1p (CMT2A). Recently a second CMT2 locus has been described on chromosome 7 in a single large CMT2 family (CMT2D). We have performed pedigree linkage analysis on 15 CMT2 families (N = 371 individuals, 106 affected family members) and have confirmed linkage to chromosome 7. Furthermore, using both admixture and multipoint linkage analysis we show conclusive evidence for additional heterogeneity within this clinical subtype with evidence of families that exclude linkage to both the CMT2D and CMT2A regions. In addition, unlike the previous report we found no obvious consistent clinical differences between the linked family types.

The localization of the gene for the majority of cases of facioscapulohumeral muscular dystrophy is established as 4q35-qter (FSHD1A), although locus heterogeneity has been demonstrated with a minority of families unlinked to 4q. In FSHD1A, the disease is associated with a deletion of 3.3 kb repeats from a tandem repeat located near the as-yet-unidentified gene. This repeat cross-hybridizes with a telomeric region on 10q, making this cross-hybridizing region a feasible candidate gene for FSHD1B. We have tested the most telomeric marker on 10q (sAVA4) and excluded approximately 17 cM on either side of this marker as harboring the FSHD1B gene.