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The spinal muscular atrophies (SMAs) are among the most common autosomal recessive disorders. The mapping of the gene responsible for SMA to chromosome 5 has allowed the assessment of genetic heterogeneity in kindreds with a putative diagnosis of SMA. We report linkage analysis of 71 Canadian SMA families (types 1, 2, and 3) using polymorphisms that both flank and are linked to SMA. Data demonstrating nonlinkage to 5q markers were initially obtained in five kindreds; reexamination of the clinical status of these families showed that one fulfilled all the SMA diagnostic criteria, two showed patterns for which a diagnosis of SMA was possible but not conclusive, and two showed patterns for which the diagnosis of SMA appeared unlikely. This results in a degree of genetic heterogeneity between 1.5% and 4.5%. The three kindreds for which SMA appeared either possible or likely were simplex (ie, contained only one affected individual), and therefore the possibility that they represented new mutations could not be discounted. Thus, the significant majority of classic SMA cases are caused by a mutation in the 5q13.1 locus. Low genetic heterogeneity has implications for both genetic counseling and the applicability of conventional and genetic therapies following cloning of the SMA gene.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked gigantism syndrome characterized primarily by a coarse facies and somatic overgrowth which we have observed to be associated with an increased risk for embryonal tumors. Genetic linkage analysis for two SGBS kindreds in which X linked dominant inheritance was observed has been conducted for the X chromosome. The closest linkage to SGBS was observed for the Xq26 locus HPRT (Z max = 7.45, theta max = 0.00). SGBS-Xq marker recombinations map the disease locus to the DXS425-DXS1123 interval on Xq25-q27. This maps the disease locus to a region known to contain a previously characterized chromosomal translocation breakpoint found in a young girl with somatic overgrowth. This observation may have implications for the cloning of the SGBS gene.

The myotonic dystrophy (DM) mutation has been identified as a heritable unstable CTG trinucleotide repeat sequence. The intergenerational amplification of this sequence is an example of a new class of dynamic mutations responsible for human genetic diseases. To ascertain whether recombination activity influences, or is affected by, the presence of this unique sequence, a comprehensive study of the physical and genetic mapping data for the 1.5-Mb region of human chromosome 19q13.3, which contains the DM locus, was conducted. The recombination rate for this region was examined by correlating genetic distance to physical distance for six selected marker loci. The following markers span the DM region: 19qCEN-p alpha 1.4 (D19S37)-APOC2-CKM-pE0.8 (D19S115)-pGB2.6 (DM)-p134c (D19S51)-19qTER. Initial linear regression analysis of these two parameters failed to reveal a significant linear correlation (coefficient of determination, r2 = .19), suggesting nonuniform rates of recombination. However, the presence of a recombination hot spot was believed to be unlikely, as the marker-to-marker pairs that showed the greatest deviation in recombination frequency were not restricted to a specific region of the 1.5 Mb studied and had relatively broad confidence intervals, as reflected by low LOD values. A second linear regression analysis using only marker intervals with high LOD scores (Zmax > 22) showed linear correlation (r2 = .68) for the entire 1.5-Mb region. This analysis indicated a relatively uniform recombination frequency in the 1.5-Mb region spanning the DM locus. Furthermore, the recombinations observed were neither under- nor overrepresented on DM chromosomes. Consequently, recombination activity is unlikely to influence, or be affected by, the presence of the DM mutation.

The amplification of the CTG trinucleotide repeat in myotonic dystrophy (DM) correlates with increasingly severe phenotypes. We designate its minimal amplification the 'protomutation' since it is the mutation itself at an early stage of intergenerational evolution and is associated with very mild clinical signs. From the study of 536 DM mutation carriers (from 158 affected families), a total of 60 DM-parent/DM-offspring pairings were identified in which the parent had the protomutation. We found a strong correlation between the protomutation length and the amplification observed in the next generation. We also observed the stable transmission of the protomutation through successive generations. This stability may explain the maintenance in the population of this autosomal dominant disease despite the low reproductive fitness of severe DM phenotypes.

The myotonic dystrophy (DM) mutation has recently been identified as an unstable trinucleotide CTG repeat which is present 5-30 times in the normal population but which is amplified up to 2,000 times in DM. We have determined the status of the CTG repeat in 272 DM individuals. Infants with severe congenital DM, as well as their mothers, are shown to have on average a greater amplification of the CTG repeat than is seen in the noncongenital DM population. This fact, when viewed in conjunction with the tendency to increased CTG repeat length in our DM kindreds, provides evidence for the existence of genetic anticipation in the transmission of DM.

We report 6 affected males in a 5-generation family with x-linked Simpson-Golabi-Behmel (SGB) syndrome. All had pre- and postnatal overgrowth with 2 adult males attaining heights over 195 cm. Other features included "coarse" face with hypertelorism, broad nasal root, cleft palate, full lips with a midline groove of the lower lip, grooved tongue with tongue tie, prominent mandible, congenital heart defects, arrhythmias, supernumerary nipples, splenomegaly, large dysplastic kidneys, cryptorchidism, hypospadias, skeletal abnormalities and postaxial hexadactyly. All affected individuals were of normal intelligence. One boy died at age 19 months of a neuroblastoma. The putative origin of the gene in this family was the maternal great grandmother of the propositus. Eight carrier females, who showed varying manifestations of the gene, have been identified. Anthropometric analysis has identified preliminary characteristic craniofacial dimensions in this syndrome. Molecular studies have shown a maximal lod score of 2.81 with no recombinants observed for the SGB-DXYS68 pairing, mapping the disorder to Xqcen-Xq21.3.

Recent genetic linkage studies have mapped the myotonic dystrophy (DM) locus to 19q13.3. All closely linked DM markers identified to date have been located on the centromeric side of the disease locus, with a relatively large genetic interval (9 cM) observed between the nearest distal marker and DM. We show here that the recently described marker p134C is tightly linked to DM (peak lod score 35.8 at peak recombination fraction .006) and confirm the previous suggestion that the p134C locus, D19S51 maps distal to the disease locus. D19S51 and the closest proximal flanking loci, ERCC1 and D19S115 (pE0.8), define a small genetic interval of less than 2 cM that contains the DM locus.

Malignant hyperthermia (MH) is currently diagnosed by the caffeine-halothane contracture (CHC) test. In a previous study, this test was used to establish linkage between the human gene for MH susceptibility and the ryanodine receptor (RYR) gene. The current study extends the genetic linkage analysis to a large French-Canadian kindred. In this family, genetic linkage between RYR and MH genes was not demonstrable using the currently recommended limits of normal for the CHC test in the identification of MH-susceptible individuals. With CHC test threshold limits below those currently recommended, however, complete linkage between the RYR and MH genes was seen. Comparisons of CHC test results with genetic linkage studies will increase the diagnostic accuracy of both tests as well as generate new insights into the biology of MH.

Recent studies have shown the gene encoding creatine kinase isoform M (CKMM) to be very closely linked to the myotonic dystrophy (DM) locus on the long arm of chromosome 19. Given this close linkage to DM and the postulated role of CKMM in skeletal muscle contraction, the possibility of a defect in CKMM causing DM was investigated. CKMM cDNA was isolated from the skeletal muscle of an individual with DM. Sequencing of the CKMM cDNA from the DM chromosome 19 revealed two novel polymorphisms but no translationally significant mutation. This work rules out a defect in the coding segment of CKMM as a cause of DM in this family and, in light of genetic homogeneity shown to date for DM, probably in all cases of DM.

Recent genetic linkage analyses have mapped the myotonic dystrophy locus to the region of 19q13.2-13.3 lying distal to the gene for creatine kinase subunit M (CKM). The human excision repair gene ERCC1 has also been mapped to this region of chromosome 19. A novel polymorphic DNA marker, pEO.8, has been isolated from a chromosome 19 ERCC1-containing cosmid that maps to a 300-kb NotI fragment encompassing both CKM and ERCC1. Genetic linkage analysis reveals close linkage between pEO.8 and myotonic dystrophy (DM) (zmax = 19.3, theta max = 0.01). Analysis of two key recombinant events suggests a mapping of DM distal to pEO.8 and CKM.

The gene for human apolipoprotein CII (APOCII) is located on the proximal long arm of chromosome 19. It has been established as a closely linked marker for myotonic dystrophy (DM), the most common form of adult muscular dystrophy. In the present linkage study, we have analysed 6 APOCII RFLPs in 213 haplotypes: TaqI, 3.8/3.5 kb; BgII, 12.0/9.0 kb; BanI, 2.5/1.6 kb; BamHI, 6.0/4.9 kb; NcoI, 14.5/11.5 kb, and AvaII, 0.6/0.4 kb. The polymorphic enzyme sites were determined to be present at the following frequencies: TaqI, 0.43; BglI, 0.51; BanI, 0.25; BamHI, 0.99; NcoI, 0.51, and AvaII, 0.52. Ordering of the polymorphic sites, 5'----3', has been determined to be (NcoI-BglI)-AvaII-BanI-TaqI. Significant disequilibrium was seen between 5 of the APOCII RFLPs.

The recent cloning of cDNA encoding the Ca++ release channel (ryanodine receptor) of human sarcoplasmic reticulum has enabled us to use somatic cell hybrids to localize the ryanodine receptor gene (RYR) to the proximal long arm of human chromosome 19. Studies with additional hybrids containing deletions or translocations in chromosome 19 enabled us to localize RYR to 19q13.1 in a region distal to GPI/MAG and proximal to D19S18/DNF11. On the basis that the myotonic dystrophy (DM) locus maps near this region and that myotonia could result from a defect in the ryanodine receptor, we examined the linkage between the DM locus and RYR. Our results, showing several DM-RYR recombinants, rule out an RYR defect as the cause of DM. However, localization of RYR to a region of human chromosome 19 which is syntenic to an area of pig chromosome 6 containing the HAL gene responsible for porcine malignant hyperthermia supports the candidacy of RYR for this disorder.

The gene for myotonic dystrophy (DM), the most common form of adult muscular dystrophy, is situated on the proximal long arm of chromosome 19. Although there exist markers that are tightly linked to the DM locus, its precise location is unknown. The identification and characterization of additional DNA probes closely linked to the DM locus continue to be priorities. In this study, we report on the linkage between a new DNA marker, designated p alpha 1.4P, and the DM locus in 50 families. The probe p alpha 1.4P was derived from a cloned breakpoint junction fragment from the chromosomal translocation t(14;19)(q32;q13.1). This translocation has been previously described in some cases of chronic lymphocytic leukemia. We have identified a BanI restriction fragment length polymorphism that is detected by p alpha 1.4P. Segregation analysis between this RFLP and DM revealed close linkage between the two loci (lod = 10.95, theta = 0). Furthermore, statistical evidence for linkage disequilibrium between p alpha 1.4P and the DM locus in a French Canadian population was found. Finally, by means of a somatic cell hybrid mapping panel, p alpha 1.4P was sublocalized to 19q12----19q13.2.

The gene for myotonic dystrophy (DM), the most common form of adult muscular dystrophy, has previously been mapped to the proximal long arm of chromosome 19. We have conducted linkage analysis on 53 DM families (comprising 421 individuals) using seven DM-linked DNA markers. This analysis, combined with our somatic cell hybrid mapping panel data, places the DM locus more distal on the chromosome 19 long arm than previously thought. Further, we have been able to unequivocally identify DNA markers that flank the disease locus. The definition of a 10-cM region of chromosome 19 that contains the DM locus should prove useful in both the search for the causative gene and the molecular diagnosis of DM.

The gene for human apolipoprotein C2 (APOC2), situated on the proximal long arm of chromosome 19, is closely linked to the gene for the most common form of adult muscular dystrophy, myotonic dystrophy (DM). Six APOC2 RFLPs (TaqI, BglI, BanI, BamHI, NcoI, and AvaII) have been identified to date. We have conducted a comprehensive DM linkage study utilizing all six RFLPs and involving 50 families and 372 individuals. The most informative RFLPs are, in descending order, NcoI (lod = 6.64, theta = 0.05), BglI (lod = 6.12, theta = 0.05), AvaII (lod = 6.02, theta = 0.03), BanI (lod = 5.76, theta = 0.04), TaqI (lod = 4.29, theta = 0.06), and BamHI (lod = 1.75, theta = 0.01). A substantial increase in the lod scores over those seen with the individual RFLPs was obtained when the linkage of the entire APOC2 haplotype (composed of the six RFLPs) was studied (lod = 17.87, theta = 0.04). We have observed significant inter-APOC2 RFLP linkage disequilibrium. Consequently, the three most informative RFLPs have been found to be BanI, TaqI, and either BglI, AvaII, or NcoI polymorphisms. We also demonstrate linkage disequilibrium between DM and APOC2 in our French-Canadian population (standardized disequilibrium constant phi = .22, chi 2 = 5.12, df = 1, P less than 0.04). This represents the first evidence of linkage disequilibrium between APOC2 and the DM locus.