Biomedical subjects
Publications and source records attributed to M A Spence.
Linkage analysis of 146 informative families for MN and Ss resulted in an estimate of the recombination frequency greater than previously reported. Our total is 7 recombinant children out of 467 individuals, including 1 confirmed recombinant (retested and HLA-compatible) and 6 not verified. The 95% confidence interval of our estimate of recombination is 0.0033-0.0167. Our results are compared with two earlier studies.
Previous investigators have reported loose linkage in both sexes for phosphoglycolate phosphatase (PGP) and haptoglobin alpha (HPA). We present results of linkage studies between PGP and HPA in two data sets, one from Houston and the other an update of an earlier report from Los Angeles. Using quadratic interpolation to estimate the male (theta m) and female (theta f) recombination values from bivariate lod tables, we found for the Houston data that theta m = 0.43 and theta f = 0.03 at the maximum lod score of z = 2.23. For the Los Angeles series, we found that theta m = 0.31, theta f = 0.48, and z = 0.27. We invoke heterogeneity in the recombination value in different families as an explanation of our findings. We also recommend that bivariate lod tables should always be generated, even though not reported. This is because the usual assumption of theta m = theta f (and, rarely, theta f = 1.8 theta f) under which lod scores are computed may be invalid in many cases.
In a family with hereditary multiple exostoses (diaphyseal aclasis), six generations are known to have been affected. Thirty-three of 85 family members have had the disorder. This condition affects the long bones, pelvis, scapulae, and ribs, and the exostoses continue to enlarge until epiphyseal fusion occurs. Associated deformities, including short stature and malformations of the wrist and ankle, were found in 72%. Fifty percent of affected individuals were moderately or severely handicapped; women and men were affected with equal severity. Exostoses were usually noted by two years and always by five years of age. Hereditary multiple exostoses is inherited as an autosomal dominant condition and is inherited as an autosomal dominant condition and in this familial study the gene showed 93% penetrance. Only one individual appeared clinically normal but nevertheless transmitted the gene to offspring. Red cell antigens, enzymes, and serum enzymes were studied, but none were positive for linkage to the gene for this disease. The frequency of sarcomatous change varies between 3% and 25% in reports in the literature, but no cases occurred in six generations of this family.
One hundred and three unrelated patients with Type 1 (insulin-dependent) diabetes were typed for HLA, properdin factor B (BF), glyoxalase 1 (GLO), Kidd blood group, and 24 other genetic markers. Observed distributions of marker phenotypes among these patients were compared with those expected according to population frequencies, in an attempt to detect associations between Type 1 diabetes and the markers. Strong associations between Type 1 diabetes and both HLA and properdin factor B were confirmed, as was a lack of association between Type 1 diabetes and glyoxalase (GLO). There was an apparent deviation from Hardy-Weinberg equilibrium at the GLO locus, and statistically significant distortions in the distributions of pancreatic amylase (AMY2), galactose-1-phosphate uridyl transferase (GALT), and group-specific component (GC) among Type 1 diabetes patients, but these results are not significant when corrected for performance of multiple tests. An increase in the Lewis-negative phenotype reported elsewhere was observed here but was not statistically significant. A distortion in the distribution of Kidd types reported elsewhere was not confirmed.
Family Pi is a high-risk cancer family in which more than 40% of the members of two generations have had cancer, mostly breast, endometrial, and gastrointestinal. An analysis of over 30 polymorphic genetic markers for possible genetic linkage to a gene increasing susceptibility to cancer revealed positive LOD scores to markers within or near the major histocompatibility complex [HLA-A,B (0.639), properdin B (Bf) (0.162), glyoxylase-1 (GLO-1) (0.166)] as well as to acid phosphatas (0.566) and MNSs (0.449). While no LOD score is statistically significant in the linkage analyses of this family alone, the data are compatible with the hypothesis that a cancer-susceptibility gene(s) (CSG) may be located on chromosome 6p, 2p, or 4q. Analyses of additional families with a similar cancer syndrome are warranted to resolve this ambiquity.
Linkage analysis of 28 genetic markers was undertaken in 108 subjects from 11 families with well-documented, classic, peripheral neurofibromatosis. Fifty-four persons were affected in one four-generation family, seven three-generation families, and three two-generation families. Lod scores were calculated using the standard LIPED programme for 49 combinations of theta male and theta female from 0.01 to 0.50. Lod scores excluded close linkage with 16 markers, including most tested on chromosome 1 and HLA on chromosome 6, and were inconclusive for 12 markers, including the secretor locus, closely linked to myotonic dystrophy. Analysis of five informative families resulted in a lod score of +2.2 for close linkage with GC on chromosome 4. However, the lod score for GC in the one additional informative family was negative, so that the final interpolated maximum was Z = 0.89 for theta male = 0.03, theta female = 0.28. Further studies are needed to evaluate this suggestion of linkage and possible genetic heterogeneity.
Genetic linkage studies are reported on two families with cleft lip +/- cleft palate. For the first family (LP01) the etiology of the clefting is unknown, and the linkage analyses were done assuming both autosomal dominant and autosomal recessive inheritance. Close linkage is rejected with the Duffy blood group under the dominant model and with four loci (Duffy, Kidd, and ABO blood groups and haptoglobin) under the recessive model. The second family (LP02) is a Mexican-American family segregating the van der Woude syndrome with lip pits. The linkage analyses for this autosomal dominant trait excluded close linkage with seven genetic markers, including three on chromosome one. The maximum lod scores were 0.6 with BF (chromosome 6) and 0.4 with the P blood group, which is not yet mapped.
Explore the source record for details and available documents.
In 6 generations of a family with the trismus-pseudocamptodactyly syndrome (TPS), we identified 53 affected individuals, 33 females and 23 males. Thirty-one of the 53 were personally examined, as were 77 unaffected relatives. The clinical findings are compared with those of previous reports. Severity of expression is highly variable, but reduced penetrance was not observed. We obtained blood specimens for linkage analysis on all 108 examined individuals. Linkage could be excluded for 16 polymorphic marker loci. The largest positive lod scores were for the BF and AK1 marker systems, being 0.9 and 0.6, respectively. Since BF and AK1 are on different chromosomes (6 and 9, respectively), these results do not indicate a location for the TPS gene.
Five pedigrees (including an expanded version of a previously reported pedigree) exhibited typical autosomal dominant retinitis pigmentosa were analysed for linkage of RP to 29 genetic markers. No significant lod scores resulted. The largest lod score is +1.51 and suggests linkage between RP and Rh blood group at an estimated recombination fraction of 20% in males and 40% in females. Further studies are needed to confirm or refute this suggested linkage.
A genetic linkage study, performed on a large family with autosomal dominant retinitis pigmentosa (RP), demonstrated that the RP gene may be linked to the Rh locus, known to be on the short arm of human chromosome 1. Linkage studies on RP along with other studies, can help to more accurately classify these disease entities. Localizing the RP gene locus has the potential for allowing the early diagnosis of individuals at risk.
Explore the source record for details and available documents.
27 polymorphic genetic markers were analysed for possible linkage with insulin-dependent diabetes mellitus (IDDM). The data set contained 71 families with at least one affected member each. Under three different genetic models for IDDM, evidence was found for linkage between the disease and two distinct sets of marker loci: three markers on chromosome 6 (HLA, properdin factor B, and glyoxalase-1), and the Kidd blood group locus. The families apparently do not fall into two groups, one exhibiting linkage to the HLA complex and the other to the Kidd locus. Thus, two distinct disease-susceptibility loci may be involved in the inheritance of IDDM.
Recently it has been suggested that multiple sclerosis may be a multifactorial disorder. We found in British Columbia 364 families (sibship size greater than or equal to 2) in which at least on sibling was diagnosed as having "clinically definite" multiple sclerosis. The data were tested for goodness-of-fit to the multifactorial model using an analysis that considers various parameters including ascertainment probability heritability, and sex-dependent prevalence rates. The results suggest that multiple sclerosis does not fit the multifactorial model. As an alternative genetic model we propose that a major gene could be responsible for at least a portion of the cases of multiple sclerosis.
Genetic analyses were conducted on 51 anthropometric measurements and on four factors derived from them by factor analysis. These variables were obtained on 784 members of a religious isolate, the S-leut. Correlations were computed between relatives, and heritabilities were estimates using information on extended families. Longitudinal measurements generally exhibited the highest heritabilities. The test for fit of a major gene model was significant for 13 of the 55 variables, the circumferential and breadth measurements giving the strongest evidence for major gene control. In another approach to establishment of genetic control, linkage analysis was performed between the anthropometric variables and blood group and serum protein polymorphisms. Several traits showed some evidence for linkage but none achieved statistical significance.
This paper continues to examine the model discussed in the preceding paper. Specifically, it will be shown how a linkage analysis performed in the presence of a disease-marker association can give rise to erroneous and misleading results.
Explore the source record for details and available documents.
To test the hypothesis that a multiple sclerosis susceptibility (MSS) gene is linked to the HLA loci, formal linkage analysis was conducted on 40 multiplex families, 20 each from the Seattle and Los Angeles areas. The computer program LIPED was utilized. A dominant model of inheritance was assumed. Penetrance values of 0.05, 0.35, and 0.67 were entered into the analyses, and an age-of-onset correction was incorporated. The resulting lod scores were supportive of linkage at the lower penetrance levels. The maximum lod score, 2.411, at an estimated recombination fraction of 0.10 in both males and females, was generated at a penetrance value of 0.05. With a penetrance value of 0.67, the lod scores did not support linkage. Under an autosomal dominant model of inheritance, the results were supportive of linkage when the presumed penetrance of the MSS gene is low. The results also confirmed the importance of incorporating an age-of-onset correction into linkage analyses.