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Biomedical subjects

M A Spence

Publications and source records attributed to M A Spence.

At least 73 records · Page 4Linked to original sources
PubMed1988

Autism and genetics. A decade of research.

The last ten years of research on the genetics of infantile autism were critically reviewed. Epidemiologic findings have shown that autism is a rare disorder with a prevalence of two to five per 10,000, a male-female ratio of 3:1, and an association with mental retardation (66% to 75% of autistic subjects have full-scale IQ scores [70]). Autism is familial, as reflected in an empiric sibling recurrence risk of 3% and pooled monozygotic and dizygotic concordance rates of 64% and 9%, respectively, which are much greater than the population prevalence of 0.02% to 0.05%. Genetic heterogeneity is pronounced with potential genetic subgroups, including autosomal recessive inheritance, X-linked inheritance, and sporadic chromosomal anomalies. Studies of subclinical markers in autism have elucidated potential markers at various levels of phenotypic expression from the DNA to the behavioral level. Linkage and cytogenetic studies point to two chromosome regions as putative markers, 9q34 and Xq27. Results of family studies support a putative biochemical marker, low levels of plasma dopamine-beta-hydroxylase, and a putative cognitive marker, ie, normal visuospatial but low verbal functioning, in autism. The frequency of minor physical anomalies and presence or absence of mental retardation are two dimensions of the physical and behavioral phenotype that may demark etiologically distinct subgroups. Genetic heterogeneity is offered as one explanation of the observed sex difference in the prevalence of autism. Directions for potentially fruitful research should be considered.

Adolescent↗
PubMed1988

Possible heterogeneity in the segregation pattern of breast cancer in families with bilateral breast cancer.

We investigated the segregation pattern of breast cancer in families with bilateral breast cancer, classifying families with respect to menopausal status (premenopausal versus postmenopausal) and the interval between diagnosis of the two primary tumors in the probands. Probands were "synchronous" if both primaries were diagnosed within 1 year; "asynchronous" if the interval was at least 2 years. Results for four complex segregation analyses are here presented; the findings support heterogeneity in the transmission of breast cancer. In the asynchronous premenopausal-cases-only analysis, a dominant Mendelian gene can explain the breast cancer pattern. A recessive gene is sufficient to describe the breast cancer distribution in the synchronous premenopausal-cases-only analysis. The synchronous all-cases and the asynchronous all-cases analyses add postmenopausal cases of breast cancer to the premenopausal ones, considering any case to be affected. In the asynchronous all-cases analysis, neither the single-locus model nor the mixed model (that is, a major locus plus other factors, genetic and/or cultural) without generation differences in heritability can be rejected by the unrestricted mixed model with generation differences in heritability. For the synchronous all-cases analysis, a mixed model with generation differences in heritability is necessary to explain the breast cancer transmission. Potential sources of error and possible interpretations are discussed.

Breast Neoplasms↗
PubMed1988

Some effects of selection strategies on linkage analysis.

A study was designed to address the relative merits of different sampling strategies for detecting linkage. Genotypes of pedigree members were generated by the use of a single genetic model, and the pedigrees were subdivided into dominant-appearing, recessive-appearing, and "interesting" subsets. An investigator blind to how the data had been generated applied two different selection rules to determine which individuals in each pedigree would be "typed" for linkage analysis. Linkage analyses were then conducted on these pedigree subsets, as well as on the combined data, by the use of three autosomal dominant models, three autosomal recessive models, and the generating (i.e., "true") model. Results suggest (1) that linkage is likely to be detected even in the absence of knowledge of the mode of transmission, if a range of models can be examined; (2) that false evidence for heterogeneity will not necessarily result when pedigrees are selected according to apparent mode of transmission for analysis; (3) that recessive-appearing pedigrees (i.e., those with multiplex sibships) may be particularly useful for detecting linkage; and (4) that including information on unaffected second-degree relatives adds little to linkage studies of affected individuals and their first-degree relatives.

Genetic Linkage↗
PubMed1988

Genetic linkage analysis of autosomal dominant congenital cataracts with lens-specific DNA probes and polymorphic phenotypic markers.

The authors studied a four-generation family with autosomal dominant congenital cataracts (ADCCs) using linkage analysis with 23 polymorphic phenotypic markers and DNA restriction fragment length polymorphisms (RFLPs) detected by lens-specific DNA probes. A total of 19 family members were studied and the ten affected members had embryonal lens opacities. Close linkage was rejected with DNA probes encoding beta-crystallin, gamma-crystallin, and the major intrinsic protein of the lens fiber membrane (MIP) excluding defects of these genes as the cause of the cataract in this family. No statistically significant lod scores were produced with the polymorphic phenotypic markers. These results support the genetic heterogeneity of ADCCs.

Aquaporins↗
PubMed1988

Recombinational event between Norrie disease and DXS7 loci.

We have identified a family affected with X-linked recessive Norrie disease, in which a recombinational event occurred between the disease locus and the DXS7 locus identified by the probe L1.28. The addition of our family brings the total of published informative families to seven, with a maximum lod score of 7.58 at a recombination frequency of 0.038 +/- 0.036. This finding indicates that the L1.28 probe is useful but may not be completely reliable for prenatal diagnosis and that the gene for Norrie disease is not within the DNA sequence identified by the L1.28 probe.

Chromosome Mapping↗
PubMed1987

Genetic linkage: sampling issues and multipoint mapping.

Genetic linkage is an important tool in determining the genetic contribution to the etiology of behavior disorders and psychiatric disease. Successful linkage studies employ large sample sizes. It is of particular relevance in psychiatric diseases, where the clinical workup is so extensive, to evaluate sample requirements critically. Recent studies indicate that extensive sampling, out to second-degree relatives, will not assist in identifying linkages although it may inflate the sample size considerably. The impact of the assumption about the mode of inheritance of the psychiatric trait and the effect of reduced penetrance are discussed. Multipoint mapping has the added advantage of using information from many markers simultaneously. This is helpful both in identifying individuals at risk to develop disease and in locating a gene with sufficient precision to determine the gene product. There are complications in applying multipoint mapping but these are generally of a technical nature and soluble. Recent suggestions for handling complications for multipoint mapping are evaluated. The correct design of the sampling procedure for selecting families and for selecting marker loci to use will greatly reduce the volume of work required for linkage studies and enhance the chances for success.

Chromosome Aberrations↗
PubMed1987

Genetic linkage studies with neurofibromatosis: the question of heterogeneity.

Three new families are reported for standard gene linkage markers and classical peripheral neurofibromatosis (Von Reckling-hausen disease). Additional data are summarised for the exclusion map. One family gives slight evidence of close linkage with the Gc locus on chromosome 4, raising again the question of possible genetic heterogeneity in NF.

Chromosome Mapping↗
PubMed1987

Tests for genetic heterogeneity among 18 families with Alzheimer's disease.

Two tests for genetic heterogeneity within the framework of linkage analysis were performed among 18 caucasian families with Alzheimer's disease, for each of 27 phenotypic markers. Both tests were performed twice, first assuming that individuals with Down's syndrome were also "affected" with Alzheimer's disease, and second assuming that they were not. No statistically significant heterogeneity was found under either test, regardless of the affected status assumption. However, trends in the data were consistent with heterogeneous etiology between families with both Alzheimer's disease and Down's syndrome versus families with Alzheimer's disease only. The trends were stronger when the Down's syndrome members were considered affected, and were most striking for linkage with the MNSs locus.

Alzheimer Disease↗
PubMed1987

The autosomal dominant form of "pure" familial spastic paraplegia: clinical findings and linkage analysis of a large pedigree.

We studied 33 affected members in a family with autosomal dominant "pure" familial spastic paraplegia (FSP). Symptoms began in the fourth or fifth decade, expression varied, and progression was slow. We excluded close linkage to the HLA locus (distal end of short arm of chromosome 6); C8 alpha-gamma locus (proximal end of short arm of chromosome 1); PGM1 (middle region of short arm of chromosome 1); and P blood group (location unknown). Although there was no statistically significant linkage between FSP and any of the other markers, lod scores were positive with loci for GC (vitamin D binding globulin) located on chromosome 4 (4q11-q13) and Rh located on chromosome 1 (1p34-p36).

Adolescent↗
PubMed1986

Genetic linkage analysis of autosomal dominant congenital cataracts.

Clinical studies and genetic linkage analysis in 64 members of a family with autosomal dominant congenital cataracts demonstrated intrafamilial variable expressivity and asymmetry between the two eyes. On the basis of 26 polymorphic phenotypic gene markers, linkage was excluded with the Duffy blood group (located on chromosome 1), haptoglobin (chromosome 16), and others. These data supported genetic heterogeneity of congenital cataracts as previous linkage assignments have included the pulverulent or Coppock cataract to chromosome 1 with Duffy and a posterior polar cataract to chromosome 16 with haptoglobin.

Cataract↗
PubMed1986

Familial diaphragmatic defects: early prenatal diagnosis and evidence for major gene inheritance.

Congenital diaphragmatic defect (CDD) is a relatively common malformation and results in neonatal death in over 50% of affected infants [Harrison and de Lorimier, 1981]. Although most cases are sporadic, familial aggregation occurs, and controversy exists as to whether this is a "multifactorial" or autosomal recessive trait. Statistical genetic analysis of affected families has not been reported. We report on two new families with multiple occurrence of CDD. In one of the families, the lesion was detected in the fetus by ultrasound at 14 weeks, the earliest reported prenatal diagnosis of CDD. Segregation analysis of our data and of 17 additional multiplex families from the literature led to the conclusion that the autosomal recessive hypothesis cannot be rejected. Multifactorial determination is rejected by the data. The analyses are complicated by several factors, including phenotypic variability, probable genetic heterogeneity, and inadequate description of defects and studies of first-degree relatives. Recurrence risk figures based on a model of multifactorial determination give an underestimate of risk in multiplex families and should not be used until the major gene model is rejected or heterogeneity is clearly demonstrated.

Adult↗
PubMed1986

Cleft lip with or without cleft palate: reanalysis of a three-generation family study from England.

The study population consists of 424 three-generation families originally ascertained through nonsyndromic cleft lip with or without cleft palate (CL +/- P) surgical probands by Carter et al [J Med Genet 19:246-261, 1982] in London, England. Carter et al proposed that the multifactorial threshold model (MF/T) could explain the data. The goal of our study was to test that hypothesis, plus alternatives, rigorously. Two approaches were used: 1) Carter et al had proposed that these data were consistent with the predictions of the MF/T as presented by Carter [Br Med Bull 25:52-57, 1969]. However, we tested those predictions using standard chi 2 tests and found statistically significant departures from the predictions in these families. 2) Complex segregation analysis under the mixed model was performed. Again, the MF/T model could be rejected, as could a model of a major locus alone. The best-fitting model included both major locus and multifactorial components. When the data were analyzed in two parts based on the proband's phenotype (CL vs CL + P) there was some evidence of heterogeneity in that there was a significant proportion of sporadic cases in the families of CL probands but not in the families of CL + P probands. Our results provide no support for the MF/T model. The results from segregation analyses of CL +/- P in these families were most consistent with autosomal major gene inheritance plus multifactorial contributions.

Cleft Lip↗