Needlestick injury and implantable venous access systems.
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Catheters, Indwelling↗
Biomedical subjects
M A Spence
Publications and source records attributed to M A Spence.
Pseudo low penetrance in retinoblastoma. Fortuitous familial aggregation of sporadic cases caused by independently derived mutations in two large pedigrees.
OBJECTIVE: The disparate occurrence of few cases of retinoblastoma in the same extended pedigree confronts us with the unsolved problem of a low-penetrant autosomal-dominant trait vs fortuitous familial aggregation of sporadic cases. Determination as to whether the disease arises from a common inherited mutation or sporadic mutations has important implications for genetic counseling. This is illustrated in this report of two presumed low-penetrant retinoblastoma pedigrees characterized by two distantly affected relatives connected through apparently healthy carriers. DESIGN: We mathematically modeled the inheritance patterns and calculated the a priori relative probabilities of heredity with low penetrance vs chance occurrence of independent mutations for each pedigree. The derived odds clearly show that the disease, which occurred twice in each family, most likely resulted from unrelated mutations. To prove this, extensive DNA testing was conducted, including determination of intragenic RB1 DNA sequence polymorphisms and screening for mutation using the polymerase chain reaction coupled with single-strand conformation polymorphism analysis. PATIENTS: All living key members from both pedigrees were included. RESULTS: Consistent with our initial expectation, there was no common intragenic haplotype or common germ-line mutation that segregated with the disease phenotype in either of these two families. CONCLUSIONS: We therefore conclude that collateral incidence of retinoblastoma in these two pedigrees occurred by chance and not according to autosomal-dominant inheritance with low penetrance. Furthermore, our data provide the first evidence, to our knowledge, that related individuals may have independent mutations involving an identical gene locus, giving rise to an artefactual inheritance pattern.
Child, Preschool↗
Genetics of essential hypertension.
Blood pressure is a complex quantitative trait that is determined by multiple environmental and genetic factors. Although some simple Mendelian forms of high blood pressure have been described, essential hypertension is characterized by a complex mode of inheritance. Based on recent advances in molecular biology and statistical genetics, it has become feasible to search for chromosome regions that may contain genes contributing to the pathogenesis of hypertension in humans. For example, recent linkage and association studies have raised the possibility that a blood pressure regulatory locus may exist in or near the angiotensinogen gene on chromosome 1. Detailed genetic experiments in animal models of hypertension may help to guide further clinical studies and lead to an improved understanding of gene action in the pathogenesis of essential hypertension.
Animals↗
Linkage analysis of Norrie disease with an X-chromosomal ornithine aminotransferase locus.
Norrie disease is a rare disease of newborn males caused by prenatal or perinatal retinal detachment, which may be associated with mental retardation, psychosis, and/or hearing loss. DXS7 (L1.28) and MAO A and B loci have been linked to the ND locus on the short arm of the X chromosome. Sequences homologous to OAT also have been mapped to the short arm of the X chromosome. We performed linkage analyses between the ND locus and one of the OAT-like clusters of sequences on the X chromosome (OATL1), using a ScaI RFLP in a ND family, and increased the previously calculated lod score (z) to over 3 (3.38; theta = 0.05). Similarly, we calculated a lod score of 4.06 (theta = 0.01) between the OATL1 and DXS7 loci. Alone, the OATL1 ScaI RFLP system is expected to be informative in 48% of females. If this system were used in combination with the DXS7 TaqI polymorphism, 71% of females would be informative for at least one of the markers and 21% would be informative for both. Because the OATL1 ScaI RFLP is a relatively common polymorphism, this system should be useful for the identification of ND carriers and affected male fetuses and newborns.
DNA↗
Paternal selection favoring mutant alleles of the retinoblastoma susceptibility gene.
Penetrance and segregation rates of mutant Rb-1 alleles were assessed in all 51 members of eight kindreds with hereditary retinoblastoma by concomitant ophthalmologic examination and determination of seven intragenic restriction fragment length polymorphisms (RFLPs). Penetrance was in the range reported in the literature except for one family in which it was only 42.8%. However, the odds of transmitting a mutant Rb-1 allele from one generation to the next were 25:9 in this population, much above the Mendelian 1:1 ratio (P less than 0.025). This preferential transmission was discovered through the use of molecular information. Further analysis revealed that this distortion was due to preferential inheritance among children of male carriers (18:4, P less than 0.005). No difference from a 1:1 segregation ratio could be detected among the children of female carriers (7:5). These findings were consistent with a review of relevant data in the literature.
Alleles↗
Cleft lip with or without cleft palate in Shanghai, China: evidence for an autosomal major locus.
Orientals are at higher risk for cleft lip with or without cleft palate (CL +/- P) than Caucasians or blacks. We collected demographic and family data to study factors contributing to the etiology of CL +/- P in Shanghai. The birth incidence of nonsyndromic CL +/- P (Shanghai 1980-87) was 1.11/1,000, with a male/female ratio of 1.42. Almost 2,000 nonsyndromic CL +/- P probands were ascertained from individuals operated on during the years 1956-83 at surgical hospitals in Shanghai. Detailed family histories and medical examinations were obtained for the probands and all available family members. Genetic analyses of the probands' families were performed under the mixed model with major locus (ML) and multifactorial (MFT) components. The hypotheses of no familial transmission and of MFT alone could be rejected. Of the ML models, the autosomal recessive was significantly most likely and was assumed for testing three complex hypotheses: (1) ML and sporadics; (2) ML and MFT; (3) ML, MFT, and sporadics. None of the complex models were more likely than the ML alone model. In conclusion, the best-fitting, most parsimonious model for CL +/- P in Shanghai was that of an autosomal recessive major locus.
Asian People↗
Confirmation of linkage between juvenile myoclonic epilepsy locus and the HLA region of chromosome 6.
Juvenile myoclonic epilepsy (JME) is a generalized, non-progressive epilepsy characterized by an adolescent onset of sudden, involuntary myoclonic jerks. Greenberg et al. (American Journal of Medical Genetics 31:185-192, 1988b; Cytogenetics and Cell Genetics 51:1008, 1989b) reported tight linkage of a JME locus to the HLA region of chromosome 6p. We confirm this linkage assignment, although at a larger recombination fraction than previously reported. Twenty-three, mostly nuclear, families were ascertained through a JME proband. The affected status of relatives of the probands was assigned by 4 different clinical criteria, and separate analyses were done assuming an autosomal dominant model with 90% penetrance and an autosomal recessive model with full penetrance. A linear age-of-onset correction with maximum penetrance at age 20 years was incorporated into the analyses. The maximum lod score obtained was 3.11 at (-)m = 0.001, (-)f = 0.20, assuming autosomal dominant inheritance and using the second definition of the disease phenotype. There was strong support for linkage using the other phenotype definitions and the autosomal dominant model, although the lod scores did not exceed 3.0. There was also support for linkage of a JME locus to this region under the autosomal recessive model, although the results varied depending upon the definition of the disease phenotype. There was no significant evidence for linkage heterogeneity.
Chromosome Mapping↗
Severe combined immunodeficiency among the Navajo. I. Characterization of phenotypes, epidemiology, and population genetics.
Previous studies have identified a high incidence of severe combined immunodeficiency (SCID) among the Navajo Native American population. To determine the incidence and population genetics of this condition, we reviewed the death certificates of all children who died between 1969 and 1982, established the cases that met criteria identified in previously investigated cases, and interviewed the selected children's families. SCID cases were distributed spatially and temporally. Segregation parameter estimates of 0.27-0.38 were obtained from data from 24 interviewed families, suggesting an estimated gene frequency of 2.1% (arguing against a multifactorial inheritance). SCID cases referred to specialty centers lacked T and B cells in their blood, and their serum immunoglobulins ranged from absent to near normal.
Arizona↗
Ornithine aminotransferase (OAT): recombination between an X-linked OAT sequence (7.5 kb) and the Norrie disease locus.
A human ornithine aminotransferase (OAT) locus has been mapped to the Xp11.2, as has the Norrie disease locus. We used a cDNA probe to investigate a 3-generation UCLA family with Norrie disease; a 4.2-kb RFLP was detected and a maximum lod score of 0.602 at zero recombination fraction was calculated. We used the same probe to study a second multigeneration family with Norrie disease from Utah. A different RFLP of 7.5 kb in size was identified and a recombinational event between the OAT locus represented by this RFLP and the disease loci was observed. Linkage analysis of these two loci in this family revealed a maximum load score of 1.88 at a recombination fraction of 0.10. Although both families have affected members with the same disease, the lod scores are reported separately because the 4.2- and 7.5-kb RFLPs may represent two different loci for the X-linked OAT.
Blotting, Southern↗
Electronic data interchange finds a ready home.
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Canada↗
Linkage of an autosomal dominant clefting syndrome (Van der Woude) to loci on chromosome Iq.
Van der Woude syndrome (VWS) is an autosomal dominant disorder in which affected individuals have one or more of the following manifestations: cleft lip, cleft palate, hypodontia, or paramedian lower-lip pits. VWS is a well-characterized example of a single-gene abnormality that disturbs normal craniofacial morphogenesis. As a first step in identifying genes involved in human development, we used a candidate-gene-and-region approach to look for a linkage to VWS. Six families with 3 or more generations of affected individuals were studied. Evidence for linkage (theta = 0.02, lod score = 9.09) was found between the renin (REN) gene on 1q and VWS. Other linked loci included CR1, D1S58, and D1S53. The genes for laminin B2 (LAMB2), a basement-membrane protein, and for decay-accelerating factor (DAF) were studied as possible candidate genes on 1q. Recombinants between VWS and both LAMB2 and DAF excluded these genes from a causal role in the etiology of VWS for the families studied in this report. Multipoint linkage analysis indicated that the VWS locus was flanked by REN and D1S65 at a lod score of 10.83. This tight linkage with renin and other nearby loci provides a first step in identifying the molecular abnormality underlying this disturbance of human development.
Chromosomes, Human, Pair 1↗
Linkage studies of bipolar disorder: methodologic and analytic issues. Report of MacArthur Foundation Workshop on Linkage and Clinical Features in Affective Disorders.
To review the findings of the linkage studies of affective disorders, a workshop, "Linkage and Clinical Features in Affective Disorders," was organized by the MacArthur Foundation Mental Health Research Network I on the Psychobiology of Depression meeting in Alexandria, Va, April 13 to 15, 1989. The major goals of the workshop for affective disorders were to explore the relationship between genetic and clinical heterogeneity, to identify major impediments to linkage studies, and to develop recommendations for the application of standardized methods of conducting linkage studies. The participants in the conference presented detailed demographic and clinical data from most of the published linkage studies of affective disorders. No systematic correspondence between genetic and clinical subtypes of bipolar disorder pedigrees was evident. The major problems hampering the linkage analyses of psychiatric disorders that were identified follow: (1) the major psychiatric disorders--the affective disorders in particular--constituting complex human disorders; (2) the lack of valid definitions of affective disorders; (3) comorbidity between the affective disorders with other disorders; (4) nonrandom mating; (5) a cohort effect, with younger birth cohorts exhibiting higher rates of affective disorders; and (6) the lack of replication of current linkage studies. The recommendations that were made for linkage study designs that incorporate some of the complexities of the affective disorders are reported.
Bipolar Disorder↗
Duplicate report crossing over in Norrie disease family.
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Blindness↗
Mapping studies of the serum cholinesterase-2 locus (CHE2).
Serum cholinesterase (butyrylcholinesterase, EC 3.1.1.8, BChE) is controlled by two genetic loci, CHE1 and CHE2. The CHE1 locus has been mapped to 3q, but the map location of CHE2 is uncertain. In an effort to clarify the location of CHE2, we combined all the published linkage analysis data for CHE2 (as summarized in the Keats Linkage Database) with the data from the UCLA Linkage Database. Exclusions with substantial portions of the genome could be made (notably with portions of chromosomes 1, 2, 3, 4, 6, 7, 8, 9, 14, 16, 18, 19, 20, 22, and LG1). Although not quite statistically significant (zeta = 2.51), loose linkage (theta = 0.32) of CHE2 with the haptoglobin locus on 16q22 was the most likely conclusion from the family data. In addition, calculating the lod score between CHE2 and the available linkage map of chromosome 16 (markers HBA, PGP, FRA16A, and HP) resulted in an overall lod score of 3.2. This result is particularly intriguing given the hybridization of a BChE cDNA (designated CHEL3) to the same region. Resolution of the issue will require more detailed linkage studies of CHE2 on chromosome 16 and a better understanding of the relationship between the CHE1 and CHE2 loci with respect to production of serum cholinesterases.
Cholinesterases↗
Genetic influences on spatial ability: transmission in an extended kindred.
Transmission of six spatial tests, Card Rotations, Cube Comparisons, Group Embedded Figures, Hidden Patterns, Mental Rotations, and portable Rod and Frame, is examined among 73 members in four generations of an extended kindred. Nonadditive genetic variance is substantial for one of the six tests, Card Rotations. Whether this nonadditive genetic variance is due to a major autosomal gene is equivocal based on results from segregation and linkage analysis. There is no evidence for genetic variance for Mental Rotations or Hidden Patterns, in contrast to previous findings suggesting major gene involvement (Ashton et al., 1979). If spatial ability is due, in part, to an autosomal major gene, the gene has variable expression (reflected in different tests) or genetic heterogeneity is pronounced.
Adolescent↗
Norrie disease: linkage analysis using a 4.2-kb RFLP detected by a human ornithine aminotransferase cDNA probe.
Previous study has shown that the usual DNA marker for Norrie disease, the L1.28 probe which identifies the DXS7 locus, can recombine with the disease locus. In this study, we used a human ornithine aminotransferase (OAT) cDNA which detects OAT-related DNA sequences mapped to the same region on the X chromosome as that of the L1.28 probe to investigate the family with Norrie disease who exhibited the recombinational event. When genomic DNA from this family was digested with the PvuII restriction endonuclease, we found a restriction fragment length polymorphism (RFLP) of 4.2 kb in size. This fragment was absent in the affected males and cosegregated with the disease locus; we calculated a lod score of 0.602, at theta = 0.00. No deletion could be detected by chromosomal analysis or on Southern blots with other enzymes. These results suggest that one of the OAT-related sequences on the X chromosome may be in close proximity to the Norrie disease locus and represent the first report which indicates that the OAT cDNA may be useful for the identification of carrier status and/or prenatal diagnosis.
Animals↗
A genetic epidemiologic investigation of breast cancer in families with bilateral breast cancer. II. Linkage analysis.
We conducted genetic linkage analyses of breast cancer in 20 pedigrees, each having at least one case of bilateral breast cancer diagnosed before 50 years of age. We tested for linkage using inheritance models from previous segregation analyses, incorporating differences in risk based on menopausal status into the analyses. We tested for heterogeneity by predividing the data set based on the interval between diagnoses of the proband's two primaries (less than 1 year (synchronous) versus at least 2 years (asynchronous], and on the histological types of breast cancer in the pedigrees. Very tight linkage could be excluded between breast cancer and ABO, GC, GPT, MNS, and PGM1 for some of the different linkage analyses. A maximum lod score of +1.01 (at theta = 0.001) between ACP1 and a breast cancer susceptibility locus was seen in the asynchronous all-cases subsample.
Breast Neoplasms↗
Report of the committee on the genetic constitution of chromosome 6.
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Chromosome Mapping↗