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PubMed1977

Linking of medical records to form pedigrees.

The human pedigree provides a highly organized representation of historical family morbidity. In order to allow for careful analysis of large numbers of pedigrees, we have developed an interactive computer system for their storage, retrieval and statistical review. The system is capable of integration with our computerized medical record through the use of a common classification (ICHPPC) for patient morbidity. This linkage of pedigrees to clinical data may allow a richer utilization of the clinical experience within Family Practice for the support of research into disease patterns within the family.

Computers↗

PubMed1992

Polymorphisms at the GLUT2 (beta-cell/liver) glucose transporter gene and non-insulin-dependent diabetes mellitus (NIDDM): analysis in affected pedigree members.

The precise genetic defects underlying the etiology of non-insulin-dependent diabetes mellitus (NIDDM) have yet to be identified. The beta-cell/liver glucose transporter gene GLUT2 represents a good candidate for the etiology of the disease, being involved in the glucose signalling for beta-cell insulin release. Population association studies of the GLUT2 gene in NIDDM have so far yielded controversial results. In order to determine the possible contribution of this gene to the inheritance of NIDDM, we have employed a new approach, where two polymorphic markers of the GLUT2 locus, detected with the restriction enzyme Taq-1, were examined for linkage with the disease in a group of 22 Italian pedigrees with affected members (n = 50). Departure from independent segregation between markers and disease was analyzed by the Affected-Pedigree-Members (APM) statistical method. Furthermore, association analysis between the Taq-1 RFLPs at the GLUT2 locus and NIDDM was performed in a group of diabetics with a strong family history, comprising the 22 probands and 23 other diabetics with an affected first-degree relative. The results indicate that there was no segregation distortion between the Taq-1 markers of the GLUT2 gene and the disease in the pedigrees examined. Also, no significant difference in genotype distribution, haplotype and allele frequencies was found between diabetics and controls for the two Taq-1 RFLPs. We conclude that genetic variation at the GLUT2 transporter gene is unlikely to contribute in a major way to the inheritance for NIDDM in this Italian population.

Aged↗

PubMed1993

Familial syndactyly type III--report of a large pedigree.

We present a pedigree containing 14 cases of familial syndactyly of the ring and little finger (Type III syndactyly). Three of these were treated surgically in this unit, and a fourth had previously been treated elsewhere by the senior author of this paper. Analysis of the pedigree confirms the autosomal dominant nature of the genetic defect, while clinical study reveals variable phenotypical expression. This is one of the largest pedigrees et reported for this variety of syndactyly.

Adolescent↗

PubMed1998

Presenilin 1 Met146Leu variant due to an A --> T transversion in an early-onset familial Alzheimer's disease pedigree from Argentina.

Most of the cases of early-onset familial Alzheimer's disease (FAD) are related to missense mutations in the presenilin 1 (PS-1) gene on chromosome 14. Although PS-1 mutations are distributed throughout the entire open reading frame, most mutations are found in transmembrane region II and hydrophilic loop VI encoded by exons 5 and 8, respectively. These two groups of substitutions are associated with an age of onset of 40-43 years for exon 5 and 45-55 years for exon 8, respectively. We have previously described a South American pedigree from Argentina with early-onset FAD (mean age of onset 38.9 +/- 3.9 years) with no mutations in exons 16 and 17 of the beta-protein precursor gene (betaPP770 transcript). Here we report the identification of an A --> T transversion at the first position of codon 146 of PS-1 in these patients. This missense mutation results in a Met --> Leu substitution, as reported for the Italian pedigrees Tor1.1 and FAD4. The significant differences in ages of onset and death among members of generations II-III and IV suggest that other genetic and/or environmental factors may influence disease phenotype in this pedigree.

Adenine↗

PubMed2005

Pedigree information reveals moderate to high levels of inbreeding and a weak population structure in the endangered Catalonian donkey breed.

The Catalonian donkey is one of the most endangered donkey breeds in the world. At present, five main subpopulations exist: AFRAC, which consists of many genetically connected Catalonian localities; Berga, which consists of a single herd located also in Catalunya but under private management; and three minor non-Catalonian subpopulations (Huesca, Sevilla and Toledo). In this study, we analysed the pedigree information of the Catalonian donkey herdbook to assess the genetic diversity and population structure of the breed. We found that the Catalonian donkey has suffered an important loss of genetic diversity and moderate to high increases of inbreeding because of the abuse of a few individuals in matings. This scenario is mainly characterized by the fact that both the effective number of founders and ancestors for the whole population was 70.6 and 27, respectively, while the equivalent number of founders was 146.5 and the number of ancestors explaining overall genetic variability was 93. In addition, only 14% of animals born between the 1960s and 1970s were significantly represented in the pedigree. Our results also show that subpopulations where breeders exchanged reproductive individuals had low levels of inbreeding and average relatedness. One subpopulation, Berga, was reproductively isolated and showed high levels of inbreeding (F = 7.22%), with average relatedness (AR = 6.61%) playing an important role in increasing the values of these coefficients in the whole pedigree. Using genealogical F-statistics we have found little evidence of population structuring (F(ST) = 0.0083) with major genetic differences among non-Catalonian subpopulations.

Animals↗

PubMed2006

Analysis of pedigree and conformation data to explain genetic variability of the horse breed Franches-Montagnes.

Franches-Montagnes is the only native horse breed in Switzerland, therefore special efforts should be made for ensuring its survival. The objectives of this study were to characterize the structure of this population as well as genetic variability with pedigree data, conformation traits and molecular markers. Studies were focused to clarify if this population is composed of a heavy- and a light-type subpopulation. Extended pedigree records of 3-year-old stallions (n = 68) and mares (n = 108) were available. Evaluations of body conformation traits as well as pedigree data and molecular markers did not support the two-subpopulation hypothesis. The generation interval ranged from 7.8 to 9.3 years. The complete generation equivalent was high (>12). The number of effective ancestors varied between 18.9 and 20.1, whereof 50% of the genetic variability was attributed to seven of them. Genetic contribution of Warmblood horses ranged from 36% to 42% and that of Coldblood horses from 4% to 6%. The average inbreeding coefficient reached 6%. Inbreeding effective population size was 114.5 when the average increase of the inbreeding coefficient per year since 1910 was taken. Our results suggest that bottleneck situations occurred because of selection of a small number of sire lines. Promotion of planned matings between parents that are less related is recommended in order to avoid a reduction of the genetic diversity.

Animals↗

PubMed2004

Case for blending pedigrees, genograms and ecomaps: nursing's contribution to the 'big picture'.

In the 21st century, knowledge of genetics is closely linked to the ability to provide good care for all patients, not just the few with uncommon genetic diseases. The authors suggest that what is needed in nursing is a comprehensive, three generation pedigree that records a patient's medical, social and environmental history, thereby communicating a 'big picture' scenario for holistic nursing care. The case is made for blending pedigrees, genograms and ecomaps. Such a tool can guide risk factor identification and inform patient and family clinical decisions vis-a-vis care management strategies, psychosocial support and education for reproductive decisions, risk reduction, and the prevention, screening, diagnosis, referral and long-term management of disease. Pedigrees, genograms and ecomaps are defined, and their clinical application and reliability are described. A case example that blends these tools is presented. Ethical, legal, educational and research implications are discussed.

Directories as Topic↗

PubMedDate not supplied

Canine limbal melanoma: 30 cases (1992-2004). Part 1. Signalment, clinical and histological features and pedigree analysis.

OBJECTIVES: (1) To review the signalment, clinical, and histological features of canine limbal melanoma; (2) to perform pedigree analysis on breeds predisposed to limbal melanoma to establish if common ancestry exists; and (3) to investigate if any ancestral relationship exists between canine limbal melanoma and canine anterior uveal melanoma (CAUM). DESIGN: Retrospective study. ANIMALS STUDIED: Thirty dogs with limbal melanoma. METHODS: Medical records of patients were reviewed. Follow-up information was obtained by re-examination of patients or telecommunications with the referring veterinary surgeons or the owners. Pedigrees were analyzed for common ancestry amongst affected dogs. RESULTS The mean age (+/- SD) at diagnosis was 6.2 (+/- 2.75) years with a range from 1 to 11 years. There was a bimodal distribution of ages with a peak at 3-4 years and a peak at 7-10 years. There was no eye predilection or predisposition for sex or coat color. Twenty-five (83%) of the limbal melanomas occurred within a dorsal arc from the dorsomedial to the ventrolateral limbus. Golden retrievers were four times more common in the melanoma group compared to the Animal Health Trust population (P < 0.0001). Labrador retrievers were three times more common in the melanoma group (P=0.01). Pedigree analysis on eight Golden retrievers [limbal melanoma (n=5), CAUM (n=2) and diffuse ocular melanosis (n=1)], revealed a pattern of inter-relatedness consistent with the condition(s) being caused, at least in part, by a genetic mutation(s). A similar level of inter relatedness was evident in six Labrador retrievers (limbal melanoma (n=2) and CAUM (n=4)). In 5/22 cases (23%), histological features suggestive of malignancy were present including intratumor necrosis in 4/22 cases (18%) and cellular atypia in 1/22 cases (5%). CONCLUSIONS: In Golden and Labrador retrievers there is evidence that limbal melanomas, CAUM and ocular melanosis are at least in part heritable and that the same genetic mutation(s) may be causally associated with melanocytic disease at different ocular sites. The same genetic mutation(s) may be present in these two breeds. Histology should be performed on all cases to identify those with greater malignant potential.

Age Factors↗

PubMed1976

Extensions to pedigree analysis. III. Variance components by the scoring method.

The classic variance components for simple polygenic traits - additive, dominance, and environmental variance - have traditionally been estimated from sample covariances between first-degree relatives. If data is gathered on pedigrees, this statistical procedure wastes information. Recently Elston & Stewart suggested an alternative likelihood procedure that uses all the information in a set of pedigrees. A refinement of their method based on the scoring technique gives rapidly converging maximum likelihood estimates of the variance components and of the male and female means. Tests of statistical hypotheses about the various parameters can then be made by the likelihood ratio method. Furthermore, using classical regression analysis, the estimated parameter values allow prediction of unknown trait values from known trait values within a pedigree. These methods should apply to traits like total finger ridge count and to quantitative measurements associated with disease traits. Since the model postulates independent environmental effects and no assortative mating, its utility in human behaviour genetics seems limited.

Female↗

PubMed2004

Genome scan of venous thrombosis in a pedigree with protein C deficiency.

Kindred Vermont II has a high frequency of venous thrombosis, occurring primarily in pedigree members with type I protein C deficiency due to a 3363 inserted (Ins) C mutation in exon 6 of the protein C gene. However, only a subset of 3363 InsC carriers have suffered thrombotic episodes, suggesting that the increased risk of thrombosis results upon the co-occurrence of 3363 InsC with a second, unknown, thrombophilic mutation that segregates independently within the pedigree. To test this hypothesis and to localize the co-occurring gene, we performed a genome scan of venous thrombosis in Kindred Vermont II. Non-parametric linkage statistics identified three potential gene locations, on chromosomes 11q23 (nominal P < 0.0001), 18p11.2-q11.2 (P < 0.0007), and 10p12 (P < 0.0003), supporting the presence of at least one additional thrombophilic mutation in the pedigree. Identification of the unknown mutation(s) promises to reveal a new genetic risk factor for thrombophilia, contribute to our understanding of the blood clotting mechanism, and expand our knowledge of the diversity of oligogenic disease.

Adolescent↗

PubMed2006

An association of candidate gene haplotypes and bleeding severity in von Willebrand disease type 2A, 2B, and 2M pedigrees.

We analyzed the association of bleeding severity with candidate gene haplotypes within pedigrees of 11 index cases of von Willebrand disease (VWD) type 2 (two type 2A, three type 2B and six type 2M), using the QTL Association model (MENDEL 5.5). In addition to the 11 index cases, these pedigrees included 47 affected and 49 unaffected relatives, as defined by VWF mutations and/or phenotype. A bleeding severity score was derived from a detailed history and adjusted for age. Donors were genotyped using a primer extension method, and eight candidate genes were selected for analysis. VWF antigen (or ristocetin cofactor activity) levels had the strongest influence on bleeding severity score. After Bonferroni correction for multiple testing, only ITGA2 promoter haplotype -52T was associated with an increased bleeding severity score (P < 0.01). This association remained statistically significant when the three type 2B pedigrees were excluded (P = 0.012) or when gender-specific bleeding categories were excluded (P < 0.01). The major haplotypes of seven other candidate genes, GP1BA, ITGA2B, ITGB3, GP6, VWF, FGB, and IL6, were not associated with bleeding severity. These results establish that genetic differences in the expression of the integrin subunit alpha2 can influence the bleeding phenotype of VWD type 2 and complement our previous findings in VWD type 1. Genetically controlled attenuation of platelet collagen receptor expression can influence risk for morbidity in clinical settings where hemostasis is compromised.

Adolescent↗

PubMed1995

Early onset Alzheimer's disease in a South American pedigree from Argentina.

We report the clinical, SPET, immunohistochemical and DNA features of an early-onset familial Alzheimer's disease (FAD) in an Argentine pedigree of South American indian ethnic background. Pedigree spans 5 generations comprising more than 110 biological relatives. Clinical data supported the diagnosis of early onset FAD (mean age at onset 38.9 years) in 10 family members, including 3 with pathological confirmation (mean age at death 48.5). The pattern of transmission suggested autosomal dominant inheritance. Prominent features were mood changes, early language impairment, myoclonus, seizures and cerebellar signs. SPET displayed bilateral frontal, temporo-parietal and cerebellar hypoperfusion in early stages and in an asymptomatic member at risk, suggesting that SPET may have predictive value in this family. Immunohistochemistry showed beta amyloid deposits within neuritic plaques and vessel walls and no anti-PrP immunoreactivity. DNA analysis showed no abnormalities in the beta amyloid precursor protein gene. The identification of additional genetic defects in well characterized independent FAD pedigrees will contribute to the understanding of the pathogenesis of Alzheimer's disease.

Adult↗

PubMed2006

Colour vision defects in asymptomatic carriers of the Leber's hereditary optic neuropathy (LHON) mtDNA 11778 mutation from a large Brazilian LHON pedigree: a case-control study.

AIMS: To determine if asymptomatic carriers from a previously identified large pedigree of the Leber's hereditary optic neuropathy (LHON) 11778 mtDNA mutation have colour vision deficits. METHODS: As part of a comprehensive analysis of over 200 members of a large Brazilian LHON pedigree spanning seven generations, colour vision tests were obtained from 91 members. Colour vision was tested one eye at a time using the Farnsworth-Munsell 100 (FM-100) hue colour vision test. The test was administered under uniform conditions, taking into account: ambient light levels, daylight colour temperature of 6700 kelvin, and neutral uniform background. Tests were scored using the FM-100 MS-Excel computer scoring program. Defects were determined and categorised as tritan, deutan, or protan. Categorisation of each dyschromatopsia was based on review of demonstrated axis computer generated plots and age adjusted error scores which coincided with Verriest 95% confidence intervals. Only the axis with the greatest magnitude error score was used to classify the defect. 55 of the 91 test subjects were LHON mtDNA 11778 J haplotype mutation carriers, proved by mtDNA analysis. The remaining 36 subjects were age matched non-blood relatives (off pedigree), who served as controls. RESULTS: 27 of 55 carriers (49.10%) were shown to have colour vision defects in one or both eyes. 13 of the 27 (48%) abnormal tests in the carrier group were tritan defects and the remaining 14 (52%) were deutan defects. Nine of the 27 (33%) abnormals in the carrier group were identified as having bilateral defects. Six of these were deutan, and the remaining three were tritan dyschromatopsias. Only six of the 36 (16.66%) age matched controls were found to have any type of dyschromatopsia. Five (83.3%) of these were deutan defects. The remaining one was a tritan defect. The difference between the two groups using a chi(2) test with one degree of freedom was statistically significant with a p value less that 0.001. CONCLUSIONS: Until now, LHON has always been characterised by a sudden, devastating vision loss. Asymptomatic carriers, those without vision loss, were considered unaffected by the disease. It now appears that asymptomatic carriers of the LHON mutation are affected by colour vision defects and may manifest other subtle, yet chronic, changes.

Brazil↗

PubMed1996

Diagnosis of malignant hyperthermia: a comparison of the in vitro contracture test with the molecular genetic diagnosis in a large pedigree.

Malignant hyperthermia (MH) is an inherited skeletal muscle disorder and is one of the major causes of death resulting from anaesthesia. MH is currently diagnosed by the in vitro contracture test performed on a muscle biopsy. Genetic linkage analysis on an Irish MH pedigree showed that when the thresholds for the standardised European protocol for MHS diagnosis was applied, linkage between the MHS phenotype and the RYR1 locus was excluded. When we raised the threshold values for assignment of MHS status and assumed MHN diagnosis in subjects where this threshold was not attained, tight linkage between MHS and RYR1 markers was observed, suggesting that MHS is linked to the RYR1 locus in this pedigree. Confirmation of these results was borne out by the fact that all of the MHS patients in the pedigree exceeding the raised threshold carried the known MHS Gly341Arg RYR1 mutation. The results obtained could be explained (1) by false positive diagnosis of MHS in the recombinant subjects, (2) by the presence of a mutation in a predisposing gene other than RYR1, or (3) by the presence of mild subclinical myopathies. The implications of these results for heterogeneity studies is discussed.

Contracture↗

PubMedDate not supplied

Generating consistent genotypic configurations for multi-allelic loci and large complex pedigrees.

Markov chain Monte Carlo techniques have been applied to many different genetic analysis problems. Gibbs sampling in particular has been widely used because of its simplicity and because it can be extended to arbitrarily complex pedigrees and genetic models (albeit with modifications for multi-allelic loci). Gibbs sampling requires an initial genotypic configuration, consistent with observed data, the generation of which is not trivial with large complex pedigrees and multi-allelic loci. A method to generate feasible genotype configurations in these circumstances using a combination of peeling and genotype elimination is described. The method is illustrated using two complex multi-generation pedigrees, one real and one simulated, each partially typed for one highly polymorphic marker locus.

Alleles↗

PubMedDate not supplied

Haplotyping in pedigrees via a genetic algorithm.

Genome-wide screening for localization of disease genes necessitates the efficient reconstruction of haplotypes of members of a pedigree from genotype data at multiple loci. We propose a genetic algorithmic approach to haplotyping and show that it works fast, efficiently and reliably. This algorithm uses certain principles of biological evolution to find optimal solutions to complex problems. The optimality criterion used in the present problem is the minimum number of recombinations over possible haplotype configurations of members of a pedigree. The proposed algorithm is much less demanding in terms of data and assumption requirements compared to the currently used likelihood-based methods of haplotype reconstruction. It also provides multiple optimal haplotype configurations of a pedigree, if such multiple optima exist.

Algorithms↗

PubMed2004

Selecting loop breakers in general pedigrees.

The presence of loops in pedigrees poses severe computational problems in likelihood calculation that can be solved by creating an equivalent unlooped pedigree. We introduce a heuristic polynomial-time dynamic-programming algorithm, called SFH, that addresses the problem of selecting a minimal-cost set of loop breakers. We report computational experiments on simulated pedigrees with up to 1000 individuals and 361 loops, and multiple marriages. We compare the loop-breaker set selected by our method with that obtained using the software package FASTLINK 4.1P. Our approach outperforms FASTLINK 4.1P on the computational-time point of view, on the point of view of quality of the loop-breaker set obtained, and on the point of view of the size of the problem that can be addressed.

Algorithms↗

PubMed2005

A family study in Oman: large, consanguineous, polygamous Omani Arab pedigrees.

OBJECTIVE: To establish a suitable human model for the study of the genetics of complex diseases. METHODS: We have selected an Omani Arab population to provide the statistical power required to study the genetics of complex diseases with confidence. This model consists of five multigenerational highly inbred pedigrees, descending from a small number of founders just a few generations ago with environmental homogeneity, restricted geographical distribution, detailed records and well-ascertained and -validated pedigrees. Stringent criteria were adopted for defining the phenotypes of hypertension, diabetes mellitus, dyslipidemias and obesity. The SOLAR genetic software package was used to draw the pedigree structure. RESULTS: Outstanding statistical power to detect susceptibility loci was obtained. CONCLUSIONS: This model represents a large homogeneous human family-based population for the study of genetic and environmental factors contributing to complex diseases.

Consanguinity↗