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PubMed1999

A pedigree with a novel presenilin 1 mutation at a residue that is not conserved in presenilin 2.

OBJECTIVE: To disclose a novel mutation of the presenilin 1 (PS1) gene responsible for early-onset Alzheimer disease and to clarify genotype-phenotype correlation that should help to establish the function of this protein. BACKGROUND: The PS1 and presenilin 2 (PS2) genes carry missense mutations in families with Alzheimer disease. The PS1 and PS2 proteins have similar structures, and all presently known mutations are in nucleotides coding for amino acids that are conserved between the 2 presenilins. METHODS: Sequence and restriction fragment length polymorphism analyses of PS1 gene of DNA from a pedigree with early-onset Alzheimer disease. RESULTS: Sequence analysis disclosed a novel PS1 mutation in a pedigree of Japanese origin with early-onset Alzheimer disease. This mutation, which is predicted to cause a missense substitution of lysine for glutamic acid, occurred at codon 123 of PS1 that was not a conserved residue in PS2. The 2 patients of this pedigree shared an early clinical phenotype consisting of later-onset, progressive aphasia, but preserved visuospatial ability, which was indistinguishable from those of other PS1-associated Alzheimer disease cases. CONCLUSION: These results demonstrate that a missense mutation in a region not conserved between PS1 and PS2 can cause Alzheimer disease.

Age of Onset↗

PubMed1991

Lack of linkage to chromosome 5q11-q13 markers in six schizophrenia pedigrees.

We examined linkage between schizophrenia and five genetic markers on chromosome 5 in six pedigrees. Analyses were run considering the affected phenotype to be schizophrenia, schizophrenia plus a spectrum of related disorders, and these disorders plus any axis I diagnosis. None of the analyses were suggestive of linkage at any of the markers, either considering the pedigrees individually or in the aggregate. In our pedigrees, multipoint linkage analyses excluded much of the region that had supported linkage in an earlier study. These findings are consistent with other attempts to replicate the chromosome 5 linkage finding.

Chromosome Mapping↗

PubMed1993

Pseudoautosomal locus for schizophrenia excluded in 12 pedigrees.

A pseudoautosomal locus for schizophrenia has been proposed based on observations of an excess of same-sex affected sibling pairs over opposite-sex pairs when the transmitting parent is the father. Such a pattern of partial concordance by sex related to paternal transmission would be difficult to explain by any biologic mechanism other than pseudoautosomal transmission of schizophrenia. To test the pseudoautosomal hypothesis, 37 sibling pairs concordant for the schizophrenia spectrum were identified from 24 nuclear pedigrees. No significant difference in concordance for sex was found between sibships of paternal and maternal transmission of schizophrenia. Next, a linkage analysis was performed in 12 informative pedigrees, examining seven marker loci spanning the pseudoautosomal region. Both strict schizophrenia and a broader schizophrenia spectrum were analyzed as the affected phenotype, and both autosomal dominant and autosomal recessive models were tested. None of the markers supported linkage to either schizophrenia or the schizophrenia spectrum. Lod scores of less than -4 were obtained across the entire pseudoautosomal region by means of multipoint linkage analyses in the autosomal dominant model. In the autosomal recessive model, the respective lod scores were less than -2. We conclude that there is no evidence of a pseudoautosomal locus for schizophrenia in our pedigrees in any of the genetic models we tested.

Chromosome Mapping↗

PubMed1996

An approach to investigating linkage for bipolar disorder using large Costa Rican pedigrees.

Despite the evidence that major gene effects exist for bipolar disorder (BP), efforts to map BP loci have so far been unsuccessful. A strategy for mapping BP loci is described, focused on investigation of large pedigrees from a genetically homogenous population, that of Costa Rica. This approach is based on the use of a conservative definition of the BP phenotype in preparation for whole genome screening with polymorphic markers. Linkage simulation analyses are utilized to indicate the probability of detecting evidence suggestive of linkage, using these pedigrees. These analyses are performed under a series of single locus models, ranging from recessive to nearly dominant, utilizing both lod score and affected pedigree member analyses. Additional calculations demonstrate that with any of the models employed, most of the information for linkage derives from affected rather than unaffected individuals.

Bipolar Disorder↗

PubMed1999

Protein S gene analysis reveals the presence of a cosegregating mutation in most pedigrees with type I but not type III PS deficiency.

DNA sequence analysis of the protein S gene (PROS1) in 22 Spanish probands with type I or III PS deficiency, has allowed the identification of 10 different mutations and 2 new sequence variants in 15 probands. Nine of the mutations, 8 of which are novel, cosegregate with type I or quantitative PS deficiency in 12 of the 13 pedigrees analyzed. One of these mutations (Q238X) also cosegregates with both type I and III PS-deficient phenotypes coexisting in a type I/III pedigree. Another mutation identified in a pedigree with these two PS phenotypes is the missense mutation R520G, present in the homozygous form in the type I propositus and in the heterozygous form in his type III relatives. By contrast, no cosegregating PROS1 mutation has been found in any of the six families with only type III phenotypes. Three of these families, as well as the two families with type I and I/III phenotypes where no other PROS1 mutation has been identified, segregate the P allele of the S460P variant, although this allele does not always cosegregate with the deficient phenotype. From these results we conclude that while mutations in PROS1 are the main cause of type I PS deficiency, the molecular basis of the type III phenotype is probably more complex, with many cases not being explained by a PROS1 mutation.

Adolescent↗

PubMed2000

The practical importance of pedigree analysis in women considering invasive prenatal diagnosis for advanced maternal age or abnormal serum screening tests.

Genetic counselling prior to prenatal diagnosis subserves several functions, one of them to put the planned prenatal test into the wider context of the personal and familial medical history. Even though considered a pivotal part of counselling, little is known about the informational yield and practical relevance of a comprehensive pre-test pedigree analysis. This is particularly true for patients who do not consider prenatal diagnosis for a specific heritable disorder with a high recurrence risk in the ongoing pregnancy, but for a moderate risk for conditions such as Down syndrome that mostly arise de novo. We analysed the informational yield of pedigree analysis for such patients through a retrospective analysis of 1356 consecutive genetic counselling sessions. All cases were referred for advanced maternal age or an abnormal result upon triple serum marker screening. 148 cases (10.9%) were classified as having a significant and previously unknown genetic or teratologic risk factor for the fetus that was uncovered through pedigree analysis. Of these cases, 55% could be recommended a specific prenatal test covering the previously unknown genetic risk factor.

Abnormalities, Drug-Induced↗

PubMed1986

Univariate and bivariate analyses of cholesterol and triglyceride levels in pedigrees.

A multivariate normal model for pedigree analysis is applied to fasting total serum cholesterol and total serum triglyceride measurements on 771 individuals in 95 pedigrees from Rochester, MN. Univariate and bivariate analyses are carried out to determine to what extent the aggregation and coaggregation in families of these two traits may be attributed to shared genetic and environmental factors. Pedigrees were ascertained through a sample of schoolchildren enriched for those with serum cholesterol levels in the highest and lowest deciles of their age- and sex-specific distributions. Ascertainment is corrected for by conditioning the likelihood on the trait values of the probands. Univariate results confirm the findings of previous studies indicating that familial aggregation of serum cholesterol and triglyceride levels is due both to shared genes and to shared environmental factors. Results of the bivariate analyses suggest that the coaggregation of cholesterol and triglyceride levels in these families is strongly influenced by both shared genes (pleiotropy) and shared environmental factors. These findings are consistent with our understanding of lipid metabolism and of specific environmental factors known to influence both traits.

Adolescent↗

PubMed1990

Persistent hyperinsulinemic hypoglycemia of infancy ("nesidioblastosis"): autosomal recessive inheritance in 7 pedigrees.

Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) is a rare disease characterized clinically by persistent hypoglycemia with inappropriately elevated circulating insulin concentrations. Here we report on 7 pedigrees including 21 cases. The pedigrees are derived from 3 distinct ethnic groups, and include a very large Bedouin family, and Arab family, and 5 smaller pedigrees of Jewish families all of Eastern European origin. Data obtained from these families and from other families reported in the literature strongly suggest that PHHI is inherited as an autosomal recessive disorder.

Female↗

PubMed2006

A genome-wide linkage search for bipolar disorder susceptibility loci in a large and complex pedigree from the eastern part of Cuba.

We present results from a genome-wide scan of a six generation pedigree with 28 affected members with apparently dominant bipolar I disorder from eastern Cuba. Genotypes were obtained using the early access version of the Genechip Mapping 10K Xba array from AFFYMETRIX. Parametric and non-parametric linkage analyses under dominant and recessive models were performed using GENEHUNTER v2.1r5. Two phenotypic models were included in the analyses: bipolar I disorder and recurrent depressive disorder, or bipolar I disorder only. LOD scores were calculated for the entire family combined, and for four subdivisions of the family. For the entire family a suggestive parametric LOD score was obtained under the dominant model and the broader phenotype at 14q11.2-12 (LOD = 2.05). In the same region, a non-parametric LOD score close to genome-wide significance was also obtained, based on the entire family (NPL = 7.31, P-value = 0.07). For two individual branches of the pedigree, genome-wide significance (P < 0.005) was obtained with NPL scores of 8.71 and 12.99, respectively, also in the same region on chromosome 14. Chromosome 5q21.3-22.3 also showed close to genome-wide significant linkage for the complete pedigree (NPL = 7.26, P = 0.07), also supported by significant linkage in one individual branch (NPL = 9.86, P < 0.005). In addition, genome-wide significant nonparametric results (P-values <0.005) were obtained for individual branches at 5p13.1-q12.3, 6p22.3, 8q13.3-21.13, and 10q22.3-23.32. Finally, 2p25.1-25.3, 2p13.3-14, 3p14.2, 6p22.3-24.1, 7p14.1-14.2, 8q12.2-12.3, 10q21.1-21.2, 14q13.1-21.1, 15q15.1-21.2, and 22q12.3-13.32 showed suggestive linkage in the complete family. Most of these potential susceptibility loci overlap with, or are close, to previous linkage findings. The locus on 5q may, however, represent a novel susceptibility locus.

Bipolar Disorder↗

PubMed2002

A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees.

Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive muscular disorder characterized by weakness of the anterior compartment of the lower limbs with onset in early adulthood and sparing of the quadricep muscles. The UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene was recently identified as the causative gene for hereditary inclusion body myopathy (HIBM). To investigate whether DMRV and HIBM are allelic diseases, we conducted mutational analysis of the GNE gene of six Japanese DMRV pedigrees and found that all the pedigrees share a homozygous mutation (V572L) associated with a strong linkage disequilibrium, suggesting a strong founder effect in Japanese DMRV pedigrees.

Carbohydrate Epimerases↗

PubMed1986

A log-linear model for binary pedigree data.

A pedigree model for binary data, motivated by log-linear modelling, has been developed to examine evidence for familial aggregation in disease status. From an epidemiological point of view a convenient way to express disease concordance between a pair of relatives is in terms of the odds ratio. For a rare disease this is almost equivalent to the relative risk of one family member being affected given that the other is affected, and in extending this to pedigrees it is assumed that these relative risks are multiplicative. In applying the model to the breast cancer data, pedigrees on a rare disease ascertained through an affected proband, it has been shown that estimation of concordance is dependent critically on knowing the probability that a sampled individual is affected. Therefore known population estimates of prevalence or cumulative risk, and an appropriate ascertainment correction, need to be invoked for the model to give proper estimates of disease concordance. The model is flexible in that measured ancillary risk factors, including genetic marker information, can be incorporated into the analysis. Therefore in future studies this information should be collected on all individuals, not just those affected. Suggested statistics for examining a fitted model are presented.

Alanine Transaminase↗

PubMed1993

Is a single mutation at the same locus responsible for all affected cases in a large Alzheimer pedigree (FAD4)?

Analysis of marker segregation in the large Alzheimer pedigree, FAD4, leads to the conclusion, with a type I error of 5%, of linkage heterogeneity between two branches of the pedigree: the disease cosegregates with chromosome 21 markers flanking the APP area in one branch and not in the other one. Thus, we conclude that a single mutation in the chromosome 21 region surrounding APP cannot be responsible for all the affected cases in this pedigree.

Alleles↗

PubMed2007

MCMC-based linkage analysis for complex traits on general pedigrees: multipoint analysis with a two-locus model and a polygenic component.

We describe a new program lm_twoqtl, part of the MORGAN package, for parametric linkage analysis with a quantitative trait locus (QTL) model having one or two QTLs and a polygenic component, which models additional familial correlation from other unlinked QTLs. The program has no restriction on number of markers or complexity of pedigrees, facilitating use of more complex models with general pedigrees. This is the first available program that can handle a model with both two QTLs and a polygenic component. Competing programs use only simpler models: one QTL, one QTL plus a polygenic component, or variance components (VC). Use of simple models when they are incorrect, as for complex traits that are influenced by multiple genes, can bias estimates of QTL location or reduce power to detect linkage. We compute the likelihood with Markov Chain Monte Carlo (MCMC) realization of segregation indicators at the hypothesized QTL locations conditional on marker data, summation over phased multilocus genotypes of founders, and peeling of the polygenic component. Simulated examples, with various sized pedigrees, show that two-QTL analysis correctly identifies the location of both QTLs, even when they are closely linked, whereas other analyses, including the VC approach, fail to identify the location of QTLs with modest contribution. Our examples illustrate the advantage of parametric linkage analysis with two QTLs, which provides higher power for linkage detection and better localization than use of simpler models.

Chromosome Mapping↗

PubMed2004

The pedigree tool: web-based visualization of a family tree.

We describe the development of a novel tool that facilitates the design and visualization of pedigrees using a special Internet application. The tool is programmed in Java, using a PHP script as an interface. This web-based tool is used to generate, edit, and/or view pedigrees. The advantage of our novel tool is that it is based on a notation that allows the representation of any given number of generations, family members per generation, and multiple clinical or genetic features of an individual family member. In addition, the notation allows us to minimize the storage space by 100% to 500% and to standardize the presentation of family trees and segregation analysis for inheritance of mendelian disorders or even complex traits. This pedigree tool has been implemented with a database of thyroid-stimulating hormone receptor (TSHR) mutations (http://www.uni-leipzig.de/innere/tshr/).

Computer Graphics↗

PubMed2006

Brisk deep-tendon reflexes as a distinctive phenotype in an Argentinean spinocerebellar ataxia type 2 pedigree.

Slow saccades, postural/intention tremor, peripheral neuropathy, and decreased deep-tendon reflexes are valuable neurological signs for clinical suspicion of spinocerebellar ataxia type 2 (SCA2). We report the presence of abnormally brisk deep-tendon reflexes in nonsymptomatic carriers and mildly and severely affected subjects of a large Argentinean SCA2 pedigree. The identification of this distinctive SCA2 phenotype in an entire pedigree reinforces the current concept that clinical algorithms are of limited value as indicators for genetic testing in SCA. Combined with published pedigrees of SCA2 manifesting as levodopa-responsive parkinsonism, this finding suggests that modifier genes could influence the clinical phenotype of SCA2.

Adult↗

PubMed2001

Presence of a major WFS1 mutation in Spanish Wolfram syndrome pedigrees.

Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disease mainly characterized by familial diabetes mellitus and optic atrophy. WS patients frequently present with other clinical features such as diabetes insipidus, renal abnormalities, psychiatric disorders, and a variety of neurologic symptoms: deafness, ataxia, peripheral neuropathy. A gene responsible for Wolfram Syndrome (WFS1) has been recently identified on chromosome 4p16.1. Twenty-two Wolfram patients from 16 Spanish families were screened for mutations in the WFS1 coding region by SSCP analysis and direct sequencing. Since WS has been considered a mitochondrial disorder for some time, mitochondrial DNA (mtDNA) in these families was also examined. WFS1 mutations were detected in 75% of families (12 of 16). One of these mutations, an insertion of 16 base pairs in exon 4, turned out to be notably frequent in Spanish pedigrees. As many as 50% of pedigrees with WFS1 mutations harbored this insertion, either in one (33% of cases) or in two chromosomes (67%). Ten other mutations were identified: 7 missense changes, 2 deletions, and 1 nonsense mutation. Only 3 of these changes had been previously described in non-Spanish pedigrees. Large mtDNA rearrangements and LHON point mutations were detected in four and six families, respectively. No correlation could be established between WFS1 gene mutations and specific point mutations or rearrangements in mtDNA. We would suggest first screening for the 16-bp insertion in exon 4 when a new Spanish WS case is reported.

Alleles↗

PubMed1993

The two locus control of Leber hereditary optic neuropathy and a high penetrance in Japanese pedigrees.

The maternal transmission of Leber hereditary optic neuropathy (LHON) can be explained by the mitochondrial DNA mutation. However, the characteristic mode of inheritance, i.e. male predominance and reduced penetrance with late onset in females, suggests the simultaneous involvement of an X-linked gene in development of optic atrophy. We have assessed such a two-locus model of mitochondrial and X-linked genes in Japanese LHON pedigrees. The goodness-of-fit test on individual male sibship data with a presumed heterozygous mother from maternal lines showed an excellent fit for the 1:1 segregation of a putative X-linked gene, thus supporting the two-locus model in the Japanese pedigrees tested. A calculated frequency of the X-linked gene was 0.10. We could not determine whether the present value is different from the reported one (= 0.08). On the other hand, the estimated penetrance for a heterozygous female was 0.196 +/- 0.039, which was about twice as high as the reported value (= 0.111) with a 5% level of significance. Such a high penetrance may primarily arise from a low threshold of LHON manifestation, suggesting the ethnic difference between the LHON pedigrees in Japan and in other countries.

Asian People↗

PubMed1992

Genetic linkage analysis of bipolar affective disorder in an Old Order Amish pedigree.

We have used genetic linkage analysis in an effort to identify a gene responsible for bipolar affective disorder (BAD) in an Old Order Amish pedigree. The initial study of this pedigree showed strong evidence for linkage of the chromosome 11p15 markers HRAS1 and the insulin gene (INS) to BAD, whereas a second report found no evidence for linkage. We have independently determined the INS and HRAS1 genotypes from 81 individuals in this pedigree. A polymerase chain reaction (PCR) assay was used to score INS alleles that are difficult to distinguish from one another by conventional agarose gel electrophoresis. In addition, we used four separate diagnostic models to score individuals with psychiatric illness as either affected or unaffected. No evidence of significant linkage between BAD and the markers was found with either two-point or multipoint analysis regardless of which diagnostic model was used. However, exclusion of the region of chromosome 11 between INS and RAS1 as a possible location for the BAD gene in this family depended on the diagnostic model. Further genetic linkage studies with additional DNA markers that span the genome are necessary to determine the chromosomal location of the BAD gene in this family.

Base Sequence↗