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At least 163 records · Page 9Linked to original sources
PubMed2003

[A novel keratin 17 gene mutation in a Chinese pedigree of delayed-onset pachyonychia congenita type II].

OBJECTIVE: To detect the keratin 17 gene mutation in a Chinese pedigree of typical delayed-onset pachyonychia congenita type II (PC-II) and to explore the relationship between the genetic mutation and the phenotype of PC-II. METHODS: The DNA was extracted from the blood samples of 19 patients with PC-II in four generations in the pedigree, 1 unaffected member of the pedigree, and 50 un-related normal persons. Nested PCR was used to amplify the mutation hot spot in the exon 1 of keratin 17 gene. The PCR products were directly sequenced to detect the mutation. RESULTS: Sequencing of the PCR products revealed that the codon 109 (AAC) was mutated as GAC in the nine affected members of the pedigree, causing the substitution of asparagine by aspartic acid in codon 109 (N109D) located in the 1A domain of keratin 17 gene. No such mutation was found in the unaffected member of the pedigree and the 50 unrelated controls. CONCLUSION: The novel missense mutation (N109D) located in the second half of 1A domain of keratin 17 gene underlies the affected members' phenotype, delayed-onset pachyonychia congenita type II.

Age of Onset↗
PubMed2004

Biochemical activity and gene analysis of inherited protein C and antithrombin deficiency in two Chinese pedigrees.

BACKGROUND: We identified the gene mutations in two Chinese pedigree of type I hereditary protein C deficiency and type I hereditary antithrombin deficiency. METHODS: The plasma level of protein C activity (PC:A), protein C antigen (PC:Ag), protein S activity, antithrombin activity (AT:A) and antithrombin antigen (AT:Ag) of propositi and two family members were detected using ELISA and chromogenic assay, respectively. All exons and intron-exon boundaries of protein C gene and antithrombin gene were analyzed by direct sequencing of the corresponding amplified PCR products in DNA from the propositus. RESULTS: The plasma PC:A and PC:Ag of propositus 1 was 26% and 1.43 mg/dl, respectively. The PC:Ag and PC:A of his father were normal. The decreased PC:A level was seen in his mother and 4 of his maternal pedigree. PS:A and AT:A were all normal in pedigree 1 members. A C5498T heterozygous mutation in exon 3 of protein C gene, resulting in the substitution of Arg for Trp at the 15th amino acid, was identified in propositus 1 and 8 of his relatives. The plasma AT:A and AT:Ag of propositus 2 was 48.6% and 10.4 mg/dl, respectively. The reduced AT:A and AT:Ag levels were found in his father and 5 of paternal pedigree. PC:A, PC:Ag and PS:A were all in normal range. A heterozygous 13387-9G deletion in exon 6 of antithrombin gene was identified in propositus 2. This mutation introduced a frameshift and a premature stop at codon 426 and existed in 6 members of pedigree 2. CONCLUSION: The C5498T heterozygous mutation in exon 3 of protein C gene, first reported in China, leads to type I hereditary protein C deficiency. The 13387-9G deletion, a novel mutation, can cause antithrombin deficiency and thrombosis.

Adolescent↗
PubMed2005

[Pedigree study of pathological myopia].

90 pedigrees including 1822 individuals were investigated and analyzed to find out the genetic mode of pathological myopia in Chinese population. 169 screened nuclear pedigrees from the total were divided into two groups according to mating mode, Affected * Normal or Normal * Normal. Simple segregation analysis on A * N and N * N pedigrees was performed respectively. The results showed that A * N pedigrees fit the autosomal dominant inheritance, with segregation ratio 0.6033 and sporadic proportion 13.8%, while N * N pedigrees fit autosomal recessive inheritance, with segregation ratio 0.235245 and sporadic proportion 16.3%, although autosomal dominant inheritance could not be rejected. In complex segregation analysis,SAGE-REGD software was used to fit several genetic model, including Mendelian inheritance (major gene, dominant, recessive, codominant) and non-Mendelian inheritance (non-transmitted, environment, general), and at last all Mendelian inheritances including major gene, dominant, recessive, codominant inheritance were accepted, while codominant inheritance with minimus AIC was best fitted. Our study manifests that pathological myopia in Chinese population fits autosomal dominant and autosomal recessive inheritance with certain sporadic proportion, which demonstrates the high genetic heterogeneity of pathological myopia.

Chromosome Segregation↗
PubMed2005

[Investigation of steroid sulfatase gene in two pedigrees with X-linked ichthyosis].

OBJECTIVE: To investigate the gene mutation in two pedigrees with X-linked ichthyosis (XLI) and explore the relationship between the mutation and clinical manifestations. METHODS: Genomic DNA of the affected and normal members of the pedigrees and 50 unrelated normal subjects from different regions was extracted with a whole blood genomic DNA extraction kit for use of the template for PCR amplification of exon 1, exon 2 and exon 10 of the steroid sulfatase (STS) gene. RESULTS: The STS gene was partially deleted in the affected members in the pedigrees with XLI, leaving only exon 1 but not the other exons. The normal member of the pedigree and 50 unrelated normal subjects had no such deletion. CONCLUSION: Partial deletion of the STS gene exists in the two pedigrees with XLI, which is responsible for pathological skin changes characteristic of XLI.

Adolescent↗
PubMed2006

[Mitochondrial 12S rRNA gene A827G in two pedigrees with nonsyndromic deafness].

OBJECTIVE: To investigate the relationship of associating mitochondrial DNA 12S rRNA gene mutations with non-syndromic and aminoglycoside-induced hearing loss happening to Chinese families. METHODS: The diagnosis was validated by hearing tests. Blood samples were collected from 20 family members (13 subjects from pedigree A and 7 from pedigree B) and 32 sporadic deafness cases. DNA was extracted from the leukocytes in blood samples. The gene fragments of mitochondrial DNA 12S rRNA, tRNA(Ser(UCN)) and GJB(2) were amplified by polymerase chain reaction (PCR). PCR products were analyzed by sequencing. RESULTS: The target gene fragments of all individuals were successfully amplified by PCR. The mitochondrial DNA 12S rRNA 827 A to G transition was detected from all maternal members including 12 patients with hearing loss, which was the homoplasmic mutation. Non-maternal members in two pedigrees did not carry this mutation. However, the tRNA(Ser(UCN)) A7445G, 12SrRNA A1555G and GJB2 gene mutations were not found from both the family members of two pedigrees and sporadic patients. One sporadic individual (1/32) who was diagnosed as aminoglycoside-induced hearing impairment carried A827G mutation too. CONCLUSION: It is confirmed that the mitochondrial DNA 12S rRNA gene is a hot spot for mutations associated with non-syndromic inherited hearing loss. The 12S rRNA nt827 A to G mutation may play a pivotal role in the pathogenesis of hearing impairment in two Chinese pedigrees.

Adolescent↗
PubMed1991

Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.

Biochemical and molecular genetic evidence is presented that in six independent pedigrees the development of Leber hereditary optic neuropathy (LHON) is due to the same primary mutation in the mitochondrial ND1 gene. A LHON family from the Newcastle area of Great Britain was analyzed in depth to determine the mitochondrial genetic etiology of their disease. Biochemical assays of mitochondrial electron transport in organelles isolated from the platelet/white-blood-cell fraction have established that the members of this family have a substantial and specific lowering of flux through complex I (NADH-ubiquinone oxidoreductase). To determine the site of the primary mitochondrial gene mutation in this pedigree, all seven mitochondrial complex I genes were sequenced, in their entirety, from two family members. The primary mutation was identified as a homoplasmic transition at nucleotide 3460, which results in the substitution of threonine for alanine at position 52 of the ND1 protein. This residue occurs within a very highly conserved hydrophilic loop, is invariantly alanine or glycine in all ND1 proteins, and is adjacent to an invariant aspartic acid residue. This is only the second instance in which both a biochemical abnormality and a mitochondrial gene mutation have been identified in an LHON pedigree. The sequence analysis of the ND81 gene was extended to a further 11, unrelated LHON pedigrees that had been screened previously and found not to carry the mitochondrial ND4/R340H mutation. The ND1/A52T mutation at nucleotide 3460 was found in five of these 11 pedigrees. In contrast, this sequence change was not found in any of the 47 non-LHON controls. The possible role of secondary complex I mutations in the etiology of LHON is also addressed in these studies.

Amino Acid Sequence↗
PubMed1990

Construction of a family pedigree in genetic counseling before amniocentesis.

The construction of a family pedigree consumes an average of 15-20 minutes during a typical preamniocentesis counseling session. The records of 1,131 patients were reviewed to determine whether development of a pedigree before amniocentesis reveals conditions other than those for which the patient was referred often enough to justify the time spent in the process. The patients were referred for a variety of reasons, with increased maternal age the most common. A positive finding in the pedigree was any condition other than that for which the patient was referred and that required additional comments or testing. It was found that 72.15% of the pedigrees contained at least one other positive finding. Thus, construction of a pedigree before genetic amniocentesis is a valuable objective since it reveals, in the majority of cases, additional factors that may influence the current or future pregnancies or may provide information for other family members.

Amniocentesis↗
PubMed1989

A pedigree primer.

Pedigree-taking skills can promote an understanding of how genetic information relates to a comprehensive family health assessment. The format of the pedigree is used to structure and organize data gathered in the assessment process. The pedigree can assist the nurse and genetics specialist to identify possible patterns of inheritance. This article outlines for the staff nurse the pertinent areas that need to be explored during the assessment process. It discusses common terms and symbols used in the pedigree. Information gathered from the health assessment of an adolescent with Usher's syndrome is used for an example of how the pedigree is constructed.

Adolescent↗
PubMed1989

Genetic analysis of total cholesterol and triglycerides in a pedigree of St. Thomas rabbits.

A pedigree consisting of 103 New Zealand White hyperlipidemic and normal rabbits was used in a genetic analysis of total cholesterol and triglyceride levels to test for Mendelian control of hyperlipidemia. The founder male of this pedigree was identified through hypercholesterolemia and evidence suggested vertical transmission of a hypercholesterolemic phenotype in this pedigree, although a combined hyperlipidemia phenotype (elevated cholesterol and triglycerides) also occurred in many descendents of the original founders. Segregation analysis of quantitative measures of total cholesterol and triglycerides in this pedigree was employed to test hypotheses about Mendelian control in the presence of substantial inbreeding. A simple Mendelian model was the best explanation for triglycerides in these animals. This best fitting model was essentially co-dominant with genotypic specific variances, where the heterozygote was hypertriglyceridemic and the mutant homozygote showed even more extreme values. The observed distribution of total cholesterol was also compatible with a mixture of distinct genotypic distributions, but there was evidence of non-Mendelian transmission in this pedigree. The observed hypertriglyceridemia in these animals may reflect an abnormality of very low density lipoprotein metabolism described previously. Further studies will be required to elucidate the genetic control of hypercholesterolemia and the associated combined hyperlipidemia in these rabbits.

Animals↗
PubMed1986

A linkage study of cystic fibrosis in extended multigenerational pedigrees.

The linkage of polymorphic DNA markers on chromosome 7 to cystic fibrosis (CF) was examined in two pedigrees and a number of smaller nuclear families. The pedigrees are multigenerational and together consist of more than 300 members including 30 affected individuals, while the nuclear families each have two generations and either two or three children with CF. Tight linkage was observed between the CF locus and the met oncogene locus theta = 0, zeta = 15.45), pJ3.11 (theta = 0, zeta = 10.07), and 7C22 (theta = 0, zeta = 6.64) in both the pedigrees and nuclear families with no evidence for recombination between CF and any of the DNA markers. Weaker linkage between the CF locus and the locus for the serum enzyme activity marker paraoxonase (PON) was detected, theta = 0.18, zeta = 0.76. The two pedigrees were sufficiently informative to detect significant linkage between CF and each of the three DNA markers previously shown to be tightly linked to the CF locus. These results establish a locus for CF in these pedigrees in the region of chromosome 7 nearest the three DNA markers met, pJ3.11, and 7C22 and are consistent with locus homogeneity for the defect causing CF in these populations and others that have been examined to date.

Chromosomes, Human, Pair 7↗
PubMed1978

Inbreeding as measured by isonymy, pedigrees, and population size in Törbel, Switzerland.

Törbel provides an interesting test case for the study of the relationship between inbreeding measured by pedigrees and inbreeding measured by isonymy. At the start of this investigation, we were aware that isonymy could introduce biases into the calculation of the inbreeding coefficient in either direction. However, it was expected that in Switzerland, inbreeding from isonymy would be an overestimate due to patrilocal residence and polyphyletic names. One way of dealing with this problem [13] was not to be concerned with the absolute value of inbreeding but only in the difference between estimates. Any bias introduced in the estimate itself disappears in such comparisons, so that a trend of inbreeding can be ascertained correctly. However, it was considered equally important to subject several populations to both a complete pedigree analysis and an isonymic analysis to determine the relationship between estimates of inbreeding. Despite the fact that several authors (Swedlund [18], for example) warned users of isonymy to exercise caution, the careless application of isonymy still persists. In the present study, estimates of inbreeding from isonymy were brought into line with other methods based on pedigree analysis and population size. However, it was possible to do this only in Törbel where pedigree depth was extensive and relatively complete. Similar corrections are possible only when the distribution of mono- and polyphyletic names is known and when migration data are reliable. If the trouble is taken to make these corrections, the same time and effort might as well be spent in pedigree analysis (when fairly complete ascertainment is possible) to achieve the same end result.

Consanguinity↗
PubMed1993

Some developments on the affected-pedigree-member method of linkage analysis.

Some improvements are presented for the affected-pedigree-member method of linkage analysis, which is a generalization of the sib-pair method. The test statistic is extended to include contrasts between affected and unaffected pedigree members, so that it now utilizes marker information from all typed pedigree members rather than just the typed affected members. Computer simulation using a sample pedigree of 14 individuals shows that this modification can substantially increase statistical power where there is a direct association between marker variation and disease and where disease risk is elevated in carriers of the disease allele. Data on Huntington disease in 16 British families, which were analyzed previously using only the affected individuals, are reanalyzed with the unaffected individuals included. Strong rejection of the null hypothesis of no association between Huntington disease and the HindIII polymorphism is confirmed, but the particular families in which the association is significant differs from that obtained through an analysis based only on affected individuals and reflects more closely the results obtained from a lod-score analysis. The test statistic is also modified here to incorporate contrasts between individuals of zero kinship, if needed. This enables contrasts between individuals from different pedigrees, as well as contrasts involving individuals sampled from the general population, to be incorporated into the test of association. For population data, the methodology reduces to a type of contingency-table analysis, in which the rows of the table correspond to different marker-locus genotypes and in which the two columns categorize subjects into an "affected" group versus an "unaffected," or control, group. This aspect of the methodology is illustrated using two population data sets, the first relating APO-E genotype to the frequency of individuals undergoing maintenance hemodialysis and the second relating APO-B genotype to the frequency of coronary artery disease. The present methodology confirms the lack of association between marker and disease in the former data set and confirms the presence of association in the latter. Finally, the methodology is formulated here in terms of ordinary, multiperson kinship coefficients rather than in terms of the generalized kinship coefficients originally proposed. This greatly reduces the number of coefficients to be calculated, thereby enhancing the computational efficiency of the computer program.

Apolipoproteins B↗
PubMed2024

BICEP: Bayesian inference for rare genomic variant causality evaluation in pedigrees.

Next-generation sequencing is widely applied to the investigation of pedigree data for gene discovery. However, identifying plausible disease-causing variants within a robust statistical framework is challenging. Here, we introduce BICEP: a Bayesian inference tool for rare variant causality evaluation in pedigree-based cohorts. BICEP calculates the posterior odds that a genomic variant is causal for a phenotype based on the variant cosegregation as well as a priori evidence such as deleteriousness and functional consequence. BICEP can correctly identify causal variants for phenotypes with both Mendelian and complex genetic architectures, outperforming existing methodologies. Additionally, BICEP can correctly down-weight common variants that are unlikely to be involved in phenotypic liability in the context of a pedigree, even if they have reasonable cosegregation patterns. The output metrics from BICEP allow for the quantitative comparison of variant causality within and across pedigrees, which is not possible with existing approaches.

Pedigree↗
PubMed2003

Glaucoma phenotype in pedigrees with the myocilin Thr377Met mutation.

OBJECTIVE: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the myocilin mutation Thr377Met. METHOD AND DESIGN: Cross-sectional genetic study. Four unrelated pedigrees carrying the Thr377Met mutation were ascertained from more than 2000 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania and from families with glaucoma referred to the study from throughout Australia. Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Thr377Met mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. RESULTS: From the 4 pedigrees carrying the Thr377Met mutation, 23 individuals with either ocular hypertension (OHT) or POAG were found, with a mean +/- SD age at diagnosis of 41.2 +/- 11.5 years, and a mean peak intraocular pressure of 31.7 +/- 9.9 mm Hg. A further 9 mutation carriers older than 18 years were studied who as yet showed no signs of OHT or POAG (6 of these 9 were younger than 30 years). A single individual with POAG was identified who did not carry the Thr377Met mutation. For Thr377Met carriers, age-related penetrance for OHT or POAG was 88% at age 30 years. A positive family history of POAG was present for 3 of the 4 index cases. Thirteen (57%) of the 23 Thr377Met carriers with OHT or POAG had undergone glaucoma drainage surgery. Although the glaucoma in these families appears to be pressure dependent, 2 individuals showed optic disc cupping before detected elevation in intraocular pressure. One family was of British origin, with a different background haplotype from the other 3 families from Greece or Macedonia, who shared a common haplotype. CONCLUSIONS: The GLC1A Thr377Met mutation is associated with POAG that, in the pedigrees studied, had a younger age at onset and higher peak intraocular pressure than in pedigrees with the more common Gln368STOP mutation. In addition, patients with glaucoma with the Thr377Met mutation were more likely to have undergone glaucoma drainage surgery.

Adult↗
PubMed1990

A survey of accessory auricle anomaly. Pedigree analysis of seven cases.

We performed an investigation of 50 accessory auricles on subjects encountered during 1983 through 1985. Fifteen of the families were found to have the same accessory auricular deformity among the probands' family members. From these 15 families, we selected seven pedigrees that were not accompanied by auricular deformities who had filial generations for analysis. Pedigrees 1 through 6 showed autosomal dominant inheritance; two also had irregular dominant properties (pedigrees 4 and 7), and one (pedigree 7) could not be excluded from the possibility of having an X-linked recessive inheritance. During the investigation, there were latent accessory auricles in which the cartilages were seen to be subcutaneous only or protruding slightly. Genetically, the pathogenesis of an accessory auricle should be related to the accessory auricular gene.

Adolescent↗
PubMed1990

X-chromosome markers and manic-depressive illness. Rejection of linkage to Xq28 in nine bipolar pedigrees.

Numerous reports have been published concerning linkage of X-chromosome markers of the q28 region (including protan and deutan color blindness [CB] and glucose-6-phosphate dehydrogenase deficiency) to manic-depressive illness. We studied nine bipolar pedigrees (in which there was no male-to-male transmission) in an attempt to detect linkage, using three tightly linked polymorphic DNA loci, DXS15, DXS52 and F8C (factor 8 gene), all of which are closely linked to the CB and glucose 6-phosphate dehydrogenase classic Xq28 markers. Linkage to this region of Xq28 could be excluded unequivocally in these nine families. When these data were combined with our earlier series of bipolar pedigrees, informative for either protan or deutan CB, a total of 14 bipolar pedigrees have been studied, with no evidence of linkage or heterogeneity. At a recombination fraction (theta) of 1%, this series had greater than 95% power to detect linkage if only 50% of the pedigrees studied were linked to the CB region. Our failure to confirm the previously reported linkage of manic-depressive illness to the CB region of the X chromosome indicates that this linkage is not as common as previously suggested.

Bipolar Disorder↗
PubMed1993

DNA diagnosis of neurofibromatosis 2. Altered coding sequence of the merlin tumor suppressor in an extended pedigree.

OBJECTIVE: To define the DNA mutation causing neurofibromatosis 2 (NF2), a severe genetic disorder involving the development of multiple nervous system tumors in adulthood, in a large, well-studied NF2 pedigree previously used to chromosomally map and to isolate the disease gene. DESIGN: Single-strand conformational polymorphism (SSCP) and DNA sequence analysis of the NF2 gene amplified from affected and unaffected family members. PARTICIPANTS: Affected, unaffected, and at-risk members of a large pedigree segregating NF2, an autosomal dominant disorder caused by inactivation of the merlin tumor suppressor encoded in chromosome band 22q12. RESULTS: A DNA alteration in the merlin coding sequence caused a shift on SSCP gels that was characteristic of the disease chromosome in this NF2 pedigree, being transmitted with the disorder, present only in affected members of the pedigree, absent in unaffected members of the family, and absent from 158 unrelated individuals. The alteration caused substitution of a tyrosine for an asparagine at position 220 of the merlin protein, in a region highly conserved in closely related members of the family of cytoskeletal-associated proteins. The DNA change could also be detected by restriction enzyme digestion with Rsa I. CONCLUSION: Current practice dictates screening of all those "at risk" for NF2 with magnetic resonance imaging, but the frequency and duration of screening are problematic because of the variable course of the disease. The identification of a DNA alteration in the NF2 gene will permit predictive molecular testing of individuals at risk in this specific family, sparing the expense and emotional burden of protracted screening programs. This information, by providing diagnostic certainty, should also reduce psychological and financial burdens and improve medical care for affected family members. A similar approach to defining the underlying lesion and developing a predictive test is applicable in any documented NF2 family.

Amino Acid Sequence↗
PubMed1997

Affected-only multiplex pedigree analysis of GAW10 problem 2.

From a single extended pedigree simulation replicate, high density, affected only subpedigrees were isolated, based on the T > 40 affected status for the disease trait, Q1. On this sample of 14 pedigrees, with a range of two to six affected members (48 total), we conducted a haplotype based, multilocus, nonparametric genome-wide search of the provided data (367 markers) using the computer program GENEHUNTER. As with most genome screens in complex diseases, the objective of this strategy was to identify regions (hot-spots) which breached our predetermined threshold (p < 0.05), requiring confirmation by other groups or consortia. Of the six regions with threshold breaching scores (p < 0.05), the most promising, on chromosome 8 and chromosome 4, corresponded to the locations of MG2 and MG3. Both of these regions have multiple, consecutive markers above threshold and contained the only scores that exceeded p < 0.01. In addition, a fourth hot-spot consisting of a single marker above threshold, was less than 15 cM from MG1 on chromosome 5. The positions of the remaining three hot-spots did not correspond to the any of the major genes and are therefore false positives. An additional analysis of a single nuclear pedigree simulation replicate, using the extended transmission disequilibrium test (ETDT), was applied to markers in each of the above hot-spot regions to look for evidence of disequilibrium with the disease trait. This analysis provided weak additional support for the chromosome 8 finding, even though the sample was very small (36 pedigrees containing 44 affected offspring).

Chromosome Mapping↗