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At least 235 records · Page 13Linked to original sources
PubMed1992

Analysis of the DNA duplication 17p11.2 in Charcot-Marie-Tooth neuropathy type 1 pedigrees: additional evidence for a third autosomal CMT1 locus.

We have restudied two clinically typical Charcot-Marie-Tooth neuropathy type 1 (CMT1; also known as hereditary motor and sensory neuropathy 1) pedigrees that were previously reported to be unlinked to the regions of proximal chromosome 1q and chromosome 17p by multipoint linkage analyses. In these two pedigrees, there is no evidence for linkage to additional DNA markers that flank and span the CMT1A locus on chromosome 17p11.2, and a duplication associated with CMT1A is not present in these pedigrees. These findings confirm that the CMT1 locus in these two pedigrees does not map to chromosome 17p11.2 or 1q, and provide further evidence for the existence of a third autosomal locus for CMT1.

Charcot-Marie-Tooth Disease↗
PubMed1992

A 17th-century founder gives rise to a large north American pedigree of autosomal dominant spinocerebellar ataxia not linked to the SCA1 locus on chromosome 6.

There have been three reports since 1969 of members of a "W" family with autosomal dominant spinocerebellar ataxia (SCA), and various conclusions have been drawn about the nosology. This pedigree has been traced back over 300 years through 11 generations. Although phenotypically similar to the disorder in the Schut-Swier, Nino, and other kindreds, the disorder in the W family is not linked to the SCA1 locus on chromosome 6, as reported in those hereditary ataxia pedigrees. The W family represents the largest such North American kindred yet reported. We examined 33 family members of a distantly related branch of the W family, determined the cumulative age of onset, and projected the number of present-day gene carriers. Two cases illustrate the spectrum of symptoms among family members. Age of onset and presenting symptom, however, seem to correlate both in our patients and in those previously reported. Between 2,000 and 5,000 individuals are estimated to be at risk of developing the disorder within this pedigree alone. The pedigree reported here will be valuable in the identification and cloning of a gene for hereditary ataxia, designated "SCA2" at the Eleventh International Workshop on Human Gene Mapping.

Adult↗
PubMed2001

Familial Paget's disease of bone: nonlinkage to the PDB1 and PDB2 loci on chromosomes 6p and 18q in a large pedigree.

Paget's disease of bone is a common condition characterized by bone pain, deformity, pathological fracture, and an increased incidence of osteosarcoma. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis remains largely unknown. Susceptibility loci for Paget's disease of bone have been mapped to chromosome 6p21.3 (PDB1) and 18q21.1-q22 (PDB2) in different pedigrees. We have identified a large pedigree of over 250 individuals with 49 informative individuals affected with Paget's disease of bone; 31 of whom are available for genotypic analysis. The disease is inherited as an autosomal dominant trait in the pedigree with high penetrance by the sixth decade. Linkage analysis has been performed with markers at PDB1; these data show significant exclusion of linkage with log10 of the odds ratio (LOD) scores < -2 in this region. Linkage analysis of microsatellite markers from the PDB2 region has excluded linkage with this region, with a 30 cM exclusion region (LOD score < -2.0) centered on D18S42. These data confirm the genetic heterogeneity of Paget's disease of bone. Our hypothesis is that a novel susceptibility gene relevant to the pathogenesis of Paget's disease of bone lies elsewhere in the genome in the affected members of this pedigree and will be identified using a microsatellite genomewide scan followed by positional cloning.

Adult↗
PubMed2006

[IT15 gene analysis in two pedigrees of Huntington's disease].

To investigate the relationship between the clinical features and (CAG)n trinucleotide repeats in two pedigrees of Chinese Huntington's disease (HD). Clinical and neuroimaging features, the age of disease onset and pattern of transmission of the patients were studied in the two pedigrees of HD. Genomic DNA of 42 family members was used for amplification of the (CAG)n repeats of IT15 gene by PCR. The numbers of (CAG)n were determined by electrophoresis through a 6% polyacrylamide gel and direct sequence analysis. Results showed that patients in pedigree 1 were absent of the typical triad of HD symptoms or caudate atrophy. A total of 9 (5 patients and 4 asymptomatic) out of 18 family members had 40-50 (CAG)n repeats in the IT15 gene. In pedigree 2, all the patients were characterized by a triad of symptoms, including motor disturbance, cognitive impairment and psychiatric features. Three patients and two asymptomatic relatives had more than 50 (CAG)n repeats in the IT15 gene. In conclusion, the clinical symptoms are partly determined by (CAG)n repeats in the IT15 gene. The age of onset was correlated with (CAG)n repeats over 50, and the phenomenon called "anticipation" was found to have played a role.

Adolescent↗
PubMed2005

Combining the meiosis Gibbs sampler with the random walk approach for linkage and association studies with a general complex pedigree and multimarker loci.

A linkage analysis for finding inheritance states and haplotype configurations is an essential process for linkage and association mapping. The linkage analysis is routinely based upon observed pedigree information and marker genotypes for individuals in the pedigree. It is not feasible for exact methods to use all such information for a large complex pedigree especially when there are many missing genotypic data. Proposed Markov chain Monte Carlo approaches such as a single-site Gibbs sampler or the meiosis Gibbs sampler are able to handle a complex pedigree with sparse genotypic data; however, they often have reducibility problems, causing biased estimates. We present a combined method, applying the random walk approach to the reducible sites in the meiosis sampler. Therefore, one can efficiently obtain reliable estimates such as identity-by-descent coefficients between individuals based on inheritance states or haplotype configurations, and a wider range of data can be used for mapping of quantitative trait loci within a reasonable time.

Computer Simulation↗
PubMed1992

Linkage analysis of glucokinase gene with NIDDM in Caucasian pedigrees.

NIDDM has a strong genetic component, as evidenced by the high level of concordance between identical twins. The nature of the genetic predisposition has remained largely unknown. Recently, the glucokinase gene locus on chromosome 7p has been shown to be linked to a subtype of NIDDM known as MODY in French and British pedigrees, and glucokinase mutations have been identified. To study the relationship between the glucokinase gene and NIDDM, we performed a linkage analysis in 12 Caucasian pedigrees ascertained through a proband with classical NIDDM. The LINKAGE program was used under four models, including autosomal dominant and recessive, with individuals with glucose intolerance counted as either affected or of unknown status. Linkage was significantly rejected with the dominant models (LOD scores -4.65, -4.25), and was unlikely with the recessive model when glucose intolerance was considered as affected (LOD score -1.38). These findings suggest that mutations in or near the glucokinase gene are unlikely to be the major cause of the inherited predisposition to NIDDM in Caucasian pedigrees, but do not exclude a role for this locus with a polygenic model, or a major role in some pedigrees.

Adult↗
PubMed1994

Abnormal insulin secretion, not insulin resistance, is the genetic or primary defect of MODY in the RW pedigree.

Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus (NIDDM) associated with autosomal-dominant inheritance. In the RW pedigree, MODY is associated with polymorphic DNA markers on chromosome 20q. To determine the early abnormalities of insulin action and insulin secretion in MODY, we studied nondiabetic members of the RW pedigree with and without the gene marker. Six nondiabetic marker-negative and 5 nondiabetic marker-positive members of the RW pedigree were studied, as were 4 diabetic marker-positive family members. Unrelated, young, healthy subjects served as comparison groups. Insulin action and insulin secretion were assessed with a frequently sampled intravenous glucose tolerance test. Insulin secretion was further assessed during constant glucose infusion by deconvolution of plasma C-peptide and by pulse analysis. The nondiabetic marker-positive group had normal sensitivity to insulin and unimpaired acute insulin response to intravenous glucose (AIRglu). However, the nondiabetic marker-positive group had decreased mean plasma C-peptide concentration and reduced absolute amplitude of insulin secretory oscillations during prolonged glucose infusion. These responses to prolonged glucose infusion were similar to those observed in the diabetic group. No alterations of insulin secretion were observed in the nondiabetic marker-negative family members. Deranged and deficient insulin secretion, and not insulin resistance, appears to be the genetic or primary abnormality that characterizes nondiabetic individuals who are predisposed to MODY in the RW pedigree.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Dyslipidemias among normoglycemic members of familial NIDDM pedigrees.

OBJECTIVE: To examine the hypothesis that hyperinsulinemia among relatives of NIDDM probands will increase the prevalence of DLPs, we measured insulin levels and examined the frequency of DLPs among NIDDM pedigree members. RESEARCH DESIGN AND METHODS: We performed 2-h 75-g OGTTs and measured lipid and insulin levels of 287 family members and 86 spouses from 16 large Utah pedigrees ascertained for greater than or equal to 2 siblings with NIDDM. RESULTS: One-hour insulin levels were higher among 206 family members with NGT than among 65 NGT spouses (483.3 vs. 361.7 pM, P = 0.05). Among the NGT family members, 32% had cholesterol levels at or above the age- and sex-specific 90th percentile level defined by the LRC studies, 33% had HDL levels less than or equal to 10th percentile, and 20% had triglyceride levels greater than or equal to 90th percentile. DLP (any of the three abnormalities) was found among 58% of NGT family members, which was significantly higher than the expected 27% (P less than 0.00001) and the prevalence among spouses of 45% (P less than 0.05). By NCEP criteria for hyperlipidemia, 40% of family members met criteria for diet and/or pharmacological therapy. CONCLUSIONS: Normoglycemic members of NIDDM pedigrees have a high prevalence of DLPs, which approaches the prevalence in patients with NIDDM. Our data suggest that members of NIDDM pedigrees should be screened carefully for lipid abnormalities.

Adult↗
PubMed2002

Quantitative genetics of traits associated with hip dysplasia in a canine pedigree constructed by mating dysplastic Labrador Retrievers with unaffected Greyhounds.

OBJECTIVE: To determine the genetic influence on expression of traits associated with canine hip dysplasia. ANIMALS: 193 dogs from an experimental canine pedigree. PROCEDURE: An experimental canine pedigree was developed for linkage analysis of hip dysplasia by mating dysplastic Labrador Retrievers with nondysplastic Greyhounds. A statistical model was designed to test the effects of Labrador Retriever and Greyhound alleles on age at detection of femoral capital epiphyseal ossification, 8-month distraction index, and 8-month dorsolateral subluxation score. RESULTS: The additive effect was significant for age at detection of femoral capital epiphyseal ossification. Restricted maximum likelihood estimates (+/-SD) for this trait were 6.4+/-1.95, 10.2+/-2.0, 10.8+/-3.1, 11.4+/-2.1, and 13.6+/-4.6 days of age for Greyhounds, Greyhound backcross dogs, F1 dogs, Labrador Retriever backcross dogs, and Labrador Retrievers, respectively. The additive effect was also significant for the distraction index. Estimates for this trait were 0.21+/-0.07, 0.29+/-0.15, 0.44+/-0.12, 0.52+/-0.18, and 0.6+/-0.17 for the same groups, respectively. For the dorsolateral subluxation score, additive and dominance effects were significant. Estimates for this trait were 73.5+/-4.1, 71.3+/-6.5, 69.1+/-6.0, 50.6+/-12.9, and 48.4+/-7.7%, respectively, for the same groups. CONCLUSIONS: In this canine pedigree, traits associated with canine hip dysplasia are heritable. Phenotypic differences exist among founder dogs of each breed and their crosses. This pedigree should be useful for identification of quantitative trait loci underlying the dysplastic phenotype.

Animals↗
PubMed1999

Familial aggregation of lupus and autoimmunity in an unusual multiplex pedigree.

OBJECTIVE: To evaluate an unusual pedigree with 8 members diagnosed with systemic lupus erythematosus (SLE) METHODS: Pedigree members were evaluated through questionnaires, interviews, and medical records. Sixty members contributed serum samples for autoantibody analysis. RESULTS: The 8 affected females shared several disease features, including arthritis (8/8), antinuclear antibodies (ANA) (8/8), pleuritis (6/8), malar rash (6/8), photosensitivity (5/8), and nephritis (4/8). A total of 15 of 51 (29%) blood relatives had autoantibodies; 9 had autoimmune disease, including 7 with SLE, one with psoriasis, and one with Sjögren's syndrome. Five of 11 (45%) nonconsanguineous spouses also had autoantibodies; one spouse had SLE, and 2 others had thyroid disease. Among 68 spouses of patients with SLE in other pedigrees, only 9 (13%) had autoantibodies, and none were symptomatic (p = 0.02). CONCLUSION: The high rate of autoimmunity among both blood relatives and nonconsanguineous mates in this unusual pedigree suggests a complex interaction of genetic and environmental factors contributing to disease.

Abortion, Spontaneous↗
PubMed2000

[The application of polymerase chain reaction-single strain conformation polymorphism in the pedigree analysis of familial hypercholerolemia patients].

OBJECTIVE: To discuss the value of polymerase chain reaction-single strand conformation polymorphism(PCR-SSCP) in the pedigree analysis of familial hypercholesterolemia(FH) patients. METHODS: For 4 patients with FH detected by PCR-SSCP and DNA sequence analysis (1 homozygote has point mutation in exon 7, 1 heterozygote in exon 14, and 2 heterozygotes in 3' part of exon 4 ), members of each pedigree, altogether 23 individuals, were analysed using PCR-SSCP. RESULTS: Every member of the 4 pedigrees was examined genetically. Besides the 4 probands, another 1 homozygote and 8 heterozygotes were found. CONCLUSION: The PCR-SSCP method can be used in the pedigree analysis of FH probands. The early diagnosis of siblings and relatives can help to provide genetic consultation and direction so as to pay attention to development of hypercholesterolemia.

Adolescent↗
PubMed1998

[Screening for the 1555G mutation in mitochondrial DNA in pedigrees with aminoglycoside antibiotic induced deafness].

OBJECTIVE: To identify the relationship between the 1555G mutation in mitochondrial DNA and aminoglycoside antibiotic induced deafness and provide theoretical evidence for establishing diagnostic method. METHODS: Blood samples were obtained from three pedigrees with aminoglycoside antibiotic induced deafness. DNA was extracted from the isolated leukocytes. The mitochondrial DNA fragments were amplified by PCR, 1555G mutation was detected by Alw26 I restriction endonuclease digestion, allele-specific oligonucleotide hybridization and DNA sequencing. RESULTS: Seven individuals from pedigrees A and C carried homoplasmic 1555G mutation, six individuals from pedigree B did not have 1555G mutation. CONCLUSION: 1555G mutation is not the only pathologic mitochondrial DNA mutation associated with aminoglycoside antibiotic induced deafness. This is the first finding of aminoglycoside antibiotic induced deafness pedigree without 1555G mutation.

Anti-Bacterial Agents↗
PubMed2002

Ehlers-Danlos syndrome: case and pedigree report and review.

OBJECTIVE: To report a case and a firstly described pedigree with Ehlers-Danlos syndrome in China. METHODS: Clinical materials of a case of Ehlers-Danlos syndrome type IV and a pedigree of 6 members with 4 generations were analyzed. Dilated internal jugular vein in the proband was removed operatively. The diagnosis, surgical treatment, and postoperative complications were retrospectively summarized. Etiology, clinical characteristics and classification of Ehlers-Danlos syndrome were also analysed. RESULTS: Vessels of the proband in the pedigree were crisp and easily lacinated during the precedure for removal of his internal jugular vein. Repeat postoperative hemotomas were found though complete stanching was made during operation. The patient successfully recovered after prompt debridement in operative theatre and needle sucking. The other 5 members of the pedigrees all had the triads of Ehlers-Danlos syndrome, but no combined vascular diseases were found in them. CONCLUSIONS: Though the morbidity rate was extremely low, green attention should be paid to the high mortality rate and complication of Ehlers-Danlos syndrome during surgical management of in patients with Ehlers-Danlos syndrome type IV. Surgeons should be aware of the ponderance of its complications and combined diseases to avoid fatal intraoprative vascular lacination and incontrollable hamorrhage.

China↗
PubMed2000

The analysis of pedigree GZ (Guangzhou). 1 with primary open angle glaucoma.

PURPOSE: To analyze the hereditary modality of primary open-angle glaucoma in China. METHODS: The genetic form of Pedigree GZ. 1 was analyzed using Mandalian hereditary rules. RESULTS: Pedigree GZ. 1 had following characteristics: 1) The pedigree had four generations, and there existed POAG patients in each generation; 2) Each patient had a parent with POAG. If the parents didn't suffer from the disease, their children would not. 3) The incidence of POAG in the relatives of the patients was 1/2. In addition, The age of onset, intraocular pressure, fundus and prognosis was different from each other in the patients. CONCLUSIONS: 1) Pedigree GZ. 1 is inherited as an autosomal dominant trait. 2) There exists individual differences of clinical manifestations in POAG patients.

Adolescent↗
PubMed2003

[Molecular scanning of candidate mtDNA gene fragment in diabetic pedigrees].

OBJECTIVE: To explore novel pathogenic mutation in the mitochondrial DNA gene in diabetic pedigree. METHODS: Twenty-eight suspected mitochondrial DNA diabetic families were recruited. The gene fragment was produced by PCR, and mutation was detected by direct sequencing. RESULTS: In one pedigree, the proband and her mother were found carrying the most common nt3243 A --> G mutation and another 16S rRNA 3205C --> T mutation. But only 3205C --> T was found in her affected brother. All the two patients were deaf and developed diabetes in early age, characterized by impaired beta cell function and low body mass index (BMI). The proband had relatively higher lactic acid concentration than normal individuals. A novel ND1 gene 3434 A --> G(TAT --> TGT) mutation was explored in another proband with deafness and her affected family members. CONCLUSION: 16SrRNA 3205C --> T mutation was found in a mitochondrial diabetes mellitus pedigree, implying its potential pathogenic role in diabetes. Another novel ND1 3434 A --> G mutation was found in another diabetic pedigree. Because this mutation causes amino acid change (Tyr --> Cys) and is co-segregated with diabetes, it may be diabetogenic.

Adult↗
PubMed2003

[Two novel factor V gene mutations associated with congenital coagulation factor V deficiency, study of one pedigree].

OBJECTIVE: To discover the gene mutations of a pedigree with inherited factor V (FV) deficiency. METHODS: The activated partial thromboplastin time (APTT), prothrombin time (PT), FV activity (FV:C) and FV antigen test were adopted for phenotype diagnosis. The genomic DNA was extracted from the peripheral blood of the 16-year-old propositus, female. All the 25 exons and their flanks in the FV gene of the propositus were amplified by polymerase chain reaction (PCR). The PCR products were screened by direct sequencing and the mutations were further confirmed by restricted enzyme digestion. Six persons in the pedigree (grandfather, grandmother, father, mother, uncle, and aunt) were examined too. 108 healthy blood donors were used as controls. RESULTS: The APTT, PT, FV:C, and FV:Ag of the propositus were 126.6s, 42.8s, 0.3% and 1.3% respectively. The Fbg and FII, FVII, FVIII, FIX, FX activities were in normal range. FV:C of the members of the pedigree was 36% - 70%, and the FV:Ag of the pedigree members was 26.4% - 45.3% that of the mixture of 30 normal plasma samples. Taking the GeneBank Z99572 sequence as the reference, totally five variations in the FV gene were found in the propositus. The mutations, A1348G and 4887 approximately 8delG, were traced to her father and her mother respectively. No 1348G-->T mutation was found in the 108 controls. CONCLUSION: The FV deficiency of the propositus is caused by missense mutation of G1348T and frameshift mutation of 4887 approximately 8delG, which haven't been identified previously.

Adolescent↗
PubMed2002

Surgical management of Ehlers-Danlos syndrome: first report of a pedigree in China.

OBJECTIVE: To describe a case of Ehlers-Danlos syndrome type IV and its pedigree in China. METHODS: Clinical materials of a case of Ehlers-Danlos syndrome type IV and a pedigree of 6 members within 4 generations were analyzed. Dilated internal jugular vein in the proband was removed by operation. The diagnosis, surgical treatment, and postoperative complications were retrospectively reviewed. RESULTS: Vessels of the proband in the pedigree were crisp and easily lacinated during the procedure of removing his internal jugular vein. Repeating postoperative hematomas were found though complete stanching was achieved during the operation. The patient was successfully recovered by promptly debridgement and needle sucking. The other 5 members of the pedigree all had the triads of Ehlers-Danlos syndrome. CONCLUSIONS: Though it was of extremely low morbidity rate, the high mortality rate and complication of Ehlers-Danlos syndrome deserve great attention during surgical management, especially in patients with Ehlers-Danlos syndrome type IV. Surgeons should be aware of the ponderance of its complications and combined diseases to avoid fatal intraoperative vascular lascination and incontrollable hemorrhage.

China↗
PubMed2003

[Molecular genetic analysis for a pedigree with severe hereditary coagulation factor VII deficiency].

OBJECTIVE: To identify the genetic mutations of a severe inherited coagulation factor VII (FVII) deficiency pedigree. METHODS: The diagnosis was validated by coagulant and haemostatic parameters. FVII gene mutations were screened in the propositus and his family members by DNA direct sequencing and confirmed by digestions of the restriction enzymes of the PCR production. RESULTS: Two heterozygous missense mutations were found in the propositus of the pedigree: a G to T transversion at position 9482 in exon 6 and a C to T mutation at position 11348 in exon 8 resulting in the amino acid substitution of Arg152 with Leu and Arg304 with Trp, respectively. A heterozygous single nucleotide deletion (C) at position 11487-11489(CCC) within exon 8 was identified, which predicted the frameshift mutation at position His351 followed by the changes of six corresponding amino acids and appearance of a premature protein caused by stop codon. The heterozygous mutations identified in the proband were derived from his father (Arg152 to Leu) and his mother (Arg304 to Trp mutation) and a heterozygous deletion (C) at position 11487-9(CCC). By tracing the other pedigree members, it was found that his grandmother had a heterozygous mutation of Arg304Trp and a heterozygous polymorphism of Arg353Gln and his grandfather had a heterozygous Arg152Leu mutation. CONCLUSION: Three heterozygous mutations were found in a pedigree with hereditary coagulation factor VII deficiency. Arg152Leu and deletion C at position 11487-9(CCC) were novel mutations.

Adult↗