Familial multiple-system tauopathy with presenile dementia is localized to chromosome 17.

An autosomal dominant presenile dementia affecting 39 individuals in a seven-generation, 383-member pedigree has been studied at Indiana University. In the affected members of this family, clinical symptoms occurred early in life, with an average age at onset of 48.8 years. The presenting clinical features include disequilibrium, neck stiffness, dysphagia, and memory loss. As the disease progresses, further cognitive decline, superior-gaze palsy, and dystaxia also are observed. The average duration from onset of symptoms to death is approximately 10 years. Neuropathologic studies of nine affected individuals showed neuronal loss in several areas of the CNS, as well as argentophilic tau-immunopositive inclusions in neurons and in oligodendroglia. A limited genomic screen by use of DNA samples from 28 family members localized the gene for this disorder to a 3-cM region on chromosome 17, between the markers THRA1 and D17S791. The gene for tau also was analyzed, through samples from the family.     

Presymptomatic direct detection of adenomatous polyposis coli (APC) gene mutations in familial adenomatous polyposis

The recent identification of the familial adenomatous polyposis (FAP) gene (designated as APC) enables conclusive genetic testing of at-risk family members for the specific mutation in families in which the germline gene mutation has been characterized. Presymptomatic molecular diagnosis of FAP was performed by direct direction of mutations in lymphocyte DNA in four families. Each of the families has a different mutation of the APC gene. Twenty-seven offspring of affected individuals (a priori risk of 50%) were tested. Ten of the 27 had already developed clinical features of FAP. Of the remaining seventeen, two had had a negative colon exam at an early age, and nine had never had colon exams (mean age, 12.1±3.1 SD years). Six children from this group (54%) were found to carry their affected parent's mutation. No change in the conventional FAP colon screening regimen is recommended for these children. In contrast, when direct tests indicate that an individual does not have the FAP mutation, we recommended that screening be decreased. Reduction of uncertainty for at-risk FAP family members is an important benefit of genetic testing.     

Phenotypical difference of Amyloid Precursor Protein (APP) V717L mutation in Japanese family

ABSTRACT: BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. Mutations in genes such as those encoding amyloid precursor protein (APP), presenilin 1 and presenilin 2, are responsible for early-onset familial AD.Case presentation In this study, we report a 275341 G > C (Val717Leu) mutation in the APP gene in a Japanese family with early onset AD by genetic screening. This mutation has previously been detected in European families. In the Japanese family we screened, the age at onset of AD was 47.1 +/- 3.1 years old (n = 9; range, 42-52). The symptoms in the affected members included psychiatric vulnerability and focal signs such as pyramidal signs, epileptic seizures, and myoclonic discharges. An MR imaging study showed relatively mild atrophic changes in the bilateral hippocampus and cerebral cortices in all affected members compared with their clinical presentations. CONCLUSION: We conclude that the clinical features of Alzheimer's disease can be different even when caused by the same mutation in the APP gene. Further clinical and genetic studies are required to clarify the relationship between phenotypes and genotypes.     

A kindred with 5 cases of multiple endocrine adenomatosis type I

Details of health, with particular reference to endocrinopathy, were acquired on all living and decreased members of a 4 generation family. Five members were found to be affected with MEA-I. Hyperparthyroidism was the most frequently diagnosed endocrinopathy, but pancreatic tumors were also found to be involved. No indications of the involvement of pituitary tumors were observed. A mediastinal tumor accompanied by a thymoma was also observed. None of the children under 18 years of age were affected. Genetic analysis confirmed the concept that the syndrome follows an autosomal dominant mode of inheritance with virtually complete penetrance but variable expressivity. A careful investigation at regular intervals of high risk members of an affected family is recommended for proper medical management of the condition.     

A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson Disease

To identify rare causal variants in late-onset Parkinson disease (PD), we investigated an Austrian family with 16 affected individuals by exome sequencing. We found a missense mutation, c.1858G>A (p.Asp620Asn), in the VPS35 gene in all seven affected family members who are alive. By screening additional PD cases, we saw the same variant cosegregating with the disease in an autosomal-dominant mode with high but incomplete penetrance in two further families with five and ten affected members, respectively. The mean age of onset in the affected individuals was 53 years. Genotyping showed that the shared haplotype extends across 65 kilobases around VPS35. Screening the entire VPS35 coding sequence in an additional 860 cases and 1014 controls revealed six further nonsynonymous missense variants. Three were only present in cases, two were only present in controls, and one was present in cases and controls. The familial mutation p.Asp620Asn and a further variant, c.1570C>T (p.Arg524Trp), detected in a sporadic PD case were predicted to be damaging by sequence-based and molecular-dynamics analyses. VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer disease.     

Disclosure of personal medical information: differences among parents and affected adults for genetic and nongenetic conditions

Protecting the confidentiality of medical information has been an issue of great interest in the fields of bioethics, public policy, and law. Few empirical studies have addressed patient experiences and attitudes toward disclosure of private medical information in multiple contexts such as health insurance, employment, and the family. Furthermore, it is unclear whether differences exist in experiences and attitudes about privacy between those living with a serious medical condition versus those who have a child with a medical condition. The study sought to determine whether attitudes and experiences related to medical privacy and confidentiality differ between affected adults and parents of affected children. Interviews were conducted with 296 adults and parents of children with sickle cell disease (SCD), cystic fibrosis (CF), or diabetes mellitus (DM). This cross-sectional study collected data regarding their experiences, attitudes, and beliefs concerning medical privacy and confidentiality. Multinomial logistic regression analysis was conducted on quantitative data. Qualitative analysis was conducted on data from open-ended response items. Parents disclose their child's diagnosis to others more often than affected adults disclose their own disease status. Parents are less likely than affected adults to regret their disclosure, to hope others do not find out, to have been pressured to share information, and to be asked about their disease by employers. Affected adults express greater concern about disclosure, a greater prevalence and greater fear of discrimination, and experience greater pressure from family members to disclose. Clinicians and researchers working with these populations should consider these differences in privacy and disclosure. Further study is necessary to examine the implications of these differences in attitudes and experiences concerning insurance, employment, and social interactions among persons with these conditions.     

The use of association data to identify family members at high risk for marker-linked diseases.

The study of genetic markers linked and associated with disease has provided important evidence of a genetic contribution to numerous diseases and has helped to establish their modes of inheritance. However, this information has not been fully utilized in counseling individuals at risk for these disorders. In the case of recessive, marker-linked diseases, such as idiopathic hemochromatosis linked to HLA in family studies and associated with specific HLA alleles in population surveys, the only current clinical application has been to identify siblings who share both HLA-marker haplotypes with the affected proband. They are considered to be presymptomatically affected, and more definitive invasive investigations are considered appropriate. All other relatives, including parents, offspring, and other siblings, who share only one marker with the proband, have been counseled only that their risk is equivalent to the gene frequency of the disease allele, for example, 3%-6% for hemochromatosis. We have developed a generally applicable method to utilize population association data to derive more specific and accurate risk figures for these other relatives of patients with marker-linked and associated diseases. We have applied this method to idiopathic hemochromatosis. If the offspring of a patient with hemochromatosis lacks A3, B7, and B14, the risk to that offspring for developing hemochromatosis is less than 2%. On the other hand, if they receive HLA A3 from their unaffected parent, their risk climbs to 9%-10%; if they receive an A3-B14 haplotype, their risk increases to virtually 100%. As demonstrated by our example, the application of association data to family members already at a basal increased risk for marker-linked disease can significantly refine the disease risk estimates given to those relatives. This information can be utilized to select individuals in whom invasive diagnostic testing or preventative intervention is indicated.     

Linkage of atypical vitelliform macular dystrophy (VMD-1) to the soluble glutamate pyruvate transaminase (GPT1) locus.

One hundred twenty-eight blood samples were drawn from members of a single family with atypical vitelliform macular dystrophy (VMD-1) characterized by variable expressivity in affected members of at least 5 generations. Because of the late onset of detectable retinal lesions in most family members, phenotype data from only 93 individuals who were at least 14 years of age were analyzed for linkage. Phenotype data from the remaining 35 members of the family who were under age 14 were excluded from the analysis. Maximum-likelihood analysis for linkage between VMD-1 and 13 biochemical and serological markers in the family demonstrated linkage between VMD-1 and the soluble glutamate pyruvate transaminase (GPT1) locus, which has been tentatively assigned to the short arm of chromosome 16. A maximum lod score of Z = 4.34 (odds favoring linkage of approximately 22,000 to 1) was obtained at a recombination fraction of theta = .05.     

Familial thrombosis: inherited deficiency of antithrombin III.

Several members of a family living on the west coast of Scotland and on one of the islands off the coast had serious thrombotic disease. The plasma antithrombin III (ATIII) concentrations were measured by both functional and immunological assay in all available members of the family. Concentrations were 25% to 66% of normal in 12 people, including all seven with thrombotic disease. The inheritance pattern was characteristic of an autosomal dominant disorder. Thrombotic disease generally affected the leg, mesenteric, and axillary veins, although one man who had died before the study began had had severe arterial atheroma. In women the first thrombotic symptoms usually occurred during pregnancy. None of these patients have developed thrombotic symptoms until they were at least 18, so four younger members of the family who have ATIII deficiency but no thrombotic disease may eventually develop symptoms.     

Combined analysis of hereditary prostate cancer linkage to 1q24-25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics

A previous linkage study provided evidence for a prostate cancer-susceptibility locus at 1q24-25. Subsequent reports in additional collections of families have yielded conflicting results. In addition, evidence for locus heterogeneity has been provided by the identification of other putative hereditary prostate cancer loci on Xq27-28, 1q42-43, and 1p36. The present study describes a combined analysis for six markers in the 1q24-25 region in 772 families affected by hereditary prostate cancer and ascertained by the members of the International Consortium for Prostate Cancer Genetics (ICPCG) from North America, Australia, Finland, Norway, Sweden, and the United Kingdom. Overall, there was some evidence for linkage, with a peak parametric multipoint LOD score assuming heterogeneity (HLOD) of 1.40 (P=.01) at D1S212. The estimated proportion of families (alpha) linked to the locus was.06 (1-LOD support interval.01-.12). This evidence was not observed by a nonparametric approach, presumably because of the extensive heterogeneity. Further parametric analysis revealed a significant effect of the presence of male-to-male disease transmission within the families. In the subset of 491 such families, the peak HLOD was 2.56 (P=.0006) and alpha =.11 (1-LOD support interval.04-.19), compared with HLODs of 0 in the remaining 281 families. Within the families with male-to-male disease transmission, alpha increased with the early mean age at diagnosis (<65 years, alpha =.19, with 1-LOD support interval.06-.34) and the number of affected family members (five or more family members, alpha =.15, with 1-LOD support interval.04-.28). The highest value of alpha was observed for the 48 families that met all three criteria (peak HLOD = 2.25, P=.001, alpha=.29, with 1-LOD support interval.08-.53). These results support the finding of a prostate cancer-susceptibility gene linked to 1q24-25, albeit in a defined subset of prostate cancer families. Although HPC1 accounts for only a small proportion of all families affected by hereditary prostate cancer, it appears to play a more prominent role in the subset of families with several members affected at an early age and with male-to-male disease transmission.     

Hereditary site-specific colon cancer in a Canadian kindred.

A large kindred with colorectal cancer unaccompanied by polyposis coli and characterized by autosomal dominant inheritance has been identified in eastern Canada. Ten family members from three successive generations have presented 17 documented colorectal cancers. The clinical features of the kindred are characteristic of hereditary site-specific colon cancer (HSSCC) (Lynch syndrome I): absence of multiple polyposis, autosomal dominant inheritance, onset of colorectal cancer at an early age and a high incidence of synchronous and metachronous colorectal cancers. A unique feature of this family is the high incidence of sporadic adenomatous polyps in affected members and their relatives. Patients with HSSCC have been managed by means of segmental colectomy followed by annual colonoscopic surveillance. All five patients with localized (Dukes'' stage A or B) cancer at initial diagnosis were alive and free of disease after 2 to 12 years of follow-up, although three had required further colonic resection for metachronous carcinomas. Five young family members without cancer have had sporadic adenomatous polyps removed and are being followed with annual colonoscopy. It is not known whether polypectomy will alter the subsequent incidence of colon cancer. Subtotal colectomy is recommended for patients with HSSCC because of the high incidence of multiple lesions. An aggressive screening protocol, including colonoscopy, is recommended for all adult first- and second-degree relatives of patients with HSSCC. Identification of a biomarker, which is currently being sought in this kindred, would help identify those at greatest risk of development of cancer and allow earlier intervention.     

Papillary renal cell carcinoma: analysis of germline mutations in the MET proto-oncogene in a clinic-based population

Approximately 10% of all renal cell carcinomas (RCCs) present a distinctive papillary histology. Familial papillary RCC (PRCC) has been described, but the majority of cases appear to be sporadic. Recently, germline mutations in the MET proto-oncogene on chromosome 7 have been identified in families with hereditary PRCC. We evaluated 59 patients with PRCC for the frequency of MET germline mutations to determine the value of genetic screening of this patient population. Between 1976 and 1997, 165 patients were identified with PRCC by retrospective chart review. Fifty-nine of 133 surviving patients agreed to provide a family history, a blood specimen, and informed consent for genetic research. DNA was isolated from peripheral blood leukocytes. Denaturing high-performance liquid chromatography (DHPLC) followed by genomic sequencing was performed on eight exons of the MET proto-oncogene, including exons 5-7 of the extracellular domain, exon 14, and exons 16-19 of the tyrosine kinase domain. The 59 patients in this study included 49 men and 10 women with a mean age at diagnosis of 61 years. Bilateral and/or multifocal disease was present in 13 cases (22%). No germline mutations were detected in the studied exons of the MET proto-oncogene (exons previously reported to contain deleterious mutations in familial PRCC). No pathological MET proto-oncogene germline mutations were identified in 59 patients with PRCC. The germline mutation rate in this clinic-based population of individuals with PRCC approaches 0% (CI = 0-6.18). MET proto-oncogene germline mutation screening does not appear to be clinically indicated in patients with PRCC without additional evidence for a genetic predisposition (positive family history, unusual age at onset, bilateral disease).     

Hereditary adenocarcinomatosis in 4 generations of a Valais family

An account is given of a family from the Canton of Valais, suffering from hereditary adenocarcinomatosis. The pedigree extends over four generations; the first three comprise 47 individuals (28 males, 19 females), of whom 21 (16 males and 5 females), i.e. 44.6%, are affected with malignant tumours. Of the 32 people in the fourth generation, only one individual is affected to date (a girl aged 21, IV/14). There were 27 tumours in all: 16 adenocarcinomas of the colon, two gastric adenocarcinomas, one duodenal adenocarcinoma, one rectal adenocarcinoma, one papillary carcinoma of the ovary, one osseous sarcoma, one cutaneous fibrosarcoma, a multiform glioblastoma of the basal nuclei of the brain, a basocellular epithelioma, also a cerebral metastasis from an adenocarcinoma, the origin of which has not been established, and a tumour invading the biliary tract. Three members of the family suffered from multiple tumours. In three of the patients, the colonic adenocarcinoma was accompanied by one or two polyps. The average age at the onset for all the tumours was 45 years. It was definitely lower in the third than the second generation (anticipation). The transmission was autosomal dominant, with predilection for the male sex (57.1% male and 26.3% female patients). The penetrance was about 80%. The author finally discusses the diagnostic criteria for hereditary adenocarcinoma and reviews the different familial forms of cancer.     

Noncompaction of the ventricular myocardium is associated with a de novo mutation in the beta-myosin heavy chain gene

Noncompaction of the ventricular myocardium (NVM) is the morphological hallmark of a rare familial or sporadic unclassified heart disease of heterogeneous origin. NVM results presumably from a congenital developmental error and has been traced back to single point mutations in various genes. The objective of this study was to determine the underlying genetic defect in a large German family suffering from NVM. Twenty four family members were clinically assessed using advanced imaging techniques. For molecular characterization, a genome-wide linkage analysis was undertaken and the disease locus was mapped to chromosome 14ptel-14q12. Subsequently, two genes of the disease interval, MYH6 and MYH7 (encoding the alpha- and beta-myosin heavy chain, respectively) were sequenced, leading to the identification of a previously unknown de novo missense mutation, c.842G>C, in the gene MYH7. The mutation affects a highly conserved amino acid in the myosin subfragment-1 (R281T). In silico simulations suggest that the mutation R281T prevents the formation of a salt bridge between residues R281 and D325, thereby destabilizing the myosin head. The mutation was exclusively present in morphologically affected family members. A few members of the family displayed NVM in combination with other heart defects, such as dislocation of the tricuspid valve (Ebstein's anomaly, EA) and atrial septal defect (ASD). A high degree of clinical variability was observed, ranging from the absence of symptoms in childhood to cardiac death in the third decade of life. The data presented in this report provide first evidence that a mutation in a sarcomeric protein can cause noncompaction of the ventricular myocardium.     

A Founder Mutation in the GK1 Gene Is Responsible for Galactokinase Deficiency in Roma (Gypsies)

Galactokinase deficiency is an inborn error in the first step of galactose metabolism. Its major clinical manifestation is the development of cataracts in the first weeks of life. It has also been suggested that carriers of the deficiency are predisposed to presenile cataracts developing at age 20-50 years. Newborn screening data suggest that the gene frequency is very low worldwide but is higher among the Roma in Europe. Since the cloning of the galactokinase gene (GK1) in 1995, only two disease-causing mutations, both confined to single families, have been identified. Here we present the results of a study of six affected Romani families from Bulgaria, where index patients with galactokinase deficiency have been detected by the mass screening. Genetic linkage mapping placed the disease locus on 17q, and haplotype analysis revealed a small conserved region of homozygosity. Using radiation hybrid mapping, we have shown that GK1 is located in this region. The founder Romani mutation identified in this study is a single nucleotide substitution in GK1 resulting in the replacement of the conserved proline residue at amino acid position 28 with threonine (P28T). The P28T carrier rate in this endogamous population is approximately 5%, suggesting that the mutation may be an important cause of early childhood blindness in countries with a sizeable Roma minority.     

A frameshift mutation in exon 28 of the OPA1 gene explains the high prevalence of dominant optic atrophy in the Danish population: evidence for a founder effect

Dominant optic atrophy (DOA) is a hereditary optic neuropathy characterised by decreased visual acuity, colour vision deficits, centro-coecal scotoma and optic nerve pallor. The gene OPA1, encoding a dynamin-related GTPase, has recently been identified within the genetic linkage interval for the major locus for DOA on chromosome 3q28 and shown to harbour genetic aberrations segregating with disease in DOA families. The prevalence of the disorder in Denmark is reported to be the highest of any geographical location, suggestive of a founder effect. In order to establish the genetic basis of disease in a sample of 33 apparently unrelated Danish families, we screened DNA from affected members for OPA1 gene mutations by heteroduplex analysis and direct sequencing. A novel identical mutation in exon 28 (2826delT) was associated with DOA in 14 pedigrees and led to a frameshift and abnormal OPA1 protein -COOH terminus. Haplotype analysis of a region of approximately 1 Mb flanking the OPA1 gene using eight polymorphic markers revealed a common haplotype shared by all 14 patients; this haplotype was markedly over-represented compared with ethnically matched controls. Statistical analysis confirmed significant linkage disequilibrium with DOA over approximately 600 kb encompassing the disease mutation. We have therefore demonstrated that the relatively high frequency of DOA in Denmark is attributable to a founder mutation responsible for approximately 42% of the examined families and suggest that presymptomatic screening for the (2826delT) mutation may facilitate diagnosis and genetic counselling in a significant proportion of DOA patients of Danish ancestry.     

Genetic heterogeneity among kindreds with Alport syndrome.

Twenty-three kindreds were ascertained through patients at renal clinics at University of Utah Associated Hospitals. Urinalysis indicated glomerulonephritis in 231 of 997 examined kindred members; medical records documented kidney disease consistent with glomerulonephritis in 88 unexamined kindred members. Renal biopsies of 35 persons in a subset of 14 kindreds showed ultrastructural changes and absence of immune phenomena consistent with the diagnosis of Alport syndrome. End-stage renal disease (ESRD) had occurred in 72 (49%) of 148 known affected males and in 13 (8%) of 171 known affected females. No father-son affected pairs occurred in any of the kindreds; 84% of daughters of affected fathers were affected, and 49% of sons and 48% of daughters of affected mothers were affected. One of three phenotypes (juvenile Alport syndrome with deafness, adult Alport syndrome with deafness, or adult Alport syndrome without deafness or other defects) occurred in each of the 23 kindreds. We applied likelihood analysis to test for genetic heterogeneity underlying the phenotypic heterogeneity. In the first application (the admixture test), we tested for the occurrence of two forms of the disease without specifying which kindred had which form; we found insufficient evidence of admixture. In the second application (the predivided-sample test), we tested for genetic heterogeneity expressed as phenotypic heterogeneity. Kindreds were successively divided into two subgroups, with admission to the first subgroup dependent upon: (1) having greater than or equal to 2 males with ESRD, (2) occurrence of deafness in most nephrologically affected male family members, and (3) intrakindred mean age of ESRD in males later than age 31. Weak evidence of heterogeneity was found for category (1); stronger evidence of heterogeneity was found for category (3). Penetrance of microscopic hematuria in female heterozygotes was estimated as 82% overall, 85% for adult Alport syndrome, and 28% for juvenile Alport syndrome.     

A study on family communication space (Part II)--A study on spatial utilization for, and familial consciousness of, family communication

Part II, based on the findings of Part I, tries to identify family Communication by delving into how it is actually practiced in view of spatial conditions within a house, and familial consciousness. Specific spatial conditions have been sampled of the housing of students at women's junior colleges, and how their family members mutually Communicate and evaluate it has been analyzed. Their views of "family" have also been examined. The findings are as follows: 1) The number of rooms, and the width of the room(s) used for family Communication are major determining factors in separating family Communication from other living activities. 2) The above separation is affected by whether family Communication is practiced in a Japanese-style room or a Western-style one. 3) The perceptual difference of the consent of "family" among a family members principally determines how they engage in family Communication and how they evaluate it. It has proved to be necessary to consider, for a spatial analysis, what kind of posture each member takes when mutually Communicating, seeking comfort and relaxation at home.     

Dominantly inherited cutaneous small-vessel lymphocytic vasculitis maps to chromosome 6q26–q27

Outside the context of hereditary deficiencies of complement and IgA, Mendelian inherited predisposition to small vessel lymphocytic vasculitis (SVLV) has rarely been documented. Here we report a large, multigenerational family segregating symmetrical cutaneous SVLV affecting the cheeks, thighs and hands. In all affected family members the disease presented in early infancy and there was no evidence for an association with systemic disease. Skin biopsy of lesions showed a lymphocytic vasculitis with red blood cell extravasation. Complementary studies, with extensive investigation focused on dysfunction of the immunological system were negative. The pattern of inheritance of SVLV in the family was compatible with an autosomal dominantly acting disease gene with incomplete penetrance. To localize the disease causing gene in the family a genome-wide linkage search was conducted using a high-density SNP array. Haplotype construction and analysis of recombination events permitted the minimal interval defining the disease locus to be refined to a 4.7 Mb region on chromosome 6q26–q27. The genes CCR6 and GPR31, which map to the linked region represent plausible candidates for the disease on the basis of their biological function. Extensive screening of both genes by mutational analysis failed to identify a deleterious mutation in the family.