Abstract：
:Recent advances in genome technology have led to mapping and subsequent isolation, by positional cloning, of a number of genes for common and/or complex human diseases. It therefore will be possible to utilize information about a known locus in the search for additional, perhaps less penetrant, genes for a particular disease. It is also unclear, under these situations, what the optimal sampling strategy should be. To address these questions, we have calculated the expected LOD score for localizing one locus in a variety of two-locus models of disease, for four different pedigree structures, and under three different scenarios regarding knowledge/testing of one of the two loci. These design considerations are evaluated by use of a cost function that incorporates the costs of ascertaining different family structures, the relative costs of genotyping and mutation testing family members, and the amount of information provided by each family structure and testing scenario. The results indicate that, in most cases, affected sib pairs are a particularly poor strategy, especially when linkage or mutation data are available at the known locus. We also demonstrate that prescreening the sample of families for mutations at known susceptibility loci is, in general, a cost-effective strategy.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Goldgar DE,Easton DFsubject
Has Abstractpub_date
1997-05-01 00:00:00pages
1222-32issue
5eissn
0002-9297issn
1537-6605journal_volume
60pub_type
杂志文章abstract：:Pooling genome-wide association studies (GWASs) increases power but also poses methodological challenges because studies are often heterogeneous. For example, combining GWASs of related but distinct traits can provide promising directions for the discovery of loci with small but common pleiotropic effects. Classical a...
journal_title：American journal of human genetics
pub_type： 杂志文章,meta分析
doi：10.1016/j.ajhg.2012.03.015
更新日期：2012-05-04 00:00:00
abstract：:To detect heterozygotes for maple-syrup-urine disease (MSUD), activities of branched-chain-alpha-ketoacid (BCKA) dehydrogenase and its components in skin fibroblasts of two obligatory heterozygotes and amnion cells of a fetus at risk were measured. Intact heterozygous cells were found to decarboxylate [1-14C] alpha-ke...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1982-05-01 00:00:00
abstract：:Ehlers-Danlos syndrome (EDS) type IV is a dominantly inherited disorder that results from mutations in the type III collagen gene (COL3A1). We studied the structure of the COL3A1 gene of an individual with EDS type IV and that of her phenotypically normal parents. The proband was heterozygous for a 2-kb deletion in CO...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1993-07-01 00:00:00
abstract：:Dowling-Degos disease (DDD), or reticular pigmented anomaly of the flexures, is a type of rare autosomal-dominant genodermatosis characterized by reticular hyperpigmentation and hypopigmentation of the flexures, such as the neck, axilla, and areas below the breasts and groin, and shows considerable heterogeneity. Loss...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2013.04.022
更新日期：2013-06-06 00:00:00
abstract：:Molecular analysis of the human beta-galactosidase gene revealed six different mutations in 10 of 11 Japanese GM1-gangliosidosis patients. They were the only abnormalities in each allele examined in this study. A 165-nucleotide duplication (positions 1103-1267) was found in two infantile patients, producing an abnorma...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1991-08-01 00:00:00
abstract：:Ichthyosis prematurity syndrome (IPS) is an autosomal-recessive disorder characterized by premature birth and neonatal asphyxia, followed by a lifelong nonscaly ichthyosis with atopic manifestations. Here we show that the gene encoding the fatty acid transport protein 4 (FATP4) is mutated in individuals with IPS. Fibr...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2009.06.021
更新日期：2009-08-01 00:00:00
abstract：:Three uncommon stable Gm haplotypes, Gm3;23;--, Gm1,2,17;..;-- and Gm1,17;..;-- have been transmitted through 3 generations of two related Lebanese and Syrian families. No pathological consequence was noted in seven individuals, aged 14--65, whose sera were deficient for all the allotypes carried by the IgG3 chains. A...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1976-01-01 00:00:00
abstract：:Esterase D (EsD), purified from human erythrocytes and tested with a variety of substrates, hydrolyzed only triacetin, tributyrin, and certain soluble aryl esters of aliphatic acids. Esters of 4-methylumbelliferone were easily the best substrates. When the three genetically different isozymes were compared, the less c...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1978-01-01 00:00:00
abstract：:Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with development...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2020.02.001
更新日期：2020-03-05 00:00:00
abstract：:Using the technique of in vitro human-hamster fertilization, sperm of four men heterozygous for 4 reciprocal translocations--t(4;17),t(5;13),t(6;7), and t(9;18)--was studied. Frequencies of numerical abnormalities unrelated to the translocations range from 8.3% to 13.3%, and the incidence of imbalances ranges from 23....
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1989-04-01 00:00:00
abstract：:Pelizaeus-Merzbacher disease (PMD) is an X-linked, dysmyelinating disorder of the CNS. Duplications of the proteolipid protein (PLP) gene have been found in a proportion of patients, suggesting that, in addition to coding-region or splice-site mutations, overdosage of the gene can cause PMD. We show that the duplicati...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/301933
更新日期：1998-07-01 00:00:00
abstract：:Canavan disease is an autosomal recessive leukodystrophy caused by the deficiency of aspartoacylase (ASPA). Sixty-four probands were analyzed for mutations in the ASPA gene. Three point mutations--693C-->A, 854A-->C, and 914C-->A--were identified in the coding sequence. The 693C-->A and 914C-->A base changes, resultin...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1994-07-01 00:00:00
abstract：:We tested 519 chromosome 3-specific cosmids for the presence of rare restriction-endonuclease sites in a search for cosmids containing HTF islands. We have identified 49 cosmids (9% of those tested) that contain multiple rare restriction-endonuclease sites. The cosmids were digested with several common cutting restric...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1991-09-01 00:00:00
abstract：:Case-control studies compare marker-allele distributions in affected and unaffected individuals, and significant results suggest linkage but may simply reflect population structure. For markers with m alleles (m > or = 2), a McNemar-like statistic, I, estimates the level of population association between marker and di...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1997-03-01 00:00:00
abstract：:We have previously shown that a quantitative-trait locus linked to the OCA2 region of 15q accounts for 74% of variation in human eye color. We conducted additional genotyping to clarify the role of the OCA2 locus in the inheritance of eye color and other pigmentary traits associated with skin-cancer risk in white popu...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/510885
更新日期：2007-02-01 00:00:00
abstract：:The purpose of this study was to characterize the mutant enzyme in nine patients with gyrate atrophy of the choroid and retina associated with ornithine aminotransferase (OAT) deficiency, to elucidate the mechanism of response to pyridoxine in four pyridoxine-responsive patients, and to determine the extent of genetic...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1989-03-01 00:00:00
abstract：:Uniparental disomy (UPD) refers to the presence of two copies of a chromosome from one parent and none from the other parent. In genetic studies of UPDs, many genetic markers are usually used to identify the stage of nondisjunction that leads to UPD and to uncover the associated unusual patterns of recombinations. How...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/303072
更新日期：2000-10-01 00:00:00
abstract：:Galactosemia is an autosomal recessive disorder of human galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT). The molecular basis of this disorder is at present not well understood. We report here two missense mutations which result in low or undetectable enzymatic a...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1991-10-01 00:00:00
abstract：:Knowledge of the number of causative loci is necessary to estimate the power of mapping studies of complex diseases. In the present article, we reexamine a theory developed by Risch and its implications for estimating the number L of causative loci affecting a complex inherited disease. We first show that methods base...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/344779
更新日期：2002-12-01 00:00:00
abstract：:Genetic mapping of complex diseases to date depends on variations inside or close to the genes that perturb their activities. A strong body of evidence suggests that changes in gene expression play a key role in complex diseases and that numerous loci perturb gene expression in trans. The information in trans variants...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2013.03.022
更新日期：2013-05-02 00:00:00
abstract：:A total of 254 affected parent-child pairs with Huntington disease (HD) and 440 parent-child pairs with CAG size in the normal range were assessed to determine the nature and frequency of intergenerational CAG changes in the HD gene. Intergenerational CAG changes are extremely rare (3/440 [0.68%]) on normal chromosome...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1995-08-01 00:00:00
abstract：:Helicobacter pylori is considered the most prevalent infectious agent among humans, and it causes gastric inflammation, gastroduodenal ulcers, and a risk of gastric cancer. We performed a genomewide linkage analysis among Senegalese siblings phenotyped for H. pylori-reactive serum immunoglobulin G. A multipoint LOD sc...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/367714
更新日期：2003-02-01 00:00:00
abstract：:Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2020.03.001
更新日期：2020-04-02 00:00:00
abstract：:A mutation in transthyretin (TTR Asn 90) has been identified in the Portuguese and German populations. This variant has a lower pI and was found by screening analyses in 2/4,000 German subjects and in 4/1,200 Portuguese by using either double one-dimensional (D1-D) electrophoresis with isoelectric focusing (IEF) or hy...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1991-05-01 00:00:00
abstract：:Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC-susceptibility genes explain CRC risk in fewer than 10% of affected individuals. Germline mutations in DNA-repair genes (DRGs) have recently been reported in CRC, but their contribution to CRC risk is largely ...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2018.01.018
更新日期：2018-03-01 00:00:00
abstract：:We studied a group of individuals with elevated urinary excretion of 3-methylglutaconic acid, neutropenia that can develop into leukemia, a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early dea...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2014.12.013
更新日期：2015-02-05 00:00:00
abstract：:Primary defects in motile cilia result in dysfunction of the apparatus responsible for generating fluid flows. Defects in these mechanisms underlie disorders characterized by poor mucus clearance, resulting in susceptibility to chronic recurrent respiratory infections, often associated with infertility; laterality def...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2018.10.003
更新日期：2018-11-01 00:00:00
abstract：:Genetic linkage studies have linked congenital contractural arachnodactyly (CCA), a usually mild heritable connective-tissue disorder, to FBN2, the fibrillin gene on chromosome 5. Recently, FBN2 mutations in two patients with CCA have been described. Here we report an A-->T transversion at the -2 position of the conse...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1996-11-01 00:00:00
abstract：:Association studies offer an exciting approach to finding underlying genetic variants of complex human diseases. However, identification of genetic variants still includes difficult challenges, and it is important to develop powerful new statistical methods. Currently, association methods may depend on single-locus an...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/511312
更新日期：2007-02-01 00:00:00
abstract：:Benign infantile familial convulsions is an autosomal dominant disorder characterized by nonfebrile seizures, with the first attack occurring at age 3-12 mo. It is one of the rare forms of epilepsy that are inherited as monogenic Mendelian traits, thus providing a powerful tool for mapping genes involved in epileptic ...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/514877
更新日期：1997-10-01 00:00:00
