Abstract：
:Genetic testing has increased the number of variants identified in disease genes, but the diagnostic utility is limited by lack of understanding variant function. CARD11 encodes an adaptor protein that expresses dominant-negative and gain-of-function variants associated with distinct immunodeficiencies. Here, we used a "cloning-free" saturation genome editing approach in a diploid cell line to simultaneously score 2,542 variants for decreased or increased function in the region of CARD11 associated with immunodeficiency. We also described an exon-skipping mechanism for CARD11 dominant-negative activity. The classification of reported clinical variants was sensitive (94.6%) and specific (88.9%), which rendered the data immediately useful for interpretation of seven coding and splicing variants implicated in immunodeficiency found in our clinic. This approach is generalizable for variant interpretation in many other clinically actionable genes, in any relevant cell type.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Meitlis I,Allenspach EJ,Bauman BM,Phan IQ,Dabbah G,Schmitt EG,Camp ND,Torgerson TR,Nickerson DA,Bamshad MJ,Hagin D,Luthers CR,Stinson JR,Gray J,Lundgren I,Church JA,Butte MJ,Jordan MB,Aceves SS,Schwartz DM,Milnerdoi
10.1016/j.ajhg.2020.10.015subject
Has Abstractpub_date
2020-12-03 00:00:00pages
1029-1043issue
6eissn
0002-9297issn
1537-6605pii
S0002-9297(20)30373-6journal_volume
107pub_type
杂志文章abstract：:We identified four different missense mutations in the single-exon gene MAB21L2 in eight individuals with bilateral eye malformations from five unrelated families via three independent exome sequencing projects. Three mutational events altered the same amino acid (Arg51), and two were identical de novo mutations (c.15...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2014.05.005
更新日期：2014-06-05 00:00:00
abstract：:A non-Jewish family is presented in which the genes for Tay-Sachs disease and Sandhoff disease are segregating. Individuals heterozygous for both alleles have low serum and white cell total hexosaminidase levels together with a proportion of heat-labile hexosaminidase A (HEX A) which falls in the normal range. The ind...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1980-11-01 00:00:00
abstract：:Palindromic AT-rich repeats (PATRRs) on chromosomes 11q23 and 22q11 at the constitutional t(11;22) breakpoint are predicted to induce genomic instability, which mediates the translocation. A PCR-based translocation-detection system for the t(11;22) has been developed with PCR primers flanking the PATRRs of both chromo...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/303054
更新日期：2000-09-01 00:00:00
abstract：:Transthyretin (TTR) (122 Val----Ile), caused by a point mutation which destroys a MaeIII restriction site, is associated with cardiac amyloidosis in black individuals. To estimate the frequency of the MaeIII(-) gene in the black population without overt cardiac disease, DNA from 177 black individuals without amyloidos...
journal_title：American journal of human genetics
pub_type： 杂志文章,评审
doi：
更新日期：1991-07-01 00:00:00
abstract：:Autosomal dominant progressive external ophthalmoplegia (adPEO) is a disorder characterized by ptosis, progressive weakness of the external eye muscles, and general muscle weakness. The patients have multiple deletions of mtDNA on Southern blots or in PCR analysis of muscle DNA and a mild deficiency of one or more res...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1996-04-01 00:00:00
abstract：:The original family with the Allan-Herndon type of X-linked mental retardation has been investigated for linkage by using DNA probes spanning the length of the X chromosome. Available for study, over 3 generations, were 13 affected males, three obligate carriers, and three normal sons of the obligate carriers. Initial...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1990-09-01 00:00:00
abstract：:The construction of an accurate family pedigree is a fundamental component of a clinical genetic evaluation and of human genetic research. Previous surveys of genetic counselors and human genetic publications have demonstrated significant inconsistencies in the usage of common pedigree symbols representing situations ...
journal_title：American journal of human genetics
pub_type： 指南,杂志文章
doi：
更新日期：1995-03-01 00:00:00
abstract：:We devised a rapid PCR-based method to screen for an A----G transition at nucleotide 8344 of the human mitochondrial tRNA(Lys) gene, which was recently reported, by Shoffner and co-workers, to be associated with myoclonus epilepsy and ragged-red fibers (MERRF), a maternally transmitted mitochondrial encephalomyopathy ...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1991-02-01 00:00:00
abstract：:To determine the receptivity of prenatal care providers and their patients to carrier testing for cystic fibrosis (CF), we offered free carrier screening, followed by genetic counseling of carriers, to all prenatal care providers in Rochester, NY, for all their female patients of reproductive age, pregnant or not. Of ...
journal_title：American journal of human genetics
pub_type： 临床试验,杂志文章
doi：
更新日期：1996-07-01 00:00:00
abstract：:Interleukin-12 (IL12) is a cytokine that is secreted by activated phagocytes and dendritic cells and that induces interferon-gamma production by natural-killer and T lymphocytes. It consists of two subunits, p35 and p40, which are encoded by IL12A and IL12B, respectively. The first reported patient with a genetic cyto...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/338625
更新日期：2002-02-01 00:00:00
abstract：:Functional characterization of a gene often requires the discovery of the full spectrum of its associated phenotypes. Mutations in the human GLI3 gene have been identified in Greig cepalopolysyndactyly, Pallister-Hall syndrome (PHS), and postaxial polydactyly type-A (PAP-A). We studied the involvement of GLI3 in addit...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/302557
更新日期：1999-09-01 00:00:00
abstract：:Family studies of schizophrenia have reported elevated rates of both definite and definite-plus-probable schizophrenia among the relatives of definite schizophrenics. These elevated rates imply a strong association between the two forms of diagnosis and suggest some form of familial transmission. Here we have used rec...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1983-11-01 00:00:00
abstract：:Independent replication of linkage in previously studied pedigrees is desirable when genetic heterogeneity is suspected or when the illness is very rare. When the likelihood of the new data in this type of replication study is computed as conditional on the previously reported linkage results, it can be considered ind...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1994-04-01 00:00:00
abstract：:The National Research Council recommended the use of the ceiling principle in forensic applications of DNA testing on the grounds that the ceiling principle was believed to be "conservative," giving estimates greater than or equal to the actual genotype frequencies in the appropriate reference population. We show here...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1993-08-01 00:00:00
abstract：:A nonparametric statistical methodology is used for the analysis of biochemical frequency data observed on a series of nine Jewish and six non-Jewish populations. Two categories of statistics are used: heterogeneity indices and various distance measures with respect to a standard. The latter are more discriminating in...
journal_title：American journal of human genetics
pub_type： 历史文章,杂志文章
doi：
更新日期：1979-05-01 00:00:00
abstract：:A genetic analysis is presented of data from 22 Brazilian sibships with cases of acheiropodia (the handless and footless families of Brazil). Segregation analysis performed using a 16K CDC 3100 computer showed a segregation frequency of .245 +/- .040, which is close to the expected value of .25. No sporadic cases wer...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1975-07-01 00:00:00
abstract：:Humans vary >100-fold in their sensitivity to the harmful effects of ultraviolet radiation. The main determinants of sensitivity are melanin pigmentation and less-well-characterized differences in skin inflammation and repair processes. Pigmentation has a high heritability, but susceptibility to cancers of the skin, a...
journal_title：American journal of human genetics
pub_type： 杂志文章,评审
doi：10.1086/425285
更新日期：2004-11-01 00:00:00
abstract：:In studies of expression quantitative trait loci (eQTLs), it is of increasing interest to identify eGenes, the genes whose expression levels are associated with variation at a particular genetic variant. Detecting eGenes is important for follow-up analyses and prioritization because genes are the main entities in biol...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2015.04.012
更新日期：2015-06-04 00:00:00
abstract：:It is generally accepted that the blood group subtypes A1 and A2 expressions are controlled by two different blood group N-acetylgalactosaminyl-transferases, that is, A1-enzyme and A2-enzyme, respectively, and that the two types of enzymes are governed by the allelic A1 and A2 genes. The observed frequencies of blood ...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1983-11-01 00:00:00
abstract：:Gaucher disease (GD) is one of the most prevalent lysosomal storage disorders and one of the rare genetic diseases now accessible to therapy. Outside the Ashkenazi Jewish community, a high molecular diversity is observed, leaving approximately 30% of alleles undetected. Nevertheless, very few exhaustive methods have b...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/301969
更新日期：1998-08-01 00:00:00
abstract：:Culture of human amniotic-fluid cells from cases of fetal neural tube defects produces a population of rapidly adhering cells that were initially thought to be macrophages and later interpreted to be of neural origin. In this study double and triple labeling systems for the simultaneous detection of glial and macropha...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1989-11-01 00:00:00
abstract：:Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion (≥50 copies) of a non-coding trinucleotide repeat in TCF4 confers >76-fold risk for FECD in our large c...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2018.02.010
更新日期：2018-04-05 00:00:00
abstract：:The numbers of progeny born to 355 patients with heritable polyposis of the colon and to 315 related, but normal, subjects, all old enough to have completed their families, are presented, as well as data on 432 subjects still young enough to have more children. Two main indices are used: mean family size ("genetic fit...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1980-09-01 00:00:00
abstract：:Genome-wide association studies (GWASs) have successfully identified thousands of genetic variants for many complex diseases; however, these variants explain only a small fraction of the heritability. Recently, genetic association studies that leverage external transcriptome data have received much attention and shown...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2018.03.019
更新日期：2018-05-03 00:00:00
abstract：:Cancer occurrence in 164 families with breast/ovarian cancer and germline BRCA2 mutations was studied to evaluate the evidence for genotype-phenotype correlations. Mutations in a central portion of the gene (the "ovarian cancer cluster region" [OCCR]) were associated with a significantly higher ratio of cases of ovari...
journal_title：American journal of human genetics
pub_type： 杂志文章,多中心研究
doi：10.1086/318181
更新日期：2001-02-01 00:00:00
abstract：:We performed a genomewide linkage analysis of six separate measurements of body mass index (BMI) taken over a span of 28 years, from 1971 to 1998, in the Framingham Heart Study. Variance-components linkage analysis was performed on 330 families, using 401 polymorphic markers. The number of individuals with data at eac...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/343822
更新日期：2002-11-01 00:00:00
abstract：:Insulin resistance and hyperinsulinemia are strong correlates of obesity and type 2 diabetes, but little is known about their genetic determinants. Using data on nondiabetics from Mexican American families and a multipoint linkage approach, we scanned the genome and identified a major locus near marker D6S403 for fast...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/320100
更新日期：2001-05-01 00:00:00
abstract：:Tibetan high-altitude adaptation (HAA) has been studied extensively, and many candidate genes have been reported. Subsequent efforts targeting HAA functional variants, however, have not been that successful (e.g., no functional variant has been suggested for the top candidate HAA gene, EPAS1). With WinXPCNVer, a metho...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2015.05.005
更新日期：2015-07-02 00:00:00
abstract：:Although Africa has played a central role in human evolutionary history, certain studies have suggested that not all contemporary human genetic diversity is of recent African origin. We investigated 35 simple polymorphic sites and one T(n) microsatellite in an 8-kb segment of the dystrophin gene. We found 86 haplotype...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1086/378777
更新日期：2003-11-01 00:00:00
abstract：:Autosomal-recessive congenital ichthyoses represent a large and heterogeneous group of disorders of epidermal cornification. Recent data suggest that most of these disorders might result from defective lipid transport and metabolism. In the present study, we describe a late-onset form of recessive ichthyosis in a larg...
journal_title：American journal of human genetics
pub_type： 杂志文章
doi：10.1016/j.ajhg.2011.02.011
更新日期：2011-04-08 00:00:00
