Abstract:
:Timely molecular diagnosis of RB1 mutations enables earlier treatment, lower risk, and better health outcomes for patients with retinoblastoma; empowers families to make informed family-planning decisions; and costs less than conventional surveillance. However, complexity has hindered clinical implementation of molecular diagnosis. The majority of RB1 mutations are unique and distributed throughout the RB1 gene, with no real hot spots. We devised a sensitive and efficient strategy to identify RB1 mutations that combines quantitative multiplex polymerase chain reaction (QM-PCR), double-exon sequencing, and promoter-targeted methylation-sensitive PCR. Optimization of test order by stochastic dynamic programming and the development of allele-specific PCR for four recurrent point mutations decreased the estimated turnaround time to <3 wk and decreased direct costs by one-third. The multistep method reported here detected 89% (199/224) of mutations in bilaterally affected probands and both mutant alleles in 84% (112/134) of tumors from unilaterally affected probands. For 23 of 27 exons and the promoter region, QM-PCR was a highly accurate measure of deletions and insertions (accuracy 95%). By revealing those family members who did not carry the mutation found in the related proband, molecular analysis enabled 97 at-risk children from 20 representative families to avoid 313 surveillance examinations under anesthetic and 852 clinic visits. The average savings in direct costs from clinical examinations avoided by children in these families substantially exceeded the cost of molecular testing. Moreover, health care savings continue to accrue, as children in succeeding generations avoid unnecessary repeated anaesthetics and examinations.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Richter S,Vandezande K,Chen N,Zhang K,Sutherland J,Anderson J,Han L,Panton R,Branco P,Gallie Bdoi
10.1086/345651subject
Has Abstractpub_date
2003-02-01 00:00:00pages
253-69issue
2eissn
0002-9297issn
1537-6605pii
S0002-9297(07)60537-0journal_volume
72pub_type
杂志文章abstract::Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive genetic disease caused by a deficiency of the lysosomal glycosidase alpha-L-iduronidase. Hurler (severe), Scheie (mild), and Hurler/Scheie (intermediate) syndromes are clinical subtypes of MPS-I, but it is difficult to distinguish between these subtypes by...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1993-11-01 00:00:00
abstract::Estimation of the components of variance for a quantitative trait allows one to evaluate both the degree to which genetics influences the trait and the trait's underlying genetic architecture. For particular traits, the estimates also may have implications for discriminating between potential models of selection and f...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/320112
更新日期:2001-05-01 00:00:00
abstract::Activating mutations in the genes for fibroblast growth factor receptors 1-3 (FGFR1-3) are responsible for a diverse group of skeletal disorders. In general, mutations in FGFR1 and FGFR2 cause the majority of syndromes involving craniosynostosis, whereas the dwarfing syndromes are largely associated with FGFR3 mutatio...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/427956
更新日期:2005-02-01 00:00:00
abstract::Early B cell factor 3 (EBF3) is an atypical transcription factor that is thought to influence the laminar formation of the cerebral cortex. Here, we report that de novo mutations in EBF3 cause a complex neurodevelopmental syndrome. The mutations were identified in two large-scale sequencing projects: the UK Decipherin...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2016.11.020
更新日期:2017-01-05 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::Electrophoretic and quantitative studies reveal that 85% of Japanese carry an atypical liver alcohol dehydrogenase (ADH). The frequency of ADH polymorphism is identical with the reported frequency of alcohol sensitivity in the Japanese population. This identity in population frequencies points to a causative relations...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1975-11-01 00:00:00
abstract::The lysosomal hydrolase alpha-L-iduronidase (IDUA) is one of the enzymes in the metabolic pathway responsible for the degradation of the glycosaminoglycans heparan sulfate and dermatan sulfate. In humans a deficiency of IDUA leads to the accumulation of glycosaminoglycans, resulting in the lysosomal storage disorder m...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1990-11-01 00:00:00
abstract::X-linked ichthyosis (XLI) is an inborn error of metabolism caused by steroid sulfatase (STS) deficiency. In more than 80% of XLI patients the enzyme deficiency is due to large deletions involving the entire STS gene and flanking sequences. However, some patients with the classical XLI phenotype and complete STS defici...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1992-03-01 00:00:00
abstract::Personalized genetic information is not widely utilized as a resource in learning environments, in part because of concerns about data privacy and the treatment of sensitive personal information. Here we describe the implementation of a curriculum centered on analyzing personalized genetic-ancestry test results during...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2019.01.001
更新日期:2019-02-07 00:00:00
abstract::Autism is a neurodevelopmental disorder of complex etiology in which genetic factors play a major role. We have implicated the neurexin 1 (NRXN1) gene in two independent subjects who display an autism spectrum disorder (ASD) in association with a balanced chromosomal abnormality involving 2p16.3. In the first, with ka...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2007.09.011
更新日期:2008-01-01 00:00:00
abstract::Histochemical assay for ornithine transcarbamylase (OTC) activity in fixed frozen hepatic sections from a woman heterozygous for OTC deficiency revealed two populations of hepatocytes: those with normal activity and those with no activity. This observation, in conjunction with data from previous family studies, confir...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1976-07-01 00:00:00
abstract::The genomic sequences recognized by the anonymous probe 767 (DXS115) are localized to two sites within Xq28. One site lies within intron 22 of the factor VIII gene (FBC). Physical mapping suggests that the second site lies within 1.2 megabases of the F8C gene. The RFLPs detected by 767 are located within the second si...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1989-05-01 00:00:00
abstract::In a female infant with dysmorphic features, severe neurological defects, and congenital blindness, a positive urinary Bratton-Marshall test led to identification of a massive excretion of 5-amino-4-imidazolecarboxamide (AICA)-riboside, the dephosphorylated counterpart of AICAR (also termed "ZMP"), an intermediate of ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/421475
更新日期:2004-06-01 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::Studies in mouse and chick have shown that the 5' HoxD genes play major roles in the development of the limbs and genitalia. In humans, mutations in HOXD13 cause the dominantly inherited limb malformation synpolydactyly (SPD). Haploinsufficiency for the 5' HOXD genes has recently been proposed to underlie the monodact...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/338921
更新日期:2002-02-01 00:00:00
abstract::Autosomal recessive Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of disorders affecting the peripheral nervous system. The axonal form of the disease is designated as "CMT type 2" (CMT2), and one locus (1q21.2-q21.3) has been reported for the autosomal recessive form. Here we report the results o...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/316934
更新日期:2001-01-01 00:00:00
abstract::X-linked adrenoleukodystrophy (ALD), a neurodegenerative disorder associated with impaired beta-oxidation of very-long-chain fatty acids (VLCFA), is due to mutations in a gene encoding a peroxisomal ATP-binding cassette (ABC) transporter (ALD protein [ALDP]). We analyzed the open reading frame of the ALD gene in 44 Fr...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1996-06-01 00:00:00
abstract::A girl with a prenatal 46,XY karyotype was born with a completely normal female phenotype, including uterus and histologically normal ovaries. In mice with a similar phenotype, the ablation of M33, an ortholog of Drosophila Polycomb, causes male-to-female sex reversal. The analysis of the human homolog of M33, Chromob...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2009.03.016
更新日期:2009-05-01 00:00:00
abstract::Central core disease (CCO) is an autosomal dominant myopathy clinically distinct from malignant hyperthermia (MHS). In a large kindred in which the gene for CCO is segregating, two-point linkage analysis gave a maximum lod score, between the central core disease locus (CCO) and the ryanodine receptor locus (RYR1), of ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1993-02-01 00:00:00
abstract::Phenylketonuria (PKU), a disorder of amino acid metabolism prevalent among Caucasians and other ethnic groups, is caused primarily by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). PKU is a highly heterogeneous disorder, with more than 60 molecular lesions identified in the PAH gene. The haplotype...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1992-12-01 00:00:00
abstract::The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2019.07.005
更新日期:2019-09-05 00:00:00
abstract::A gene for Holt-Oram syndrome (HOS) has been previously mapped to chromosome 12q2 and designated HOS1. We have identified a HOS patient with a de novo chromosomal rearrangement involving 12q. Detailed cytogenetic analysis of this case reveals three breaks on 12q, and two of these are within the HOS1 interval. By using...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1996-12-01 00:00:00
abstract::Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctiv...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2012.10.019
更新日期:2012-12-07 00:00:00
abstract::Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identifi...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2017.02.007
更新日期:2017-04-06 00:00:00
abstract::Multiple-synostosis syndrome is an autosomal dominant disorder characterized by progressive symphalangism, carpal/tarsal fusions, deafness, and mild facial dysmorphism. Heterozygosity for functional null mutations in the NOGGIN gene has been shown to be responsible for the disorder. However, in a cohort of six proband...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/503204
更新日期:2006-04-01 00:00:00
abstract::Genetic association studies of common disease often rely on linkage disequilibrium (LD) along the human genome and in the population under study. Although understanding the characteristics of this correlation has been the focus of many large-scale surveys (culminating in genomewide haplotype maps), the results of diff...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/502803
更新日期:2006-04-01 00:00:00
abstract::The recent cloning of cDNA encoding the Ca++ release channel (ryanodine receptor) of human sarcoplasmic reticulum has enabled us to use somatic cell hybrids to localize the ryanodine receptor gene (RYR) to the proximal long arm of human chromosome 19. Studies with additional hybrids containing deletions or translocati...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1990-06-01 00:00:00
abstract::A collection of 1,069 human PCR-based genetic markers has been developed, and their distribution over the 22 autosomes and the X chromosome has been determined. Each marker was developed around a short-tandem-repeat DNA sequence. The majority (85%) of the markers described here were selected to contain tetranucleotide...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1995-09-01 00:00:00
abstract::A family with three children with trisomy 21 in which the mother is a phenotypically normal, trisomy 21/normal mosaic was studied. Chromosome 21 fluorescent heteromorphisms were used to document that two of the three number 21's in two of the Down syndrome offspring were of maternal origin. Five cytogenetic surveys in...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1982-01-01 00:00:00
abstract::Deletions of the long arm of chromosome 18 occur in approximately 1 in 10,000 live births. Congenital aural atresia (CAA), or narrow external auditory canals, occurs in approximately 66% of all patients who have a terminal deletion 18q. The present report describes a series of 20 patients with CAA, of whom 18 had micr...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/375695
更新日期:2003-06-01 00:00:00