Genetics moves into the medical mainstream.
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Clinical Medicine↗
Biomedical subjects
A E Guttmacher
Publications and source records attributed to A E Guttmacher.
Genomic medicine: who will practice it? A call to open arms.
The Human Genome Project and other recent developments will broaden and increase the importance of genetics in health care. "Clinical genetics" will become "genomic medicine" and will no longer be almost the sole purview of genetic specialists-medical geneticists, genetic counselors, and genetic advanced practice nurses. The changing use of genetics in health care will require the acquisition of new knowledge, skills, and attitudes by many health care professionals who are not genetic specialists. Such health care professionals will not only be necessary to the widespread integration of genetics into clinical care, but they will make unique contributions to this integration that will add to the quality of genomic medicine. This new use of genetics in health care will also allow, even require, new ways of working for genetic specialists, who will continue to occupy unique and vital roles.
Delivery of Health Care↗
Scanning for telomeric deletions and duplications and uniparental disomy using genetic markers in 120 children with malformations.
We screened 120 children with sporadic multiple congenital anomalies and either growth or mental retardation for uniparental disomy (UPD) or subtelomeric deletions. The screening used short tandem repeat polymorphisms (STRP) from the subtelomeric regions of 41 chromosome arms. Uninformative marker results were reanalyzed by using the next available marker on that chromosome arm. In total, approximately 25,000 genotypes were generated and analyzed for this study. Subtelomeric deletions of 1 Mb in size were excluded for 27 of 40 chromosome arms. Among the 120 subjects none was found to have UPD, but five subjects (4%, 95% confidence interval 1-9%) were found to have a deletion or duplication of one or more chromosome arms. We conclude that UPD is not a frequent cause of undiagnosed multiple congenital anomaly syndrome. In addition, we determined that 9p and 7q harbor chromosome length variations in the normal population. We conclude that subtelomeric marker analysis is effective for the detection of subtelomeric duplications and deletions, although it is labor intensive. Given a detection rate that is similar to prior studies and the large workload imposed by STRPs, we conclude that STRPs are an effective, but impractical, approach to the determination of segmental aneusomy given current technology.
Abnormalities, Multiple↗
Human genetics on the web.
Use of the World Wide Web ("the web") and our knowledge of human genetics are both currently expanding rapidly. By allowing swift, universal, and free access to data, the web has already played an important role in human genetics research. It has also begun to change the way that information is shared in clinical genetics and, to a lesser degree, affect how education in human genetics occurs. There are scores of web sites helpful to those interested in either research or clinical aspects of human genetics. The web and related communication technologies should continue to play increasingly important roles in human genetics.
Databases, Genetic↗
A piece of my mind: twenty lessons from the heart of medicine.
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Attitude to Death↗
Did Robert Louis Stevenson have hereditary hemorrhagic telangiectasia?
Chronic illness played a major role in the life and literary success of Robert Louis Stevenson. However, the exact nature of his chronic illness remains unclear. It is possible that Stevenson had hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber Syndrome). This would explain his chronic respiratory complaints, recurrent episodes of pulmonary hemorrhage, and his death, at age 44 years, of probable cerebral hemorrhage. It would also explain his mother's hitherto unreported but apparent stroke, at age 38 years. Further support for this hypothesis might come from new details about the health of Stevenson and his relatives or from molecular analysis of tissue specimens remaining from him.
Famous Persons↗
Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).
Hereditary Hemorrhagic Telangiectasia (HHT) is easily recognized in individuals displaying the classical triad of epistaxis, telangiectasia, and a suitable family history, but the disease is more difficult to diagnosis in many patients. Serious consequences may result if visceral arteriovenous malformations, particularly in the pulmonary circulation, are unrecognized and left untreated. In spite of the identification of two of the disease-causing genes (endoglin and ALK-1), only a clinical diagnosis of HHT can be provided for the majority of individuals. On behalf of the Scientific Advisory Board of the HHT Foundation International, Inc., we present consensus clinical diagnostic criteria. The four criteria (epistaxes, telangiectasia, visceral lesions and an appropriate family history) are carefully delineated. The HHT diagnosis is definite if three criteria are present. A diagnosis of HHT cannot be established in patients with only two criteria, but should be recorded as possible or suspected to maintain a high index of clinical suspicion. If fewer than two criteria are present, HHT is unlikely, although children of affected individuals should be considered at risk in view of age-related penetration in this disorder. These criteria may be refined as molecular diagnostic tests become available in the next few years.
Humans↗
Endoglin expression is reduced in normal vessels but still detectable in arteriovenous malformations of patients with hereditary hemorrhagic telangiectasia type 1.
Endoglin is predominantly expressed on endothelium and is mutated in hereditary hemorrhagic telangiectasia (HHT) type 1 (HHT1). We report the analysis of endoglin in tissues of a newborn (family 2), who died of a cerebral arteriovenous malformation (CAVM), and in a lung specimen surgically resected from a 78-year-old patient (family 5), with a pulmonary AVM (PAVM). The clinically affected father of the newborn revealed a novel mutation that was absent in his parents and was identified as a duplication of exons 3 to 8, by quantitative multiplex polymerase chain reaction. The corresponding mutant protein (116-kd monomer) and the missense mutant protein (80-kd monomer) present in family 5 were detected only as transient intracellular species and were unreactive by Western blot analysis and immunostaining. Normal endoglin (90-kd monomer) was reduced by 50% on peripheral blood-activated monocytes of the HHT1 patients. When analyzed by immunostaining and densitometry, presumed normal blood vessels of the newborn lung and brain and vessels adjacent to the adult PAVM showed a 50% reduction in the endoglin/PECAM-1 ratio. A similar ratio was observed in the CAVM and PAVM, suggesting that all blood vessels of HHT1 patients express reduced endoglin in situ and that AVMs are not attributed to a focal loss of endoglin.
Aged↗
Report on the workshop on Hereditary Hemorrhagic Telangiectasia, July 10-11, 1997.
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Chromosome Mapping↗
Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles.
Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia and recurrent hemorrhage from the sites of vascular lesions. Two genes have been identified for HHT. Endoglin, a TGF-beta binding protein which maps to chromosome 9q3, is the gene for HHT1. The type and location of most of the previously described mutations in the endoglin (ENG) gene suggested a dominant-negative model of receptor-complex dysfunction for the molecular basis of this disorder. In this article we describe 11 novel ENG mutations in HHT kindreds, which include missense and splice-site mutations. Two identical missense mutations in unrelated families disrupt the start codon of the gene. In addition, some frameshift and nonsense mutations lead to very low or undetectable levels of transcript from the mutant allele. These combined data suggest that the nature of most ENG mutations is to create a null (nonfunctional) allele, and that there is no requirement for the synthesis of a truncated endoglin protein in the pathogenesis of HHT.
Alleles↗
Quantitative DNA pooling to increase the efficiency of linkage analysis in autosomal dominant disease.
DNA pooling is an efficient method to rapidly perform genome-wide linkage scans in autosomal recessive diseases in inbred populations where affected individuals are likely to be homozygous for alleles near the disease gene locus. We wanted to examine whether this approach would detect linkage in autosomal dominant (AD) disorders where affected individuals may share one allele identical by descent at loci tightly linked to the disease. Two large outbred pedigrees in which the AD diseases familial venous malformation (FVM) and hereditary hemorrhagic telangiectasia (HHT1), linked to 9p and 9q, respectively, were investigated. Separate pools of DNA from affected (n = 21 for FVM and 17 for HHT1) and unaffected family members (n = 9 FVM and HHT1), and 25 unrelated population controls were established. Polymorphic markers spanning chromosome 9 at approximately 13.5-cM intervals were amplified using standard PCR. Allele quantitation was performed with a fluorimager. Visual inspection of allele intensities and frequency distributions suggested a shift in frequency of the most common allele in the affecteds lane when compared to control lanes for markers within 30 cM of the FVM and HHT1 loci. These subjective assessments were confirmed statistically by testing for the difference between two proportions (one-sided; P < or = 0.05). When using population controls, the true-positive rates for FVM and HHT1 were 5/5 and 2/5 markers, respectively. False-positive rates for FVM and HHT1 were 3/9 and 2/9, respectively. In both AD diseases investigated, quantitative DNA pooling detected shifts in allele frequency, thus identifying areas of known linkage in most cases. The utility of this technique depends on the size of the pedigree, frequency of the disease-associated allele in the population, and the choice of appropriate controls. Although the false-positive rate appears to be high, this approach still serves to reduce the amount of overall genotyping by about 60%. DNA pooling merits further investigation as a potential strategy in increasing the efficiency of genomic linkage scans.
Alleles↗
Confirmation of linkage of Clouston syndrome (hidrotic ectodermal dysplasia) to 13q11-q12.1 with evidence for multiple independent mutations.
Clouston syndrome (hidrotic ectodermal dysplasia) is an autosomal dominant disorder characterized by the triad of nail dystrophy, alopecia, and palmoplantar hyperkeratosis. Recently, linkage of a Clouston syndrome locus to chromosome 13q11-q12.1 was reported in eight families of French-Canadian descent. We have confirmed linkage to this region in four additional families: two of French-Canadian descent, one of Scottish-Irish descent, and one French family. Multipoint linkage analysis gave a lod score of 5.09 at marker D13S175. The two families of French-Canadian descent share haplotypes with those reported by Kibar et al (1996), indicating a common founder. The French and Scottish-Irish families do not demonstrate the common haplotype, indicating that the mutations in these populations are most likely of different origin.
Chromosomes, Human, Pair 13↗
Autosomal dominant postaxial polydactyly, nail dystrophy, and dental abnormalities map to chromosome 4p16, in the region containing the Ellis-van Creveld syndrome locus.
We have studied a four-generation family with features of Weyers acrofacial dysostosis, in which the proband has a more severe phenotype, resembling Ellis-van Creveld syndrome. Weyers acrofacial dysostosis is an autosomal dominant condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar condition, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease. Linkage and haplotype analysis determined that the disease locus in this pedigree resides on chromosome 4p16, distal to the genetic marker D4S3007 and within a 17-cM region flanking the genetic locus D4S2366. This region includes the Ellis-van Creveld syndrome locus, which previously was reported to map within a 3-cM region between genetic markers D4S2957 and D4S827. Either the genes for the condition in our family and for Ellis-van Creveld syndrome are near one another or these two conditions are allelic with mutations in the same gene. These data also raise the possibility that Weyers acrofacial dysostosis is the heterozygous expression of a mutation that, in homozygous form, causes the autosomal recessive disorder Ellis-van Creveld syndrome.
Abnormalities, Multiple↗
A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome.
The underlying basis of many forms of syndromic craniosynostosis has been defined on a molecular level. However, many patients with familial or sporadic craniosynostosis do not have the classical findings of those craniosynostosis syndromes. Here we present 61 individuals from 20 unrelated families where coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p. In this instance, a new clinical syndrome is being defined on the basis of the molecular finding. In addition to the skull findings, some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases; none had clinically significant syndactyly or deviation of the great toe. Sensorineural hearing loss was present in some, and developmental delay was seen in a minority. While the radiological findings of hands and feet can be very helpful in diagnosing this syndrome, it is not in all cases clearly distinguishable on a clinical basis from other craniosynostosis syndromes. Therefore, this mutation should be tested for in patients with coronal synostosis.
Adult↗
Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.
Hereditary haemorrhagic telangiectasia, or Osler-Rendu-Weber (ORW) syndrome, is an autosomal dominant vascular dysplasia. So far, two loci have been demonstrated for ORW. Linkage studies established an ORW locus at chromosome 9q3; endoglin was subsequently identified as the ORW1 gene. A second locus, designated ORW2, was mapped to chromosome 12. Here we report a new 4 cM interval for ORW2 that does not overlap with any previously defined. A 1.38-Mb YAC contig spans the entire interval. It includes the activin receptor like kinase 1 gene (ACVRLK1 or ALK1), a member of the serine-threonine kinase receptor family expressed in endothelium. We report three mutations in the coding sequence of the ALK1 gene in those families which show linkage of the ORW phenotype to chromosome 12. Our data suggest a critical role for ALK1 in the control of blood vessel development or repair.
Activin Receptors↗
Clouston syndrome (hidrotic ectodermal dysplasia) is not linked to keratin gene clusters on chromosomes 12 and 17.
Clouston syndrome is an hidrotic form of ectodermal dysplasia, inherited as an autosomal dominant trait with high penetrance. The main features of the disorder are alopecia, severe dystrophy of the nails, and palmoplantar hyperkeratosis. A molecular abnormality of keratin has long been hypothesized to be the basic defect in this disorder. We have performed linkage analyses between the disorder and markers close to the keratin gene clusters on chromosomes 12 and 17 and have excluded linkage to these candidate regions in three apparently unrelated families. In addition, linkage has been excluded to four other candidate regions including 1q2l, 17q23-qter, 18q2l, and 2Oql2. These data indicate that Clouston syndrome is not due to a defect in keratin or in a subset of keratin-associated proteins.
Chromosome Mapping↗
Clinical heterogeneity in hereditary haemorrhagic telangiectasia: are pulmonary arteriovenous malformations more common in families linked to endoglin?
Pulmonary arteriovenous malformations (PAVMs) occur in up to 27% of patients with hereditary haemorrhagic telangiectasia (HHT) and are associated with a rate of paradoxical cerebral embolism at presentation of up to 36%. At least two different loci have been shown for HHT. Mutations in endoglin have been found in some families and the locus designated ORW1. In other families this locus has been excluded. In this paper we confirm that in families linked to ORW1 there is a prevalence of PAVMs among affected members of 29.2%, compared to a prevalence of 2.9% in families in which this locus has been excluded (chi 2 = 19.2, p < 0.001). This information can be used to decide how to screen HHT patients for PAVMs.
Antigens, CD↗
Hereditary hemorrhagic telangiectasia.
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Humans↗