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Biomedical subjects

I Winship

Publications and source records attributed to I Winship.

At least 19 recordsLinked to original sources
PubMed2001

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension.

Activin Receptors↗
PubMed2001

Clinical phenotypes of nine cases of Kabuki syndrome from New Zealand.

Nine cases of Kabuki syndrome have been identified in Auckland and surrounding regions in the North Island, New Zealand since 1995. All have the characteristic facial dysmorphism and many of the well-described associated anomalies. Some of the abnormalities were unusual including a case with severe congenital mitral stenosis, two cases of eventration of the diaphragm, idiopathic thrombocytopaenic purpura and vitiligo. One child had an Arnold Chiari type 1 malformation and another had epibulbar dermoids, neither of which has previously been reported in this syndrome. There was a wide diversity of ethnic origin, with the syndrome being described in patients from the Pacific Islands for the first time. The cases described emphasize the broad range of associated anomalies found in Kabuki syndrome and further illustrate its presence in all ethnic groups.

Abnormalities, Multiple↗
PubMed2000

Sequence variation within the RPGR gene: evidence for a founder complex allele.

In our study of sequence variation within the RPGR gene associated with X-linked retinitis pigmentosa, we and others have observed a high rate of new mutation within this gene, as all reported mutations are unique or uncommon. In this article we report the identification in a single family of a complex allele of 7 sequence variants in linkage disequilibrium, of which four result in amino-acid alterations (Arg425Lys, DGlu, Thr533Met and Gly566Glu). This complex allele was initially found in a family with XLRP. However, further study revealed an estimated prevalence of 4.3% (15/344 chromosomes) with this complex allele in the European population indicating the non-pathogenic nature of this allele and, along with previously reported polymorphisms, further supporting a high level of human protein diversity for RPGR. This common complex allele may have been established in the population as a founder effect. Complete gene sequencing identified a potential pathogenic sequence variant in the family described (IVS6+5G>A). This study emphasises the need to create a more complete picture of the allelic variation within a gene, suggests cautious interpretation of a phenotypic association with variant sequences, and highlights the potential problems associated with interpreting genetic studies for diagnostic purposes.

Alleles↗
PubMed2000

Hierarchical mutation screening protocol for the BRCA1 gene.

The identification of mutations in the BRCA1 gene poses difficulties in achieving a screening outcome that satisfies the twin needs of speed and accuracy. These needs must also take into account the patient's family history and the statistical evaluation of the probability of detecting a mutation. Given the above, we present here a hierarchical mutation screening strategy that comprises two tiers: first, multiplex heteroduplex and exon 13 duplication analysis; second, exon amplification and direct sequencing using a 96-well tray format. The advantages of this strategy are two-fold: first, the division of analytical tools in order to achieve low and high-resolution mutation screening, respectively; second, a streamlined sequencing approach that leads to a sensitive and rapid assay that reduces labor costs and handling errors. The success of this approach is shown by the identification of a novel deletion mutation in exon 14 of the BRCA1 gene, which was not detected by the more conventional protein truncation assay due to the small size of the predicted truncated protein.

Adult↗
PubMed2000

Null alleles at the Huntington disease locus: implications for diagnostics and CAG repeat instability.

PCR amplification of the CAG repeat in exon 1 of the IT15 gene is routinely undertaken to confirm a clinical diagnosis of Huntington disease (HD) and to provide predictive testing for at-risk relatives of affected individuals. Our studies have detected null alleles on the chromosome carrying the expanded repeat in three of 91 apparently unrelated HD families. Sequence analysis of these alleles has revealed the same mutation event, leading to the juxtaposition of uninterrupted CAG and CCG repeats. These data suggest that a mutation-prone region exists in the IT15 gene bounded by the CAG and CCG repeats and that caution should be exercised in designing primers that anneal to the region bounded by these repeats. Two of the HD families segregated null alleles with expanded uninterrupted CAG repeats at the lower end of the zone of reduced penetrance. The expanded repeats are meiotically unstable in these families, although this instability is within a small range of repeat lengths. The haplotypes of the disease-causing chromosomes in these two families differ, only one of which is similar to that reported previously as being specific for new HD mutations. Finally, no apparent mitotic instability of the uninterrupted CAG repeat was observed in the brain of one of the HD individuals.

Aged↗
PubMed1999

A patient with VACTERL association, amelia and hemifacial microsomia.

We report on a girl with anal atresia, renal aplasia, vertebral and rib anomalies, amelia and hemifacial microsomia. The patient demonstrates the overlap between the VACTERL association and the oculoauriculovertebral dysplasia. We propose that amelia is a severe manifestation of the limb defects which occur in these developmental dysplasias.

Abnormalities, Multiple↗
PubMed1996

Molecular analysis of the Huntington's disease gene in New Zealand.

AIMS: To establish and validate a polymerase chain reaction (PCR)-based diagnostic test in New Zealand, which enables the number of CAG repeats present in the Huntington's disease (HD) gene to be determined with speed and accuracy. To develop procedures for reporting and counselling probands and families. METHODS: The analysis of the CAG repeat region in Huntington's disease and normal chromosomes involved PCR amplification of genomic DNA using either the incorporation of radioactive deoxynucleotides or fluorescent oligonucleotide primers. RESULTS: The molecular analysis of the CAG repeat sequence in the Huntington's disease gene of over 100 New Zealand individuals has been performed. Huntington's disease chromosomes contained 37-70 (median 44) repeats whereas normal chromosomes contained 9-27 (median 18) repeats. Six individuals from three families had an allele in the intermediate range (30-36 repeats). Instability of the CAG repeat upon transmission from generation to generation was also observed. A comparison of the results obtained using radioactive and fluorescent assays indicates that while both methods are reliable, the latter method is more rapid and allows for automation to be incorporated in the scoring of allele sizes. CONCLUSIONS: Our analysis of Huntington's disease alleles has shown a profile of CAG repeat lengths that is consistent with those reported internationally. In addition, reporting and counselling procedures have been established for presymptomatic testing of Huntington's disease in New Zealand.

DNA↗
PubMed1994

Genetic linkage to the type VII collagen gene (COL7A1) in 26 families with generalised recessive dystrophic epidermolysis bullosa and anchoring fibril abnormalities.

To strengthen the evidence for genetic linkage to COL7A1, we have studied 26 generalised recessive dystrophic epidermolysis bullosa (EB) families of British, Italian, Irish, and South African origin. We chose two linkage markers, a COL7A1 PvuII intragenic polymorphism and a highly informative anonymous microsatellite marker, D3S1100, which maps close to the COL7A1 locus at 3p21.1-3. Diagnosis was established by family history, clinical examination, immunofluorescence, and ultrastructural studies. The PvuII marker was informative in 16 families with a maximum lod score (Zmax) of 3.51 at recombination fraction (theta) = 0. The D3S1100 microsatellite was informative in 24 out of 25 families with Zmax = 6.8 at theta = 0.05 (Z = 4.94 at theta = 0) and no obligatory recombination events. These data strongly suggest that COL7A1 mutations cause EB in these families and, combined with previous studies, indicate locus homogeneity. The importance of anchoring fibrils for dermal-epidermal adhesion is further underlined. D3S1100 may later prove useful in prenatal diagnosis of this disease, if used in combination with other markers.

Base Sequence↗
PubMed1993

Radial ray defect and Robin sequence: a new syndrome?

We report an infant with the principal features of bilateral radial defects, club foot deformity, micrognathia and cleft palate. Other dysmorphic manifestations include the presence of bilateral clinodactyly, medial displacement of the thumb, low set ears and an unusually long 2nd toe. This constellation of signs has not been previously reported and may constitute a new syndrome.

Abnormalities, Multiple↗
PubMed1992

Phenotypic discriminants in the Waardenburg syndrome.

The gene for Waardenburg syndrome (WS) has been assigned to the locus 2q37 and further molecular investigations of affected families are now urgently required to explore the question of possible genetic heterogeneity. Firm positive or negative diagnosis in family members is crucial for studies of this type, but great variation in phenotypic expression sometimes makes this a difficult matter. Ethnic variation in craniofacial anatomical relationships further complicates the issue. We have attempted to establish diagnostic criteria for WS on the basis of an analysis of the phenotypes in 68 affected children who have been examined in special schools for the deaf in Southern Africa during the past 18 years. We then used these criteria for diagnostic evaluation of all available persons in seven multigeneration WS families in the Cape, as a preliminary to molecular investigations. With very few exceptions this approach permitted firm positive or negative diagnosis in these individuals.

Adolescent↗
PubMed1991

Piebaldism: an autonomous autosomal dominant entity.

Piebaldism is a disorder in which the major clinical features are patchy hypopigmentation of the skin and a white forelock. The manifestations of piebaldism overlap with those of other genodermatoses, in particular the Waardenburg syndrome, and it is uncertain whether piebaldism is a distinct entity. We have documented a family in which seven affected members in three generations have gross piebaldism without any additional stigmata. The intrafamilial phenotypic consistency is suggestive that this autosomal dominant disorder has independent syndromic status. Linkage studies using conventional gene markers failed to identity the locus of the faulty gene.

Adolescent↗
PubMed1991

Hearing impairment and pigmentary disturbance.

Hearing impairment is a variable manifestation of several heritable conditions in which pigmentation of the skin or eyes is abnormal. Some of these disorders are well recognized although uncommon, while others are virtually private syndromes. Practical issues concerning the major conditions of this type are reviewed in this article on a basis of a survey of 4452 profoundly deaf children attending special schools in Southern Africa, together with investigations in affected families. The Waardenburg syndrome (WS), which is the most common deafness-depigmentation disorder, was present in 121 (2.7%) of the 4452 deaf scholars. Further studies in 7 multigeneration affected families confirmed phenotypic variability and indicated a need for internationally agreed diagnostic criteria. In 4 Cape Town families of mixed ancestry the WS-I gene was linked to the 2q37 locus, but in another large kindred no linkage could be demonstrated. Nonallelic heterogeneity is possible. There is uncertainty concerning possible interrelationship between WS and piebaldism. The phenotypic consistency of a South African family in which 7 persons in 3 generations had gross piebaldism in the absence of disturbance of hearing or involvement of the eyes and periorbital structures is suggestive that this disorder and WS are separate entities. Molecular investigations indicate that the gene for piebaldism in this kindred is not situated at the WS-I locus 2q37. Deafness and hyperpigmentation are present in neurofibromatosis type II (acoustic neuromata) and the multiple lentigines syndrome, while retinal pigmentation is a feature of the Usher syndrome. This latter entity is apparently much less common in Southern Africa than in other parts of the world.

Albinism↗
PubMed1990

Boomerang dysplasia.

Boomerang dysplasia is a recently delineated form of neonatally lethal dwarfism. A fourth case has been investigated and an increased range of phenotypic manifestations is documented in this article. So far all affected infants have been males and X-linked recessive inheritance is possible. Diagnostic criteria for Boomerang dysplasia are outlined.

Dwarfism↗
PubMed1989

Evidence for genetic heterogeneity in tuberous sclerosis.

The question of genetic heterogeneity in tuberous sclerosis (TSC) was addressed by genetic linkage studies in eight affected families using nine polymorphic markers (EFD126.3, MCT136, ABO, ABL, AK1, and MCOA12 from distal 9q, and PBGD, MCT128.1, and 1CJ52.208M from distal 11q). The data as a whole supported a TSC locus on distal 9q, the peak lod score on multipoint analysis being 3.77 at 6 cM proximal to the Abelson oncogene locus (ABL). However, analysis of two point lod scores using the HOMOG programs showed significant evidence for genetic heterogeneity (p = 0.01), linkage to ABL being unlikely in one family. After exclusion of the unlinked family, multipoint analysis gave a peak lod score of 6.1 in the vicinity of ABL. The family unlinked to ABL showed no recombinants with two chromosome 11 probes, but was too small to provide significant evidence for linkage. Genetic heterogeneity in TSC will complicate efforts to clone the causative genes and severely limit the use of linked probes for carrier detection and prenatal diagnosis.

Chromosome Mapping↗