Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome.

OBJECTIVE: The purpose of this study was the clinical and pathological characterisation of a new autosomal dominant gastric polyposis syndrome, gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). METHODS: Case series were examined, documenting GAPPS in three families from Australia, the USA and Canada. The affected families were identified through referral to centralised clinical genetics centres. RESULTS: The report identifies the clinical and pathological features of this syndrome, including the predominant dysplastic fundic gland polyp histology, the exclusive involvement of the gastric body and fundus, the apparent inverse association with current Helicobacter pylori infection and the autosomal dominant mode of inheritance. CONCLUSIONS: GAPPS is a unique gastric polyposis syndrome with a significant risk of gastric adenocarcinoma. It is characterised by the autosomal dominant transmission of fundic gland polyposis, including areas of dysplasia or intestinal-type gastric adenocarcinoma, restricted to the proximal stomach, and with no evidence of colorectal or duodenal polyposis or other heritable gastrointestinal cancer syndromes.

A new DNA marker tightly linked to the fragile X locus (FRAXA).

The fragile X syndrome is the most common cause of familial mental retardation. Genetic counseling and gene isolation are hampered by a lack of DNA markers close to the disease locus. Two somatic cell hybrids that each contain a human X chromosome with a breakpoint close to the fragile X locus have been characterized. A new DNA marker (DXS296) lies between the chromosome breakpoints and is the closest marker to the fragile X locus yet reported. The Hunter syndrome gene, which causes iduronate sulfatase deficiency, is located at the X chromosome breakpoint that is distal to this new marker, thus localizing the Hunter gene distal to the fragile X locus.

Letting the family know: balancing ethics and effectiveness when notifying relatives about genetic testing for a familial disorder.

OBJECTIVE: To increase the awareness among at risk relatives of the availability of genetic testing for a familial disorder while respecting their autonomy and privacy. METHODS: This was a comparison of preintervention and postintervention cohorts of families carried out in a state wide clinical service providing genetic counselling and testing for people at risk of familial adult onset cancer. Unaffected relatives who were not clients of the service in 74 kindreds with familial mutations causing familial breast and ovarian cancer, hereditary non-polyposis colorectal cancer, or Cowden syndrome were included in the study. In the baseline cohort (41 kindreds), family members who were clients of the clinical service and had been shown to be carriers of mutations were asked to advise relatives that genetic testing was available. In the intervention cohort (33 kindreds), the clinical service obtained consent to advise at risk relatives by letter that genetic testing was available. The main outcome measures were: (a) proportion of unaffected first and second degree relatives of the proband in each family whose genetic status was clarified within 2 years of the mutation being identified in the family, and (b) concerns regarding privacy and autonomy voiced by relatives receiving these letters. RESULTS: In the baseline cohort, the average proportion of relatives in each family whose genetic status was clarified was 23%. In the intervention cohort, the average proportion of relatives in each family whose genetic status was clarified was 40% (p = 0.001). None of the relatives in the intervention cohort complained of a breach of privacy or autonomy. CONCLUSION: Clinical services can take an effective and proactive approach to notifying relatives who are not their clients of the availability of genetic testing without compromising principles of privacy and autonomy.

Arteriovenous malformations in Cowden syndrome.

Cowden syndrome (OMIM No 158350) is a pleomorphic, autosomal dominant syndrome characterised by hamartomas in tissues derived from the endoderm, mesoderm, and ectoderm. It is caused by germline mutations in the PTEN gene and is allelic to the Bannayan-Riley-Ruvalcaba and Lhermitte-Duclos syndromes. The three syndromes are defined on clinical grounds but there is overlap in their definitions. The clinical features include trichilemmomas, verrucose lesions of the skin, macrocephaly, intellectual disability, cerebellar gangliocytoma, thyroid adenomas, fibroadenomas of the breast, and hamartomatous colonic polyps. Cutaneous haemangiomas are occasionally noted. Malignancies often arise in the affected tissues. Visceral arteriovenous malformations are a recognised component of the Bannayan-Riley-Ruvalcaba syndrome but have been reported rarely in Cowden syndrome. A family is described with a clinical diagnosis of Cowden syndrome, a familial frameshift mutation in the PTEN gene, and large visceral arteriovenous malformations. The association of these pleomorphic syndromes with arteriovenous malformations can be explained by the putative role of the PTEN gene in suppressing angiogenesis. Recognition of arteriovenous malformations as a clinical feature of Cowden syndrome has implications for the clinical management of patients with this disorder.

Fragile X syndrome and nephrogenic diabetes insipidus.

We describe a man with the fra(X) syndrome and nephrogenic diabetes insipidus. The disease loci for both conditions are in the region Xq27.3-q28. This is the first report of the fra(X) syndrome associated with another X-linked disorder. Analysis of DNA markers suggested that the association in this man was coincidental.

A non-syndromal form of X-linked mental retardation (XLMR) is linked to DXS14.

An analysis of the linkage of a non-syndromal form of X-linked mental retardation (MRX1) with a number of markers on the X chromosome was performed in a large pedigree. The affected males had moderate mental retardation; in all other clinical respects and cytogenetically they were normal. No recombinants were observed between the MRX1 gene and the marker DXS14 (p58.1) located at Xp11-cen (Z (max.) = 2.12 at theta = 0.00). Recombination was observed between the MRX1 gene and the markers DXS7 and DXYS1 which flank DXS14. This form of XLMR maps to the centromeric portion of the X-chromosome.

Ring chromosome 11 and café-au-lait spots.

We report on the segregation of a cytogenetically non-deleted ring chromosome 11 and café-au-lait spots in a family. This appears to be the largest inherited ring autosome yet reported.

A distinctive syndrome of brachycephaly, deafness, cataracts and mental retardation.

A boy with brachycephaly without craniosynostosis, raised intracranial pressure, deafness, cataracts, and global developmental delay is described.

Microlissencephaly with cardiac, spinal and urogenital defects.

We describe two children with a brain defect similar to that described as 'microlissencephaly', as defined in Barkovich et aL [(1998) Neuroped 29: 113-119]. Concomitant malformations (cardiac, spinal, urogenital) may represent components of a wider syndrome complex; alternatively, or additionally, there may have been a valproate teratogenic effect. The inheritance is likely to be autosomal recessive, although X-linkage cannot be excluded.

Risky communication: pitfalls in counseling about risk, and how to avoid them.

A genetic counselor is often faced with the difficult task of conveying a set of complex and highly abstract factors associated with the client's risk of developing a familial disorder. The client is faced with the even more difficult task of making significant health-related decisions about an event which may or may not eventuate. Although there is a large corpus of research on this topic, much of the knowledge on risk communication is difficult to apply in a practical context. In this paper we draw together some insights on risk communication and decision-making under conditions of uncertainty, and apply them directly to the problem of communicating familial cancer risk. In particular, we focus on the distinction between individual risk and observed frequencies of adverse events, various framing effects, and contextualizing risk communication. We draw attention to some of the potential pitfalls in counseling about risk and offer avenues for circumventing them.

Genetic counseling in rare syndromes: a resampling method for determining an approximate confidence interval for gene location with linkage data from a single pedigree.

Multipoint linkage analysis is a powerful method for mapping a rare disease gene on the human gene map despite limited genotype and pedigree data. However, there is no standard procedure for determining a confidence interval for gene location by using multipoint linkage analysis. A genetic counselor needs to know the confidence interval for gene location in order to determine the uncertainty of risk estimates provided to a consultant on the basis of DNA studies. We describe a resampling, or "bootstrap," method for deriving an approximate confidence interval for gene location on the basis of data from a single pedigree. This method was used to define an approximate confidence interval for the location of a gene causing nonsyndromal X-linked mental retardation in a single pedigree. The approach seemed robust in that similar confidence intervals were derived by using different resampling protocols. Quantitative bounds for the confidence interval were dependent on the genetic map chosen. Once an approximate confidence interval for gene location was determined for this pedigree, it was possible to use multipoint risk analysis to estimate risk intervals for women of unknown carrier status. Despite the limited genotype data, the combination of the resampling method and multipoint risk analysis had a dramatic impact on the genetic advice available to consultants.

Control of nephroblastoma: associated hypertension and polydipsia by captopril.

A child with nephroblastoma, severe hypertension, polydipsia, and polyuria is presented. Previous reports of this association describe great difficulty in controlling the hypertension by medical means. Captopril provided prompt and continuing control of this child's hypertension and allowed for optimal preparation prior to surgery.

X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome: localization to Xq12-q21.31 by X inactivation and linkage analysis.

We have examined seven pedigrees that include individuals with a recently described X-linked form of severe mental retardation associated with alpha-thalassemia (ATR-X syndrome). Using hematologic and molecular approaches, we have shown that intellectually normal female carriers of this syndrome may be identified by the presence of rare cells containing HbH inclusions in their peripheral blood and by an extremely skewed pattern of X inactivation seen in cells from a variety of tissues. Linkage analysis has localized the ATR-X locus to an interval of approximately 11 cM between the loci DXS106 and DXYS1X (Xq12-q21.31), with a peak LOD score of 5.4 (recombination fraction of 0) at DXS72. These findings provide the basis for genetic counseling, assessment of carrier risk, and prenatal diagnosis of the ATR-X syndrome. Furthermore, they represent an important step in developing strategies to understand how the mutant ATR-X allele causes mental handicap, dysmorphism, and down-regulation of the alpha-globin genes.

Becker muscular dystrophy (BMD) and Klinefelter's syndrome: a possible cause of variable expression of BMD within a pedigree.

We describe a man with Becker muscular dystrophy whose weakness was minimal in contrast to that of his more severely affected nephews. This man had a Klinefelter karyotype (47,XXY) and his mild symptoms may be attributed to him being heterozygous for the muscular dystrophy gene. This is the first report of a person with both Klinefelter's syndrome and Becker muscular dystrophy. This combination may be one explanation for the variable expression of X linked muscular dystrophy noted in some pedigrees.

New mutations in MID1 provide support for loss of function as the cause of X-linked Opitz syndrome.

Opitz syndrome (OS) is a genetically heterogeneous malformation disorder. Patients with OS may present with a variable array of malformations that are indicative of a disturbance of the primary midline developmental field. Mutations in the C-terminal half of MID1, an RBCC (RING, B-box and coiled-coil) protein, have recently been shown to underlie the X-linked form of OS. Here we show that the MID1 gene spans at least 400 kb, almost twice the distance originally reported and has a minimum of six mRNA isoforms as a result of the alternative use of 5' untranslated exons. In addition, our detailed mutational analysis of MID1 in a cohort of 15 patients with OS has resulted in the identification of seven novel mutations, two of which disrupt the N-terminus of the protein. The most severe of these (E115X) is predicted to truncate the protein before the B-box motifs. In a separate patient, a missense change (L626P) was found that also represents the most C-terminal alteration reported to date. As noted with other C-terminal mutations, GFP fusion constructs demonstrated that the L626P mutant formed cytoplasmic clumps in contrast to the microtubular distribution seen with the wild-type sequence. Notably, however, both N-terminal mutants showed no evidence of cytoplasmic aggregation, inferring that this feature is not pathognomonic for X-linked OS. These new data and the finding of linkage to MID1 in the absence of a demonstrable open reading frame mutation in a further family support the conclusion that X-linked OS results from loss of function of MID1.

High-resolution genetic map around the spinal muscular atrophy (SMA) locus on chromosome 5.

Although autosomal recessive spinal muscular atrophy (SMA) has been mapped to chromosome 5q12-q13, there is for this region no genetic map based on highly informative markers. In this study we present the mapping of two previously reported microsatellite markers in 40 CEPH and 31 SMA pedigrees. We also describe the isolation of a new microsatellite marker at the D5S112 locus. The most likely order of markers (with recombination fractions given in parentheses) is 5cen-D5S6-(.02)-D5S125-(.04)-(JK53CA1/2,D5S11 2)-(.04)-D5S39-qter. The relative order of D5S6, D5S112, and D5S39 was confirmed by in situ hybridization. Multipoint linkage analysis in 31 SMA families indicates that the SMA locus lies in the 6-cM interval between D5S6 and JK53CA1/2, D5S112.

Four chromosomal breakpoints and four new probes mark out a 10-cM region encompassing the fragile-X locus (FRAXA).

We report the validation and use of a cell hybrid panel which allowed us a rapid physical localization of new DNA probes in the vicinity of the fragile-X locus (FRAXA). Seven regions are defined by this panel, two of which lie between DXS369 and DXS296, until now the closest genetic markers that flank FRAXA. Of those two interesting regions, one is just distal to DXS369 and defined by probe 2-71 (DXS476), which is not polymorphic. The next one contains probes St677 (DXS463) and 2-34 (DXS477), which are within 130 kb and both detect TaqI RFLPs. The combined informativeness of these two probes is 30%. We cloned from an irradiation-reduced hybrid line another new polymorphic probe, Do33 (DXS465; 42% heterozygosity). This probe maps to the DXS296 region, proximal to a chromosomal breakpoint that corresponds to the Hunter syndrome locus (IDS). The physical order is thus Cen-DXS369-DXS476-(DXS463,DXS477)-(DXS296, DXS465)-IDS-DXS304-tel. We performed a linkage analysis for five of these markers in both the Centre d'Etude du Polymorphisme Humain families and in a large set of fragile-X families. This establishes that DXS296 is distal to FRAXA. The relative position of DXS463 and DXS477 with respect to FRAXA remains uncertain, but our results place them genetically halfway between DXS369 and DXS304. Thus the DXS463-DXS477 cluster defines presently either the closest proximal or the closest distal polymorphic marker with respect to FRAXA. The three new polymorphic probes described here have a combined heterozygosity of 60% and represent a major improvement for genetic analysis of fragile-X families, in particular for diagnostic applications.

Addition of MT, D16S10, D16S4, and D16S91 to the linkage map within 16q12.1-q22.1.

A 10-point genetic linkage map of the region 16q12.1 to 16q22.1 has been constructed using the CEPH reference families. Four loci, MT, D16S10, D16S91, and D16S4, not previously localized on a multipoint linkage map, were incorporated on the map presented here. The order of loci was cen-D16S39-MT, D16S65-D16S10-FRA16B-D16S38, D16S4, D16S91, D16S46-D16S47-HP-qter. The interval between D16S10 and 4D16S38 is 3.1 cM in males and 2.3 cM in females, and contains FRA16B. The cloning strategy for FRA16B will now be based on YAC walking from D16S10 and D16S38. The location of FRA16B between D16S10 and D16S38 provides a physical reference point for the multipoint linkage map on the short arm of chromosome 16.

Tailoring communication in consultations with women from high risk breast cancer families.

This multicentre study examined the influence of patient demographic, disease status and psychological variables on clinical geneticists/genetic counsellors (consultants) behaviours in initial consultations with women from high-risk breast cancer families. One hundred and fifty-eight women completed a pre-clinic self-report questionnaire. The consultations were audiotaped, transcribed verbatim and coded. Consultants did not vary their behaviour according to women's expectations. However, significantly more aspects of genetic testing were discussed with women who were affected with breast cancer (P<0.001), screening and management with unaffected women (P=0.01) and breast cancer prevention with younger women (P=0.01). Prophylactic mastectomy was discussed more frequently with women with medical and allied health training (P=0.02), and prophylactic oophorectomy with women affected with breast cancer (P=0.03), those in non-professional occupations (P=0.04) and with a family history of breast and ovarian cancer (P<0.001). Consultants used significantly more behaviours to facilitate understanding with women who were in non-professional occupations (P=0.04); facilitated active patient involvement more with women affected with breast cancer (P<0.001) and used more supportive and counselling behaviours with affected women (P=0.02). This study showed that patient demographics were more likely to predict consultants' communication behaviours than the woman's psychological status. Methods to facilitate assessment of psychological morbidity are needed to allow more tailored communication.