O. W. J. Quarrell

Linkage disequilibrium in Huntington's disease: an improved localisation for the gene.

The search for the Huntingtons disease gene has recently concentrated on the telomere of the short arm of chromosome 4. The evidence suggesting this position has been based on single crossover events, but there is conflicting evidence regarding the position of the gene relative to the most terminal markers. We have found significant linkage disequilibrium between the markers D4S98 (probe BS731B-C) and D4S95 (probe BS674E-D) and HD, which supports a localisation for the gene proximal to D4S90 and makes a telomeric localisation unlikely. This disequilibrium may also prove to be important in the future in allowing modification of risk estimates based on genetic linkage.

Genetic linkage between Huntington's disease and the DNA polymorphism G8 in South Wales families.

Analysis of the polymorphism shown by the DNA probe G8 in eight South Wales families with Huntingtons disease has confirmed close genetic linkage between this marker and the disorder, the most likely genetic distance being two centimorgans (cM). The closeness of the linkage suggests that G8 may have clinical applications in genetic prediction for this condition.

Exclusion testing in pregnancy for Huntington's disease.

The results of DNA analysis are presented for a series of 90 couples, with one partner at 50% risk for Huntingtons disease (HD), who were referred for exclusion testing in pregnancy over a three year period. Thirty-seven couples were studied in detail. The aims of the study were to evaluate attitudes towards prenatal testing, before pregnancy and afterwards, and the effectiveness of our counseling and methods of organising the service. Problems which could arise in relation to presymptomatic testing are documented. It is concluded that exclusion testing is a valuable form of prediction for some couples, particularly where family structure does not permit prediction for the person at risk. The need for intensive counselling was highlighted by the difficulties experienced by many couples in understanding how the test worked. Particular ethical and organisational problems may arise which require careful consideration beforehand and some recommendations are made. The proportion of couples who will continue to request exclusion testing as pre-symptomatic testing becomes more widely applicable remains unknown.

Studies of a DNA marker (G8) genetically linked to Huntington disease in British families.

SummaryClose genetic linkage has been shown between the DNA sequence G8 (locus D4S10) and 16 British families with Huntington disease using the HindIII, EcoR1, Nci1, and Pst1 polymorphisms detected by G8, and by combining all the polymorphisms to give a combined haplotype. Two recombinants have been detected in these families giving a maximum lod score of 17.60 at a Θ of 0.02. These results confirm the originally reported linkage between the loci and provide evidence against significant multilocus heterogeneity for Huntington disease.

Absence of close linkage between benign hereditary chorea and the locus D4S10 (probe G8).

A genetic linkage study between benign hereditary chorea and the locus D4S10 using the DNA probe G8 has shown two recombinations in five small families. There were negative lod scores at recombination fractions that show conclusive evidence of linkage in 16 larger British Huntingtons disease families. We suggest that although benign hereditary chorea and Huntingtons disease may have some clinical similarities they are probably at two different loci.