Genetics of Hunter Syndrome: carrier detection, new mutations, segregation and linkage analysis

Abstract

We have investigated 31 families segregation for Hunter Syndrome in order to advance our understanding of the genetics of this disease. The hair root test for the diagnosis of carriers of Hunter Syndrome was improved by the adoption of a new diagnostic index that distinguishes between carrier and normal females better than previous methods of analysis. One hundred and eleven female relatives of the affected children were tested by such procedures. This showed that seven out of 31 mothers were not carriers (22.6%), thus suggesting a small deficit of new mutation relative to the expectation that 33% of lethal, recessive alleles arise anew in a population at equilibrium at a sex-linked locus with equal mutation rates in male and female gametogenesis. The difference, however, is not statistically significant. The age of the parents of new mutants was slightly but significantly raised. Nevertheless, the independent increase in the age of the fathers of new female mutants was not statistically significant. Finally, a deficit of affected males was observed. This was significant and suggests the possibility of intrauterine loss of some affected males. Linkage analysis between the Hunter Syndrome locus, three polymorphisms in the Factor IX gene and the anonymous polymorphic probes 52A and DX13 showed that the Hunter locus is fairly closely linked to DX13, and hence distal to the Factor IX gene, while no linkage was observed with the 52A polymorphic site. The maximum lod score for the linkage between factor IX and the Hunter Syndrome locus was 0.424 at theta = 0.25; and that for the linkage between the Hunter Syndrome locus and DX13 was 3.01 at theta = 0.1.

Mutation analysis of iduronate-2-sulphatase gene in 24 patients with Hunter syndrome: Characterisation of 6 novel mutations

“…The IDS gene was mapped to chromosome Xq28 by a combination of linkage studies (Upadhyaya et al, 1986;Chase et al, 1986; LeGuern et al, 1990) and cytogenetic analysis of an affected female patient (Mossman et al, 1983). IDS cDNA was sequenced (Wilson et al, 1990) and subsequently the intron-exon structure was determined by Flomen et al (1993) and Wilson et al (1993) and was found to consist of nine exons spanning approximately 24 Kb of genomic DNA.…”

Segregation and sporadic cases in families with Hunter's syndrome.

“…There was significant heterogeneity among samples in both the estimation of p (x2= 12-04, 4 df, p<0025) and the estimation of x when p was kept constant (X2=13-63, 4 df, p<0-01). In both cases the heterogeneity was the result of the substantial contribution of the Z sample (table 4).…”

“…The ax r and rx s tables for the Hunter families from the GDR are reported in table 1, along with those of 36 families collected in sample Y,' of 19 families collected in sample T,5 of nine families collected in sample Z,6 and of 31 families collected in sample C. 4 The maximum likelihood value of in the M sample was estimated as 0-88. Accordingly, our best estimates of prevalence and incidence in the GDR become 4-8 and 9-4 per million male live births, respectively.…”

Genes and genomes: Carrier detection of deletions in female relatives of X‐linked disorders by non‐isotopic in situ hybridisation

“…When this clone was used to screen a group of Hunter patients, about one third were found to have deletions or rearrangements of the gene; the remaining subjects had either small deletions or point mutations which could not be analysed by the techniques Genetic counselling of female relatives in families with an affected male Huntcr patient is hampered by tcchnical difficulties. The estimation of the levels of the specific lysosomal enzyme cu-ISS in hair root cells provides clear results in most cases, but does not reveal the cause of the a-ISS deficiency (35).…”

“…In the course of a previous study, female relatives of the patient had been testcd to assess their carrier status using the hair root assay (35). The mother, one sister, an aunt and a cousin were found to be carriers of the abnormal gene, while other relatives, including another sister, had normal a-ISS enzymatic activity.…”