Congenital absence of the vas deferens (CAVD) is a frequent cause for obstructive azoospermia and accounts for 1%-2% of male infertility. A high incidence of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has recently been reported in males with CAVD. We have investigated a cohort of 106 German patients with congenital bilateral or unilateral absence of the vas deferens for mutations in the coding region, flanking intron regions and promotor sequences of the CFTR gene. Of the CAVD patients, 75% carried CFTR mutations or disease-associated CFTR variants, such as the "5T" allele, on both chromosomes. The distribution of mutation genotypes clearly differed from that observed in cystic fibrosis. None of the CAVD patients was homozygous for delta F508 and none was compound heterozygous for delta F508 and a nonsense or frameshift mutation. Instead, homozygosity was found for a few mild missense or splicing mutations, and the majority of CAVD mutations were missense substitutions. Twenty-one German CAVD patients were compound heterozygous for delta F508 and R117H, which was the most frequent CAVD genotype in our study group. Haplotype analysis indicated a common origin for R117H in our population, whereas another frequent CAVD mutation, viz. the "5T allele" was a recurrent mutation on different intragenic haplotypes and multiple ethnic backgrounds. We identified a total of 46 different mutations and variants, of which 15 mutations have not previously been reported. Thirteen novel missense mutations and one unique amino-acid insertion may be confined to the CAVD phenotype. A few splice or missense variants, such as F508C or 1716 G-->A, are proposed here as possible candidate CAVD mutations with an apparently reduced penetrance. Clinical examination of patients with CFTR mutations on both chromosomes revealed elevated sweat chloride concentrations and discrete symptoms of respiratory disease in a subset of patients. Thus, our collaborative study shows that CAVD without renal malformation is a primary genital form of cystic fibrosis in the vast majority of German patients and links the particular expression of clinical symptoms in CAVD with a distinct subset of CFTR mutation genotypes.

Disturbances in dopamine neurotransmission have been postulated to underlie schizophrenia. We report data from two independent studies of a Ball polymorphism in the dopamine D3 receptor gene in patients with schizophrenia. In both studies, more patients than controls were homozygous (p= 0005, p = 0008). When pooled data were analysed, this difference was highly significant (p = 00001) with a relative risk of schizophrenia in homozygotes of 2-61 (95% confidence intervals 1P60-426 in the first exon that gives rise to a glycine to serine substitution in the N-terminal extracellular domain. This results in the creation of a BalI restriction enzyme site.8 The failure of ourselves and others to show genetic linkage between schizophrenia and this polymorphism in multiply affected families (unpublished data) makes it unlikely that a mutation in D3 is a major factor predisposing to illness in the majority of such families. However, we have also tested the hypothesis that variation at this locus might be associated with more subtle differences in liability to develop schizophrenia by comparing allele and genotype frequencies in patients and controls. We present data from two independent studies carried out in the UK and France. Materials and methodsIn the UK study, 68 unrelated patients with schizophrenia (25 female and 43 male) were recruited. All patients satisfied the DSMIII-R criteria for schizophrenia. Sixty-eight controls (29 female and 39 male) were recruited from among the married in members of families seeking DNA diagnosis in the

DNA fragments from a genomic library were used to establish the partial structure of the human dopamine D3 receptor gene (DRD3). Its coding sequence contains 6 exons and stretches over 40,000 base pairs. The complete DRD3 transcript and three shorter variants, in which the second and/or third exon are deleted, were detected in similar proportions in brains from four controls and three psychiatric patients. The Msp I polymorphism was localized in the fifth intron of the gene, 40,000 base pairs downstream the Bal I polymorphism and a PCR‐based method was developed for genotyping this polymorphism. The distributions of the Msp I and Bal I genotypes were not independent in 297 individuals (x2 = 10.5, df = 4, P = 0.03), but only a weak association was found between allele 1 of the Bal I polymorphism and allele 2 of the Msp I polymorphism (x2 = 3.99, df = 1, P = 0.04). The previously reported association between homozygosity at both alleles of the Bal I polymorphism and schizophrenia was presently maintained in an extended sample, comprising 119 DSM‐III‐R chronic schizophrenics and 85 controls (x2 = 5.3, df = 1, P = 0.02) and found more important in males than in females. The presence of the Bal I allele 2 is associated with an early age at onset, particularly in males (df = 35, t value = 2.6, P = 0.014). In the same sample, allelic frequencies, genotype counts, and proportion of homozygotes for the Msp I polymorphism did not differ between schizophrenics and controls (x2 = 0.06, df = 1, P = 0.80, x2 = 0.22, df = 1, P = 0.90 and x2 = 0.16, df = 1, P = 0.69, respectively). The large distance of the Msp I polymorphism from the Bal I polymorphism and its localization in the 3' part of the gene may explain the discrepant results obtained with the two polymorphisms. © 1996 Wiley‐Liss, Inc.

The analysis of 650 HLA-A:HAL-B:Bf three-factor haplotypes revealed significant associations only between alleles of the very closely linked genes HLA-A and HLA-B, and Bf, respectively. Most striking is the highly significnat association of the rare Bf variant F1 with HLA-B18 and of S1 with HLA-B13, HLA-B14, and HLA-Bw21. Only random allele distributions were observed when considering the somewhat more distant genes HLA-A and Bf or the higher order interaction at all three genes. From these findings it seems likely that the linkage disequilibrium within the MHC is not due to selective forces, but rather due to a short evolutionary period.

SUMMARY Five phenotypic females in one family had the genotype 46,XY and all had gonadal germ cell tumours. Studies of the family pedigree suggest that this form of XY gonadal dysgenesis is inherited in an X linked recessive manner.G banding of elongated metaphase chromosomes from two subjects with XY gonadal dysgenesis and a female carrier showed no aberrations of the X chromosome. The titres of H-Y antigen in three girls with XY gonadal dysgenesis were in the male control range. Thus it appears that, in the X linked form, XY gonadal dysgenesis may be caused by a point deletion or mutation of a gene on the X chromosome, which controls the gonad specific receptor for the H-Y antigen.Studies of Xg blood groups were uninformative about linkage of Xg with the X borne gene causing the XY gonadal dysgenesis.Dermatoglyphic studies in the girls with XY gonadal dysgenesis and female carriers revealed high a-b palmar ridge counts and a tendency for the A mainline to terminate in the thenar area. Both of these features have been described in patients with Turner's syndrome. XY We describe studies in a family in which XY gonadal dysgenesis appears to have been inherited in an X linked recessive manner, and in which the