Ulrike Thies

Down syndrome and male fertility: PCR-derived fingerprinting, serological and andrological investigations

Down syndrome, the most common birth defect causing mental retardation, is characterized by a specific phenotype including subfertility or sterility and hypogonadism in males. In contrast, several females with Down syndrome have borne offspring. Here, a male with trisomy 21 fathering an infant is described. This observation is verified by serological markers, DNA fingerprinting using different DNA micro‐or minisatellites and andrological investigations.

The genes for human brain factor 1 and 2, members of the fork head gene family, are clustered on chromosome 14q

Brain factor-1 (BF-1) is a member of the fork head gene family which shows expression restricted to the neurons of the developing telencephalon in rodents and man. We have isolated a second human gene (HBF-2), which is also strongly expressed in embryonic brain and has very high homology to both the rat and human brain factor-1 genes and the retroviral oncogene qin. The HBF-2 cDNA was isolated from a human fetal brain expression library and contains a putative open reading frame of 479 amino acids. The HBF-2 gene is strongly expressed in fetal brain and also with lower levels of expression in several adult tissues. At the genomic level the gene for HBF-1 contains an 500 bp intron situated between the DNA binding domain II and the fork head domain while that of HBF-2 is intronless. The two genes are clustered on human chromosome 14q11-13.

Physical mapping of two Xp markers DXS16 and DXS143.

SummaryLymphocyte karyotyping of an infant girl with the clinical features of microphthalmia, iridoschisis, goiter, hip joint dysplasia, labium synechia and craniotabes revealed an Xp deletion. The lymphocyte karyotypes of the parents were normal. Bromodeoxyuridine incorporation studies showed that, in 42 out of 43 metaphases, the deleted X chromosome was late replicating. In one metaphase, the normal X chromosome was observed to be allocyclic. Using DNA markers from the Xp22 region, the breakpoint was assigned distal to DXS16 (pXUT23) and proximal to DXS143 (dic56). Dosage intensity measurements confirmed that the STS gene and the DNA marker DXS31 were involved in the deleted area. Restriction fragment length polymorphism analysis revealed that the paternally derived X-chromosome was deleted.

Clinical, cytogenetic and molecular investigations in three patients with Wolf‐Hirschhorn syndrome

Clinical, cytogenetic and molecular studies were performed in three patients with Wolf‐Hirschhorn syndrome (WHS). In all cases the altered chromosome 4 appeared to be the result of a de novo deletion. Cytogenetic investigations located the breakpoint at 4p15.3 and 4p13. With cytogenetic methods it was not possible to decide whether these deletions were terminal or interstitial. DNA methods also failed to define a distal breakpoint within the 4p16.3 region which might have indicated an interstitial deletion. According to the literature, the paternal chromosome 4 is preferentially deleted in most patients with WHS. DNA analysis with polymorphic markers out of the 4p16.3 region revealed that in two of the cases reported here the deleted segment was of paternal and in one case of maternal origin.

Holt-Oram syndrome in four half-siblings with unaffected parents: brief clinical report.

The Holt‐Oram syndrome was diagnosed in four offspring of three mothers and the same unaffected father. One additional child lacked the characteristic clinical features of the Holt‐Oram syndrome. In contrast to the general autosomal dominant inheritance with complete penetrance, our observation suggests a paternal mutation, resulting in mosaicism, probably restricted to the germline.

PCR analysis of a three-allelic PvuII—RFLP at D4S127 closely linked to the Huntington disease locus

Willoh R, Zühlke C, Gerdes B, Wiese S, Thies U. PCR analysis of a three‐allelic PvuII—RFLP at D4S127 closely linked to the Huntington disease locus.

2. A Multilocus DNA Fingerprint with Built-in Security Devices

An unusual case of paternity testing is reported in which determination of paternity was an essential part of a genetic diagnosis. A.Y-chromosomal abnormality, observed in a 33-year-old male whose wife had experienced a series of spontaneous abortions, was not found in his alleged father. DNA fingerprinting with the oligonucleotide multilocus probe (CAC)5 yielded two aberrant bands for the proband, i.e. bands exhibited by neither parent. This finding resulted in a comparatively low paternity probability of 0.02934 which is suggestive of, but does not unequivocally prove, false paternity. Subsequent analysis with other multi- and single-locus systems, however, failed to confirm this preliminary result. The paternity probability computed on the basis of the single-locus systems was 0.99997, providing compelling evidence in favour of true paternity. The present case thus demonstrates that even when two mutations turn up in a DNA fingerprint, these may be readily recognized as such.

Allele frequencies of DNA markers genetically linked to Friedreich ataxia in the German population.

Friedreich ataxia (FRDA) is a recessive neurodegenerative disorder affecting both central and peripheral nervous systems. The mutation was mapped to chromosome 9 by its tight linkage to the polymorphic loci D9S5 and D9S15. Using informative DNA markers the allele frequencies at these loci, in up to 84 unrelated healthy persons and in 16 FRDA patients of German origin, were determined. The comparison to data from other European populations did not reveal remarkable differences. No significant linkage disequilibrium could be observed between FRDA and the loci D9S5 and D9S15 in German families.

Allele frequencies and linkage disequilibrium of polymorphic DNA markers of the Huntington disease region in the German population

Allele frequencies of 14 different restriction fragment length polymorphisms from 12 DNA markers within the Huntington disease (HD) region were evaluated in the German population. No significant differences from published data of allele frequencies from chromosomes of Caucasian ancestry were found. The analysis of eight DNA polymorphisms in 87 HD families of German origin revealed significant non-random association with the HD locus and the D4S95 locus (p674/AccI/MboI), a result that is consistent with all other published studies. These results are confirmed by the fact that the HD gene maps to this region.