Erik Niebuhr

High-Resolution Mapping of Genotype-Phenotype Relationships in Cri du Chat Syndrome Using Array Comparative Genomic Hybridization

We have used array comparative genomic hybridization to map DNA copy-number changes in 94 patients with cri du chat syndrome who had been carefully evaluated for the presence of the characteristic cry, speech delay, facial dysmorphology, and level of mental retardation (MR). Most subjects had simple deletions involving 5p (67 terminal and 12 interstitial). Genotype-phenotype correlations localized the region associated with the cry to 1.5 Mb in distal 5p15.31, between bacterial artificial chromosomes (BACs) containing markers D5S2054 and D5S676; speech delay to 3.2 Mb in 5p15.32-15.33, between BACs containing D5S417 and D5S635; and the region associated with facial dysmorphology to 2.4 Mb in 5p15.2-15.31, between BACs containing D5S208 and D5S2887. These results overlap and refine those reported in previous publications. MR depended approximately on the 5p deletion size and location, but there were many cases in which the retardation was disproportionately severe, given the 5p deletion. All 15 of these cases, approximately two-thirds of the severely retarded patients, were found to have copy-number aberrations in addition to the 5p deletion. Restriction of consideration to patients with only 5p deletions clarified the effect of such deletions and suggested the presence of three regions, MRI-III, with differing effect on retardation. Deletions including MRI, a 1.2-Mb region overlapping the previously defined cri du chat critical region but not including MRII and MRIII, produced a moderate level of retardation. Deletions restricted to MRII, located just proximal to MRI, produced a milder level of retardation, whereas deletions restricted to the still-more proximal MRIII produced no discernible phenotype. However, MR increased as deletions that included MRI extended progressively into MRII and MRIII, and MR became profound when all three regions were deleted.

Mutations in Autism Susceptibility Candidate 2 (AUTS2) in patients with mental retardation

We report on three unrelated mentally disabled patients, each carrying a de novo balanced translocation that truncates the autism susceptibility candidate 2 (AUTS2) gene at 7q11.2. One of our patients shows relatively mild mental retardation; the other two display more profound disorders. One patient is also physically disabled, exhibiting urogenital and limb malformations in addition to severe mental retardation. The function of AUTS2 is presently unknown, but it has been shown to be disrupted in monozygotic twins with autism and mental retardation, both carrying a translocation t(7;20)(q11.2;p11.2) (de la Barra et al. in Rev Chil Pediatr 57:549–554, 1986; Sultana et al. in Genomics 80:129–134, 2002). Given the overlap of this autism/mental retardation (MR) phenotype and the MR-associated disorders in our patients, together with the fact that mapping of the additional autosomal breakpoints involved did not disclose obvious candidate disease genes, we ascertain with this study that AUTS2 mutations are clearly linked to autosomal dominant mental retardation.

Triploidy in man

SummaryThis paper contains a review of possible mechanisms leading to triploidy and of cytogenetical and clinical data on about 230 human triploid abortuses and 30 live-born infants. A brief consecutive comparison is made to other species.ZusammenfassungDiese Arbeit gibt eine Übersicht über mögliche Entstehungsmechanismen der Triploidie und die cytogenetischen und klinischen Daten bei ungefähr 230 triploiden Embryonen und 30 lebendgeborenen Kindern. Ein kurzer fortlaufender Vergleich wird zu anderen Gattungen angestellt.

Down's syndrome

SummaryThis paper contains a brief survey of 12 patients with a G/G translocation en tandem and it is suggested, that trisomy of the band 21q22 might be pathogenetic in Downs syndrome.

An epidemiological study of Hirschsprung's disease and additional anomalies

Russell MB, Russell CA, Niebuhr E. An epidemiological study of Hirschsprungs disease and additional anomalies. Acta Pædiatr 1994;83:68–71. Stockholm. ISSN 0803–5253.

Interstitial deletion in the "critical region" of the long arm of the X chromosome in a mentally retarded boy and his normal mother.

SummaryA family in which an interstitial deletion of the X chromosome, del(X)(q13q21.3), is segregating was ascertained through a boy with cleft lip and palate, agenesis of the corpus callosum, and severe mental retardation. The possible causal relationship to his chromosome abnormality is discussed. Although the deletion occurred within the critical region, the mother showed no signs of gonadal dysgenesis. A phenotypically normal daughter was, as her mother, monosomic for this region of the X, and both showed random inactivation of the X chromosome.

Sister chromatid exchange (SCE) in greenlandic eskimos. dose—response relationship between SCE and seal diet, smoking, and blood cadmium and mercury concentrations

The mutagenicity of the chromosomes of the peripheral lymphocytes of 147 Greenlandic Eskimos living in the district of Angmagssalik, Greenland, and in Denmark, was evaluated by means of the sister chromatid exchange (SCE) test. Thirty cells from each person were examined. The purpose of the investigation was to determine if there was any relationship between mutagenic activity and diet, and hence the elements selenium, cadmium, mercury and lead. The probands were divided into three groups according to their intake of seal meat or industrially prepared food: group 1, those eating seal at least six times per week; group 2, two to five times per week; and group 3 once each week or not at all. The statistical analysis was performed by means of multiple linear regression analyses, with diet, living district, sex, age, tobacco smoking, and blood lead and mercury concentrations as variables. Forty-eight percent of the variation in SCE could be explained by differences in diet, living district, age, and tobacco consumption. Groups 1 and 2 had a 1.7 and 0.65 times higher SCE/cell, respectively, than group 3. For every additional 10 years of age of the probands, the SCE/cell increased by 0.4, and for every 10 g of tobacco smoked per day the SCE/cell was 0.7 higher compared to non-smokers. When priority was given to blood Hg concentration in the calculation, 16.3% of the total variation in SCE/cell could be explained. An increase in the blood Hg concentration of 10 micrograms l-1 corresponded to an increase of 0.3 SCE/cell. In 92 individuals blood Se and Cd concentrations were also analysed. The variables, tobacco smoking, diet, living district and Cd explained 53% of the total variation in SCE. Giving priority to the blood Hg and Cd concentrations, explained 21.4% of the total variation in SCE/cell. An increase of 10 micrograms l-1 in blood Cd and Hg corresponded to an increase in SCE/cell of 0.7 and 0.2, respectively. No influence on the SCE/cell could be attributed to the blood Pb and Se concentrations. Evaluated by the SCE test, seal diet, smoking, living district and blood Hg and Cd concentrations all contribute to mutagenicity in Greenlandic Eskimos, with seal diet as the most important of the factors examined.

Sister-chromatid exchange in childhood in relation to age and sex

Small children have been found to have a lower SCE/cell than adults and in recent reports females have had higher SCEs/cell than males. We here describe the relationship between SCE/cell and age and sex in 46 girls and 39 boys with an age range of 1.4-19.2 years and 2.6-18.7 years, respectively. For the calculation a transformation y = (sum SCE)1/2 + (sum SCE + 1)1/2 was used. The best fit to our material was represented by the equation y = b0 + b1 X log age. A common slope (b1) could be used for the boys and girls. This slope was significantly different from zero (P less than 0.0005). The levels of the regression lines for the two sexes were different (P = 0.0006). The girls had a 0.55-0.7 higher SCE/cell than the boys, depending on age. The following equations were found: Girls: y = 22.49 + 6.53 X log age. Boys: y = 21.11 + 6.53 X log age. By this model 43% of the variation in y could be explained. As a consequence of the result it is absolutely essential, when planning studies of children, to use age-matched groups to decrease the variability of the test system.

Determination of the ‘critical region’ for cat-like cry of Cri-du-chat syndrome and analysis of candidate genes by quantitative PCR

Cri-du-chat (CDC, OMIM 123450) is a chromosomal syndrome that results from partial deletions on the short arm of chromosome 5. The clinical features of CDC normally include high-pitched cat-like cry, mental retardation, microcephaly, hypertelorism and epicanthic folds. The cat-like cry is the most prominent clinical characteristic in newborn children and is usually considered as diagnostic for the CDC syndrome. Using a strategy of ‘phenotype dissection’, the critical region for cat-like cry was mapped to the chromosomal segment 5p15.3–5p15.2 in previous reports. In this study, the distal breakpoints of two interstitial deletions in two clinical distinctive CDC patients are analysed, one with and one without the cat-like cry. Using PCR, the critical region for the cat-like cry is mapped to a short 640 kbp region on chromosome 5p. Genome analysis of this critical region reveals a gene-rich sequence containing five known genes, five putative genes and three spliced EST sequences, altogether 71 predicted exons. Three genes, FLJ25076, a homolog to a ubiquitin-conjugating enzyme UBC-E2, FLJ20303, a nucleolar protein NOP2, which may play a role in the regulation of the cell cycle and MGC5309, a protein with similarity to Nut2, a Drosophila transcriptional coactivator, have been characterized and expression profiles determined by quantitative PCR. These results suggest that one candidate gene, FLJ25076, encodes a ubiquitin-conjugated enzyme E2 type, which is locally expressed in thoracic and scalp tissues. The other two genes are expressed uniformly in all tissues tested, which suggest that they are housekeeping genes.

X long-arm deletions. A review of non-mosaic cases studied with banding techniques

SummaryA woman with secondary amenorrhoea and an X long-arm deletion (pter→q21:) is described and compared with 30 adult non-mosaic, banded cases. Approximately 50% of the patients had gonadal dysgenesis associated with a higher frequency of short stature and “Turner stigmata” than in women with indication of ovarian activity. It is suggested that preservation of bands Xq26→28 may be decisive for normal ovarian function.