Iris Bartels

The determination of the fetal D status from maternal plasma for decision making on Rh prophylaxis is feasible

BACKGROUND: Noninvasive fetal RHD genotyping might become a valuable tool in decision making on antenatal Rh prophylaxis, which is currently in routine practice for all D− pregnancies in several countries. This study provides a large‐scale validation study of this technology to address questions concerning feasibility and applicability of its introduction into clinical routine.

Maternal levels of pregnancy-specific β1 (SP-1) are elevated in pregnancies affected by Down's syndrome

SummaryConcentrations of pregnancy-specific β1-glycoprotein (SP-1) were measured in maternal blood and amniotic fluid of patients with a trisomic fetus and compared with that of a cytogenetically normal fetus at weeks 16–19 of pregnancy. The SP-1 concentrations were significantly elevated in the sera of women with a Downs syndrome fetus, whereas amniotic fluid levels were only slightly increased. It is suggested that high levels of maternal SP-1 in the second trimester of pregnancy may be a valuable indicator in the prenatal detection of fetal trisomy 21.

Array CGH in patients with developmental delay or intellectual disability: are there phenotypic clues to pathogenic copy number variants?

Shoukier M, Klein N, Auber B, Wickert J, Schröder J, Zoll B, Burfeind P, Bartels I, Alsat EA, Lingen M, Grzmil P, Schulze S, Keyser J, Weise D, Borchers M, Hobbiebrunken E, Röbl M, Gärtner J, Brockmann K, Zirn B. Array CGH in patients with developmental delay or intellectual disability: are there phenotypic clues to pathogenic copy number variants?

First confirmed case with paternal uniparental disomy of chromosome 16.

The existence of paternal uniparental disomy of chromosome 16 [upd(16)pat] has previously been suspected but has not been proven. We report prenatal detection and follow-up of isodisomic upd(16)pat in a child with minimal defects but otherwise normal development. Our results indicate that isodisomic upd(16)pat is associated with a normal outcome if no recessive mutation is reduced to homozygosity.

Cell-free fetal DNA in specimen from pregnant women is stable up to 5 days.

Before noninvasive prenatal diagnosis on the fetal Rhesus D status (NIPD RhD) can be implemented on a mass‐scale, it is crucial to define requirements regarding sample transport. The aim of this study was to determine the relation between the transport time of samples for NIPD and the concentration of fetal DNA in maternal plasma.

Supernumerary small marker chromosome (SMC) and uniparental disomy 22 in a child with confined placental mosaicism of trisomy 22: trisomy rescue due to marker chromosome formation.

Trisomy rescue is one of various proposed mechanisms in formation of supernumerary small marker chromosomes (SMC) and uniparental disomy (UPD). In the present report a small de novo marker chromosome derived from chromosome 14 or 22 was diagnosed at prenatal diagnosis due to maternal age. Follow up investigations at birth revealed mosaicism 47,XX,+mar/46,XX. Using FISH, the marker was positive for the probe D14/22Z1, but negative for the probes midi 54 and D22Z4. Using three informative markers both chromosomes 22 were shown to be inherited from the mother (UPDmat). The results are consistent with nondisjunction at maternal meiosis I. The girl is 18 months old now and phenotypically normal. Cardiac and abdominal malformations were excluded by sonographic examinations. Motor and mental development is according to or ahead of developmental milestones (free walking with 10 months, first words at 12 months). The case confirms that maternal UPD 22 most likely is not associated with clinical abnormalities. According to FISH results, UPD 22, and 47,XX,+22 in the placenta, we conclude that the SMC was derived from alpha satellite sequences of chromosome 22. This case for the first time gives evidence that early postzygotic reduction of a chromosome to a small marker chromosome is a real existing mechanism to rescue a conceptus with trisomy.

An unbalanced translocation resulting in a duplication of Xq28 causes a Rett syndrome‐like phenotype in a female patient

To the Editor : The Xq28 region comprises 180 genes, of which 28 are associated with a phenotype. One of these genes is MECP2, the Rett syndrome (RTT)associated gene (1). Larger submicroscopic duplications of the Xq28 region have been reported as disease causing in over 90 male patients showing a discernible phenotype (2–13). To date, only three females with an Xq28 duplication have been described (14–16), and it is unclear whether there is also a recognisable phenotype in Xq28 duplication females. Here, we describe a patient with a RTT-like phenotype due to an unbalanced translocation 46,XX,der(17)t(X;17)(q28;p13.3). The patient is the third child of healthy parents. The patient was born in the 42nd week with a birth weight of 3030 g (10–25 percentile), a height of 52 cm (75 percentile) and a head circumference (OFC) of 32.5 cm (3–10 percentile). Initially, development was thought to be normal. Due to increasing feeding problems, generalised hypotonia, growth retardation and decreasing voluntary movements, developmental delay was diagnosed at the age of 5 months. At the age of 1 year, marked bilateral ptosis was noted. Stereotypic hand wringing and recurrent episodes of breath holding started at the age of 1 year and 6 months. At the age of 7 years and 6 months, she had her first generalised seizure, and now she has three to five seizures per day. Frequent pneumonias and constipations occurred since early childhood. At 9 years and 10 months, the girl was severely mentally retarded and had a remarkable joint hyperlaxity. Microcephaly, a high forehead, bilateral ptosis, large protruding ears with overfolded helices, a full lower lip, a protruding tongue and an open mouth appearance with drooling (Fig. 1a–c) were noted. Cranial magnetic resonance imaging (MRI) showed generalised brain atrophy with an extensive subcortical and periventricular gliosis. Sequence analysis of the MECP2 gene was performed without the identification of a diseasecausing mutation, but subsequent MLPA quantitative testing revealed a duplication of all MECP2 exons. Whole genome array CGH analysis showed both a terminal duplication of the Xq28 region (Fig. 1d) and a small terminal deletion of 17p13.3 (Fig. 1e). Conventional karyotyping and FISH revealed an unbalanced translocation 46,XX,der(17)t(X;17)(q28;p13.3). X-chromosome inactivation was random. The parents had normal test results for array CGH, SNP array genotyping, conventional karyotyping and FISH analysis, implicating that the translocation in the patient occurred de novo. In the present case, the deleted region on chromosome 17p13.3 comprises 13 genes or predicted transcripts. No association with a clinical phenotype was described for any of these genes or transcripts. Lugtenberg et al. (10) showed that moderate to severe mental retardation accompanied by neurological symptoms can be caused by an Xq28 duplication in up to 2% of affected males. In a cohort of 329 females with unexplained mental retardation, not a single case with an Xq28 duplication was detected (10). Because most of the Xq28 duplications described so far are located on the X-chromosome itself, females with an Xq28 duplication are usually clinically not or only mildly affected carriers with a highly skewed X-inactivation (7, 17). The duplicated Xq28 region in our patient is functionally active due to its translocation. She shows both RTT symptoms, such as a normal head circumference at birth, a postnatal deceleration of head growth, stereotypic hand movements, epileptic seizures and breathing disturbances, and symptoms frequently associated with the male Xq28 duplication syndrome (major facial and axial hypotonia, recurring chest infections and severe constipation) (7, 16).

Discordant phenotype in monozygotic twins with mosaic trisomy 12p in lymphocytes.

We report on monochorionic diamniotic male twins discordant for the trisomy 12p syndrome. Trisomy 12p mosaicism with a supernumerary der(12)(pter > q12) was detected in approximately 50% of lymphocytes in both children. Fluorescence in situ hybridisation (FISH) revealed a high grade mosaicism of approximately 77% trisomy 12p cells in buccal smear and 85% in hair follicles in the affected twin, while in the normal developing brother an additional 12p chromosome fragment could not be detected in those tissues. Instead, in 3% of buccal smear and hair follicle cells a minute supernumerary marker chromosome comprising central portions of chromosome 12 was observed. Trisomy 12p mosaicism, confined to the lymphocytes of the unaffected twin, may be due to prenatal twin-to-twin transfusion, explaining the conspicuously discordant clinical phenotype. We discuss the possible sequence of events leading to the cytogenetic findings and compare the clinical phenotype presented in the affected twin with other cases of trisomy 12p and tetrasomy 12p (Pallister-Killian syndrome).

Ring chromosome 22 and neurofibromatosis type II: proof of two-hit model for the loss of the NF2 gene in the development of meningioma

Zirn B, Arning L, Bartels I, Shoukier M, Hoffjan S, Neubauer B, Hahn A. Ring chromosome 22 and neurofibromatosis type II: proof of two‐hit model for the loss of the NF2 gene in the development of meningioma.

Chromosome segregation at meiosis I in female T(2;4)1Gö/+ mice: no evidence for a decreased crossover frequency with maternal age.

The influence of age and hormones on chromosome segregation at meiosis I was studied in female mice heterozygous for the T(2;4)1Gö translocation. Females of two age groups (18–22 and 40–56 weeks old) were stimulated for ovulation with different doses of gonadotropins (1.5 IU PMS/1.0 IU HCG or 10 IU PMS/10 IU HCG). Analysis of metaphase II oocytes revealed the highest level of hyperhaploidy (1.8%) and presegregation (4.4%) in the young females receiving the low dose. Presegregation preferentially affected the small 42 marker chromosome. There was no significant interference of the tetravalent with disjunction of the nontranslocated normal bivalents. Moreover, no remarkable difference in the mode of segregation (adjacent I, II or alternate) was observed. Recombination within the interstitial pairing segments of the chromosomes involved in the translocation allowed us to calculate crossover frequencies in ovulated oocytes. For both the large 24 and the small 42 marker chromosomes, this frequency was higher in old than in young T(2;4)1Gö/+ females. Our data do not support the production line hypothesis of Henderson and Edwards (1968) which claims that chiasma frequency in oocytes decreases with maternal age.