Patient with three euchromatic supernumerary marker chromosomes derived from chromosomes 1, 12, and 18: characterization and evaluation of the aberrations.

The genetic relevance of small supernumerary marker chromosomes (sSMCs) depends on their content of euchromatin. In case of mosaicism, the phenotype of the carrier furthermore is influenced by the distribution of the marker in the body. In the majority of reported cases no correlation of the degree of mosaicism in the tissue(s) analyzed and the phenotype could be detected. In particular, non-acrocentric derived sSMCs show a strong tendency to appear in mosaic state irrespective of the clinical picture. We present a patient with cognitive disability and mild craniofacial dysmorphisms with mosaicism of three different autosomal marker chromosomes. The extra chromosomes were analyzed by a combination of SNP array and a variety of fluorescence in situ hybridization (FISH) probes. All three markers were identified as ring chromosomes containing different amounts of euchromatic material derived from chromosome 1 (1p12 → q21), 12 (12p13.1 → q13.11) and 18 (18p11.21 → q11.2). The size and the frequency of the sSMCs were strikingly different, besides, we observed an unequal combination of the three derivates.

Duplication 3q13.11q23: Longitudinal study in a patient over a period of more than 7 years and refinements of the breakpoints.

In 2006, we reported the first case with a pure duplication of proximal 3q. In these rare aberrations, detailed clinical and developmental investigations at different ages are required to provide sufficient phenotypic documentation. Clinical and psychological differences were therefore regularly documented in our case. Supplemental genetic investigations comprised conventional karyotyping, fluorescence in-situ hybridization, single nucleotide polymorphism array analysis, and microsatellite typing. Thus, the exact position and extension of the duplication (3q13.11q23), the size (35.6 Mb), and the paternal origin could be determined. The development of our patient was followed up in detail over a period of 7.5 yr and thus enabled specific characterization of the phenotype of the patient.

Genetic counseling in Robertsonian translocations der(13;14): frequencies of reproductive outcomes and infertility in 101 pedigrees.

Robertsonian translocations 13/14 are the most common chromosome rearrangements in humans. However, most studies aimed at determining risk figures are more than 20 years old. Their results are often contradictory regarding important topics in genetic counseling such as infertility and unfavorable pregnancy outcomes. Here, we present a study on a sample of 101 previously unreported pedigrees of der(13;14)(q10;q10). In order to minimize problems of partial ascertainment, we included families with a wide range of reasons of ascertainment such as birth of a child with congenital anomalies, prenatal diagnosis due to maternal age, fertility problems and recurrent pregnancy loss. No evidence of increased infertility rates of female and male carriers was found. The detected miscarriage frequency of female carriers was higher than previously reported (27.6 +/- 4.0% of all spontaneous pregnancies). This may be explained by an over-correction of earlier studies, which excluded all unkaryotyped miscarriages. In three out of 42 amniocenteses, translocation trisomies 13 were diagnosed (7.1 +/- 4.0% of all amniocenteses). The frequency of stillbirths was 3.3 +/- 1.6% for female carriers and 1.4 +/- 1.4% for male carriers. A low risk for the live birth of translocation trisomy 13 children was confirmed since no live born children with trisomy 13 or Pätau syndrome were detected in the ascertainment-corrected sample.

Rare interstitial deletion 9q31.2 to q33.1 de novo: longitudinal study in a patient over a period of more than 20 years.

The female carrier of a de novo interstitial deletion 9q [karyotype 46,XX,del(9)(q31.2q33.1)] was followed up over a period of more than 20 years. She shows facial dysmorphisms and significant growth retardation. Motor abilities are restricted by muscular hypotonia and malposition of the feet. She has mental retardation. There was no speech development and phases of autism were reported. By analyses with FISH and short tandem repeat markers, the interstitial deletion was confirmed and characterized to span 9q31.2q33.1, comprising at least 7.07 Mb. The aberration is of paternal origin.

An excess of chromosome 1 breakpoints in male infertility.

In a search for potential infertility loci, which might be revealed by clustering of chromosomal breakpoints, we compiled 464 infertile males with a balanced rearrangement from Mendelian Cytogenetics Network database (MCNdb) and compared their karyotypes with those of a Danish nation-wide cohort. We excluded Robertsonian translocations, rearrangements involving sex chromosomes and common variants. We identified 10 autosomal bands, five of which were on chromosome 1, with a large excess of breakpoints in the infertility group. Some of these could potentially harbour a male-specific infertility locus. However, a general excess of breakpoints almost everywhere on chromosome 1 was observed among the infertile males: 26.5 versus 14.5% in the cohort. This excess was observed both for translocation and inversion carriers, especially pericentric inversions, both for published and unpublished cases, and was significantly associated with azoospermia. The largest number of breakpoints was reported in 1q21; FISH mapping of four of these breakpoints revealed that they did not involve the same region at the molecular level. We suggest that chromosome 1 harbours a critical domain whose integrity is essential for male fertility.

Clinical, cytogenetic, and molecular findings in 45,X/47,XX,+18 mosaicism: clinical report and review of the literature.

We report cytogenetic and molecular findings performed in a patient with double mosaic aneuploidy. Chromosome analysis of amniotic fluid cells from a 17-week-old fetus was performed because of advanced maternal age. Two karyotypes were detected: 45,X and 47,XX,+18 (50:50%). The same cell lines were determined in uncultured and cultured amniocytes of a second amniotic fluid sample, in fetal lymphocytes, and in uncultured and cultured cells of achilles tendon by conventional cytogenetics and fluorescence in situ hybridization (FISH). In the different investigated tissues, the percentage of cells with 45,X karyotype ranged from 20-99% and the percentage of cells with 47,XX,+18 ranged from 1-80%. The pregnancy was terminated at 22 + 0 weeks because of a severe cardiac malformation. Pathologic examination showed a fetus with aspects typical for manifestation of trisomy 18 and monosomy X, especially in the internal organs. The parent and cell stage of origin was determined by short tandem repeat typing and revealed a maternal meiotic division error that led to trisomy 18, as well as a somatic loss of a paternal sex chromosome. Only two other patients with the same mosaicism have been reported so far. Genetic counseling and prognosis remains challenging.