A new syndrome of microtia with unilateral renal agenesis and short stature.

We report on a 13-month-old girl of first cousin parents who presented with a combination of short stature, bilateral microtia, proportionate short stature, distinctive facial features (bitemporal narrowing, long philtrum), and agenesis of the left kidney and a small right kidney. Clinical findings did not match any previously described syndromes with the anomalies seen in the patient. We performed SNP array analysis to characterize the observation as a novel syndrome and this was normal. We propose that this represents a new syndrome, likely of autosomal recessive inheritance.

A translocation in acute lymphoblastic leukemia that cytogenetically mimics the recurrent MLL-AFF1 translocation and fuses SEPT11 to MLL.

A 55-year-old man sought care for aggressive acute lymphoblastic leukemia (ALL), which developed 8 years after he had received chemotherapeutic treatment for nephrotic syndrome. The sole cytogenetic abnormality observed in bone marrow-derived metaphases was a t(4;11)(q21;q23), which is a frequently occurring translocation in ALL. However, subsequent reverse transcriptase-polymerase chain reaction for the expected mixed lineage leukemia [trithorax homolog, Drosophila] (MLL)-AFF1 fusion transcript was negative. Further fluorescence in situ hybridization (FISH) analysis narrowed the 4q21 breakpoint down to a 250-kb region proximal of AFF1. This comprised four genes, of which septin11 (SEPT11) was further analyzed. Reverse transcriptase-polymerase chain reaction revealed expression of a chimeric MLL-SEPT11 transcript, thus identifying what is to our knowledge a hitherto undescribed translocation in ALL. Sequence analysis of cDNA showed in-frame fusion of MLL exon 11 to SEPT11 exon 2. This MLL-SEPT11 fusion is cytogenetically indistinguishable from the recurrent t(4;11)(q21;q23). Thus, it is crucial to characterize cytogenetic aberrations in leukemia by molecular methods, even in cases where a known recurrent translocation is presumed. This report expands the spectrum of ALL-related translocations and hypothesizes on the mechanism leading to the MLL-SEPT11 fusion. Five septins have been identified thus far as MLL fusion partners in leukemia. Their putative oncogenic role may be related to forced MLL dimerization by the septin coiled coil and GTP-binding domains, which could convert MLL to an oncogene.

Spectral karyotypic and comparative genomic analysis of the endocrine pancreatic tumor cell line BON-1.

BON-1 is a human serotonin-producing endocrine pancreatic tumor (EPT) cell line, which has been used for various studies of tumorigenesis and treatment. Because its genotype, phenotype and degree of differentiation may underlie events that are instrumental to the development of endocrine tumors and, moreover, may vary between labs and over time, we decided to comprehensively characterize the chromosomal constitution of BON-1 by applying conventional GTG-banding, spectral karyotyping (SKY), comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). BON-1 cells proved to be hyperdiploid containing a modal chromosome number of 57 (range 56-64). SKY identified a stemline containing 6 clonal aberrations including del(1p), t(9;12)del(9p)x2, der(10)t(5;10), der(19)t(8;19), der(14)t(9;14)t(9;10), and a sideline harboring an additional del(12q). CGH and FISH confirmed the SKY results and, in addition, highlighted the chromosomal regions involved in the rearrangements. Moreover, they identified a homozygous deletion of the key tumor suppressor genes CDKN2A and CDKN2B at 9p21.3, in accordance with absence of p16(INK4A) and p14(ARF) expression as revealed by immunocytochemistry. Apart from deregulation of the cell cycle and p53 pathway this finding indicates escape from replicative senescence (induced by mutated NRAS) and detachment-induced apoptosis as molecular mechanisms underlying the tumorigenesis of BON-1 cells. Immunostaining results for p53, MDM2 and pRb expression were consistent with previously published data using Western analysis. In conclusion, we provide here a comprehensive cytogenetic profile of BON-1. This cell line harbors both numerical and structural genomic alterations indicative for malignant EPTs.

Identical cryptic partial monosomy 20pter and trisomy 20qter in three adult siblings due to a large maternal pericentric inversion: detection by MLPA and breakpoint mapping by SNP array analysis.

Genotypic and phenotypic data are presented on three adult siblings with mild to moderate mental retardation and mild dysmorphic features. All three siblings showed a chromosome 20 gain at the q-telomere and loss at the p-telomere in routine subtelomeric MLPA screening. Analysis of GTG-banded chromosomes did not detect any abnormalities, but subtelomeric fluorescent in situ hybridization (FISH) confirmed cryptic partial monosomy of chromosome region 20p13 --> 20pter and cryptic partial trisomy of chromosome region 20q13.33 --> 20qter. Furthermore, FISH analysis in the mother showed a cryptic inv(20)(p13q13.33). This explained the cytogenetic mechanism underlying the chromosomal imbalance in the three children, that is, the meiotic formation of a recombinant chromosome 20 due to crossing-over in the inverted segment. All three children thus carried a rec(20)dup(20q)inv(20)(p13q13.33)mat chromosome. SNP array analysis enabled rapid and detailed imbalance sizing and showed a 1.06 Mb loss in 20p13 and a 2.51 Mb gain in 20q13.33, comprising 21 and 78 genes, respectively. The maternal inversion is the largest described thus far for chromosome 20, comprising 94.4% of its length. Such large inversions result in a particularly high risk for live-born unbalanced offspring because the partial monosomy and trisomy segments are small. Moreover, the inversion size is directly related to the percentage of unbalanced gametes due to high crossing-over change within the inverted segment. The fact that all three children carry an identical chromosomal rearrangement has consequences for genetic counseling for carriers of large pericentric inversions, as the recurrence risk is very high.