Salah Ebrahim

Transmission of ring chromosome 13 from a mother to daughter with both having a 46,XX, r(13)(p13q34) karyotype.

Ring chromosomes are thought to be the result of breakage in both arms of a chromosome, with fusion of the points of fracture and loss of the distal fragments. Another mechanism of ring formation is believed to be the simple fusion of chromosome ends with preservation of telomeric and subtelomeric sequences. Ring chromosome 13 was first described in 1968 and its incidence estimated at 1 in 58,000 live births. Severe phenotypes associated with large deletions of 13q have been described as “ring chromosome 13 syndrome.” Features of the “ring chromosome 13 syndrome” include mental retardation (often severe), growth retardation, microcephaly, facial dysmorphism, and hand, foot or toe abnormalities. We report on a case of a mother and daughter with r(13) and mild phenotypes. Our patient, IA, had chromosome analysis performed at about 4½ years of age due to some developmental delay. This revealed 46,XX, r(13)(p13q34) karyotype with no loss of any chromosomal band. Her mother, EA, was subsequently found to have the same ring 13. IAs maternal grandmother had a normal karyotype while her maternal grandfather was unavailable for testing. Fluorescence in situ hybridization (FISH) analysis showed loss of a specific subtelomeric 13q region in r(13) in the mother. Clinically, IA had macular hyperpigmentation on the chin and mild delay in speech and fine motor skills. EA, 22 years of age, had mild short stature and borderline mental retardation. To our knowledge, this is the first report of a case of familial transmission of r(13). We compare phenotypes of our cases with those from other reported cases of r(13) and discuss the possible mechanism of formation of this ring chromosome.

Prenatal cytogenetic abnormalities: Correlations of structural rearrangements and ultrasonographically detected fetal anomalies

OBJECTIVE Our purpose was to determine the distribution of karyotypic abnormalities detected at prenatal diagnosis, fetal anomalies, and ability for fluorescent in situ hybridization detection. STUDY DESIGN Our cytogenetic database from January 1988 to April 1994 was categorized according to type and potential detection by current standard fluorescent in situ hybridization probes. Fetal anomalies and cytogenetic aberrations were compared. RESULTS A total of 664 cases of abnormal fetal karyotypes were identified from 12,454 prenatal cytogenetic cases (7529 amniocenteses and 4925 chorionic villus sampling) and were classified as autosomal aneuploidy (331), sex aneuploidy (103), polyploidy (38), marker aneuploidy (19) and structural rearrangements (173). Standard fluorescent in situ hybridization probes would have missed 31% of the abnormal cases: 90 aneuploidy, 14 de novo marker aneuploidy, and 65 de novo structural aberrant cases. The 134 cases of structural chromosomal rearrangements with complete ultrasonographic records were further classified as polymorphism (42), familial (43), or de novo (49). Frequency of fetal anomaly detection by ultrasonography in de novo cases (22/49) was higher than other rearrangements (chi 2 7.4, p = 0.006). CONCLUSION The contribution of unusual aneuploidies (16%) and structural chromosomal rearrangements (26%) in prenatal diagnostic practice is significant. Fetal anomalies were detected by ultrasonography in 45% of the de novo rearrangement cases. Fluorescent in situ hybridization would miss 31% of the abnormal cases.

Differential Effect of Advanced Maternal Age on Prenatal Diagnosis of Trisomies 13, 18 and 21

Nondisjunction associated with advanced maternal age, a well-established factor in the etiology of autosomal trisomy, should equally affect all chromosomes. In this study we evaluate the association of advanced maternal age with the occurrence of potentially viable autosomal trisomies (13, 18 and 21). 275 aneuploid pregnancies were ascertained prenatally and were grouped according to chromosome anomaly diagnosed. Mean maternal age was significantly younger (p = 0.009) in pregnancies affected by trisomy 13 than in pregnancies with trisomy 21. An intermediate mean maternal age was observed in pregnancies affected by trisomy 18. Our study shows a trend of the more severe, but potentially viable, autosomal trisomies to be diagnosed at younger maternal age. This may substantiate the ‘relaxed selection hypothesis’ proposed to explain the association of aneuploid conceptions with advanced maternal age.

A novel PLAG1-RAD51L1 gene fusion resulting from a t(8;14)(q12;q24) in a case of lipoblastoma

Lipoblastomas are rare benign tumors that arise from embryonic adipose tissue and occur predominantly in the pediatric population. Here, we report a case of lipoblastoma in an 8-month-old boy. Surgical excision and subsequent histopathologic examination were consistent with features of lipoblastoma. Chromosome analysis of the tumor revealed a clonal unbalanced t(8;14) translocation. Genomic microarray analysis of the tumor delineated the exact breakpoints at 8q12.1 and 14q24.1, which involved the PLAG1 and RADA51L1 genes, respectively. Furthermore, fluorescence in situ hybridization demonstrated that the translocation fused the PLAG1-RAD51L1 genes. These results suggest that RAD51L1 is an alternative fusion partner gene for the PLAG1 gene in a lipoblastoma with an 8q12 rearrangement.

Rapid Confirmation of Previously Detected Prenatal Mosaicism by Fluorescence In Situ Hybridization in Interphase Uncultured Amniocytes

Fluorescence in situ hybridization (FISH) of chromosome-specific probes to interphase uncultured amniocytes was performed in cases in which follow-up amniocenteses were done for confirmation of previously detected mosaicism. FISH results were informative in all seven cases included in the study, and confirmed by subsequent cytogenetic analysis. FISH analysis provides rapid results for referral physicians and in most cases reassurance for patients within 24 hours of the follow-up aminocentesis. Although FISH studies are not considered accurate in determining a primary diagnosis of mosaicism in uncultured cells, the analysis is accurate and clinically useful when the diagnosis is known and mosaicism involving a specific chromosome needs to be confirmed in follow-up testing.

Prenatal diagnosis of 46,XY/46,XX mosaicism: A case report†

We report on the prenatal diagnosis of a fetus with 46,XY and 46,XX cell lines with a normal male phenotype. Cytogenetic and molecular studies ruled out the possibility of maternal cell contamination and showed that all the X chromosomes present in both fetal cell lines were derived from a single maternal X chromosome. This suggests 46,XY/46,XX mosaicism.

Prenatal evaluation of a de novo X;9 translocation.

A case of X-autosome translocation was diagnosed prenatally [46,X, t(X;9)(p21.3 approximately 22.1;q22]. We describe the use of fluorescence in situ hybridization (FISH) to estimate the integrity of the Duchenne muscular dystrophy (DMD) gene. X-inactivation studies were used as well to assess the probability of phenotypic abnormalities associated with functional partial disomy X and monosomy 9.

Development of patient-derived xenograft models from a spontaneously immortal low-grade meningioma cell line, KCI-MENG1

BackgroundThere is a paucity of effective therapies for recurrent/aggressive meningiomas. Establishment of improved in vitro and in vivo meningioma models will facilitate development and testing of novel therapeutic approaches.MethodsA primary meningioma cell line was generated from a patient with an olfactory groove meningioma. The cell line was extensively characterized by performing analysis of growth kinetics, immunocytochemistry, telomerase activity, karyotype, and comparative genomic hybridization. Xenograft models using immunocompromised SCID mice were also developed.ResultsHistopathology of the patient tumor was consistent with a WHO grade I typical meningioma composed of meningothelial cells, whorls, and occasional psammoma bodies. The original tumor and the early passage primary cells shared the standard immunohistochemical profile consistent with low-grade, good prognosis meningioma. Low passage KCI-MENG1 cells were composed of two cell types with spindle and round morphologies, showed linear growth curve, had very low telomerase activity, and were composed of two distinct unrelated clones on cytogenetic analysis. In contrast, high passage cells were homogeneously round, rapidly growing, had high telomerase activity, and were composed of a single clone with a near triploid karyotype containing 64–66 chromosomes with numerous aberrations. Following subcutaneous and orthotopic transplantation of low passage cells into SCID mice, firm tumors positive for vimentin and progesterone receptor (PR) formed, while subcutaneous implant of high passage cells yielded vimentin-positive, PR-negative tumors, concordant with a high-grade meningioma.ConclusionsAlthough derived from a benign meningioma specimen, the newly-established spontaneously immortal KCI-MENG1 meningioma cell line can be utilized to generate xenograft tumor models with either low- or high-grade features, dependent on the cell passage number (likely due to the relative abundance of the round, near-triploid cells). These human meningioma mouse xenograft models will provide biologically relevant platforms from which to investigate differences in low- vs. high-grade meningioma tumor biology and disease progression as well as to develop novel therapies to improve treatment options for poor prognosis or recurrent meningiomas.

Compound heterozygous microdeletion of chromosome 15q13.3 region in a child with hypotonia, impaired vision, and global developmental delay.

Homozygous or compound heterozygous microdeletion of 15q13.3 region is a rare but clinically recognizable syndrome manifested by profound intellectual disability, muscular hypotonia, intractable seizures, and visual impairment. We identified a compound heterozygous 15q13.3 microdeletion in a 23‐month‐old girl with global developmental delay, generalized muscular hypotonia, and visual dysfunction. The larger deletion was approximately 1.28 Mb in size and contained seven genes including the TRPM1 and CHRNA7, while the smaller deletion was estimated to be 410 Kb in size and contained only CHRNA7. Compound heterozygous 15q13.3 microdeletion is extremely rare and to the best of our knowledge only two such patients have been reported in literature thus far. The findings in our patient suggest that the pathogenesis of visual dysfunction, which is a consistent finding in homozygous/compound heterozygous 15q13.3 microdeletion depends upon the size of microdeletion. Homozygous loss of TRPM1 likely causes retinal dysfunction while homozygous loss of CHRNA7 alone may lead to visual impairment by cortical mechanisms.

Detection of M-bcr/abl fusion by fluorescence in situ hybridization (FISH) in a case of Ph negative CML

A balanced reciprocal translocation, t(6;9)(p21;q34), was identified in a female patient diagnosed with chronic myeloid leukemia (CML). Both homologs of chromosome 22 were of normal length and morphology. Southern blotting revealed a bcr rearrangement with BglII and HindIII. Two signals for the abl probe were demonstrated by fluorescence in situ hybridization (FISH), one on the normal chromosome 9 and the second on a chromosome 22. Thus, molecular rearrangement of bcr resulted from insertion of an abl gene within the bcr region despite absence of a Ph chromosome.