Cytogenetic follow-up of chromosomal mosaicism detected in first-trimester prenatal diagnosis.

OBJECTIVE: To contribute to the risk assessment of true fetal mosaicism after detection of a mosaic chromosomal anomaly in chorionic villus samples (CVS) in order to enable more effective counseling and pregnancy management. METHODS: We retrospectively reviewed 7112 consecutive CVS analyzed on both direct preparations and cultured cells. In 135 out of the 177 cases of mosaicism, we performed cytogenetic follow-up and determined the frequency of confined placental mosaicism (CPM) and true fetal mosaicism according to type and distribution of the cytogenetic abnormality. RESULTS: True fetal mosaicism was detected in 38 out of 135 cases (28.15%), confirming the higher incidence of CPM (71.85%). Confirmation rate of CV mosaicism depends on the combination of placental cell lineages affected, chromosome involved and mosaic versus non-mosaic chromosomal anomaly. The overall probability of fetal involvement significantly rises with involvement of mesenchymal cells: 5.88% abnormal cytotrophoblast, 20.96% abnormal mesenchyme and 58.97% anomalies in both tissues. CONCLUSION: Most of the mosaic findings at CVS are unreliable indicators of the fetal karyotype. Our study contributes to large series with cytogenetic information from the different tissues along the cytotrophoblast-extraembrional mesoderm-fetus axis in order to infer clinical relevance of the findings and to enable more effective genetic counseling.

Evolutionary descent of a human chromosome 6 neocentromere: a jump back to 17 million years ago.

Molecular cytogenetics provides a visual, pictorial record of the tree of life, and in this respect the fusion origin of human chromosome 2 is a well-known paradigmatic example. Here we report on a variant chromosome 6 in which the centromere jumped to 6p22.1. ChIP-chip experiments with antibodies against the centromeric proteins CENP-A and CENP-C exactly defined the neocentromere as lying at chr6:26,407-26,491 kb. We investigated in detail the evolutionary history of chromosome 6 in primates and found that the primate ancestor had a homologous chromosome with the same marker order, but with the centromere located at 6p22.1. Sometime between 17 and 23 million years ago (Mya), in the common ancestor of humans and apes, the centromere of chromosome 6 moved from 6p22.1 to its current location. The neocentromere we discovered, consequently, has jumped back to the ancestral position, where a latent centromere-forming potentiality persisted for at least 17 Myr. Because all living organisms form a tree of life, as first conceived by Darwin, evolutionary perspectives can provide compelling underlying explicative grounds for contemporary genomic phenomena.

Mosaic 22q13 deletions: evidence for concurrent mosaic segmental isodisomy and gene conversion.

Although 22q terminal deletions are well documented, very few patients with mosaicism have been reported. We describe two new cases with mosaic 22q13.2-qter deletion, detected by karyotype analysis, showing the neurological phenotype of 22q13.3 deletion syndrome. Case 1 represents an exceptional case of mosaicism for maternal 22q13.2-qter deletion (45% of cells) and 22q13.2-qter paternal segmental isodisomy (55% of cells). This complex situation was suspected because cytogenetic, FISH and array-CGH analyses showed the presence of an 8.8 Mb mosaic 22q13.2-qter deletion, whereas microsatellite marker analysis was consistent with maternal deletion without any evidence of mosaic deletion. Molecular analysis led to the definition of very close, but not coincident, deletion and uniparental disomy (UPD) break points. Furthermore, we demonstrated that the segmental UPD arose by gene conversion in the same region. In Case 2, mosaicism for a paternal 8.9 Mb 22q13.2-qter deletion (73% of cells) was detected. In both patients, the level of mosaicism was also verified in saliva samples. We propose possible causative mechanisms for both rearrangements. Although the size of the deletions was quite similar, the phenotype was more severe in Case 2 than in Case 1. As maternal UPD 22 has not been generally associated with any defects and as the size of the deletion is very similar in the two cases, phenotype severity is likely to depend entirely on the degree of mosaicism in each individual.

FISH screening for subtelomeric rearrangements in 219 patients with idiopathic mental retardation and normal karyotype.

Subtelomeric rearrangements are a common cause of idiopathic mental retardation (MR) accounting for 6.3-10.2% of moderate to severe cases and less than 1% of mildly retarded patients. We report on a cohort of 219 patients with idiopathic MR and normal 400-550 band karyotype screened for subtelomeric rearrangements by multiprobe Fluorescence in situ hybridization (FISH) in three Italian Genetics Centers. Twelve positive cases (5.5%) were found. Six were de novo deletions (1p, 7p, 9p, 9q, 20p, 22q) and four unbalanced translocations [a der(6)t(6q; 18p) and a der(18)t(8p; 18q) both de novo, a der(12)t(12p; 17q)mat and a der(2)t(2q; 17q) of unknown origin]. The remaining two cases were apparently balanced reciprocal translocations [a t(4p; 18q) and a t(1p; 16p)] of undetermined origin whose role in the pathogenesis of the clinical phenotype is doubtful. Dysmorphic features were present in all unbalanced patients, whilst a family history of MR was present in only four of them. The proposition that subtelomeric rearrangements are a significant cause of idiopathic MR is supported by our survey. Collection of the clinical data of positive patients will help to delineate the phenotype associated with the various subtelomeric abnormalities, to tailor healthcare services to the needs of these patients and their families and to determine the appropriate use of the test.