Mosaic trisomy 16: what are the obstetric and long-term childhood outcomes?

PURPOSE: To evaluate obstetric and neonatal outcomes as well as long-term neurodevelopmental outcomes and quality of life among prenatally detected cases of mosaic trisomy (MT16) and confined placental mosaicism (CPM) for trisomy 16. METHODS: We recruited participants for this cross-sectional study through an international registry of families with children diagnosed with MT16 or CPM. Parents were interviewed about expectations based on prenatal counseling as well as about actual perinatal outcomes, congenital anomalies, medical conditions, and school progress. Health-related quality of life (HRQOL) was assessed via the Pediatric Quality of Life Inventory 4.0 Generic Core Scales. RESULTS: Forty-four families were enrolled, and 68.2% of the children were female. Common complications were gestational hypertension (gHTN) or preeclampsia (38.1%), preterm delivery (PTD; 71.4%), cesarean delivery (CD; 73.8%), birth weight <10th percentile (73.8%), neonatal intensive care unit (NICU) admission (88.1%), and congenital anomalies (59.5%). However, 81.8% of school-aged children were entirely in mainstream classes, and median physical, psychosocial, and total HRQOL scores were high: 90.6 (34.4-100), 86.7 (35-100), and 84.8 (34.8-100), respectively (100 = optimal quality of life). CONCLUSION: Several obstetric and neonatal complications are common with pregnancies affected by MT16 or CPM. However, the majority of children demonstrate normal neurodevelopmental outcomes and high HRQOL.Genet Med advance online publication 06 April 2017.

Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes.

Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.

Genetic linkage and imprinting effects on body mass index in children and young adults.

Body mass index (BMI) is used as a measure of fatness. Here we performed a genome-wide scan for genes related to BMI, while allowing for the possible effects of imprinting. We applied a sib pair linkage analysis to a sample of primarily children and young adults by using the Haseman-Elston method, which we modified to model the separate effects of paternally and maternally derived genetic factors. After stratification of sib pairs according to age, a number of regions showing linkage with BMI were identified. Most linkage and imprinting effects were found in children 5-11 years of age. Strongest evidences for linkage in children were found on chromosome 20 at 20p11.2-pter near the marker D20S851 (LOD(Total)=4.08, P=0.000046) and near the marker D20S482 (LOD(Total) =3.55, P=0.00016), and Chromosome 16 at 16p13 near the marker ATA41E04 (LOD(Total) =3.12, P=0.00025), and those loci did not show significant evidence for imprinting. Six regions showing evidence of imprinting were 3p23-p24 (paternal expression), 4q31.1-q32 (maternal expression), 10p14-q11 (paternal expression), and 12p12-pter (paternal expression) in children, and 4q31-qter (paternal expression) and 8p (paternal expression) in adults.

Chromosomes exhibit preferential positioning in nuclei of quiescent human cells.

The relative spatial positioning of chromosomes 7, 8, 16, X and Y was examined in nuclei of quiescent (noncycling) diploid and triploid human fibroblasts using fluorescence in situ hybridization (FISH) with chromosome-specific DNA probes and digital imaging. In quiescent diploid cells, interhomolog distances and chromosome homolog position maps revealed a nonrandom, preferential topology for chromosomes 7, 8 and 16, whereas chromosome X approximated a more random distribution. Variations in the orientation of nuclei on the culture substratum tended to hinder detection of an ordered chromosome topology at interphase by biasing homolog position maps towards random distributions. Using two chromosome X homologs as reference points in triploid cells (karyotype = 69, XXY), the intranuclear location of chromosome Y was found to be predictable within remarkably narrow spatial limits. Dual-FISH with various combinations of chromosome-specific DNA probes and contrasting fluorochromes was used to identify adjacent chromosomes in mitotic rosettes and test whether they are similarly positioned in interphase nuclei. From among the combinations tested, chromosomes 8 and 11 were found to be closely apposed in most mitotic rosettes and interphase nuclei. Overall, results suggest the existence of an ordered interphase chromosome topology in quiescent human cells in which at least some chromosome homologs exhibit a preferred relative intranuclear location that may correspond to the observed spatial order of chromosomes in rosettes of mitotic cells.

p21WAF-1 reorganizes the nucleus in tumor suppression.

Interphasic nuclear organization has a key function in genome biology. We demonstrate that p21WAF-1, by influencing gene expression and inducing chromosomal repositioning in tumor suppression, plays a major role as a nuclear organizer. Transfection of U937 tumor cells with p21WAF-1 resulted in expression of the HUMSIAH (human seven in absentia homologue), Rb, and Rbr-2 genes and strong suppression of the malignant phenotype. p21(WAF-1) drastically modified the compartmentalization of the nuclear genome. DNase I genome exposure and fluorescence in situ hybridization show, respectively, a displacement of the sensitive sites to the periphery of the nucleus and repositioning of chromosomes 13, 16, 17, and 21. These findings, addressing nuclear architecture modulations, provide potentially significant perspectives for the understanding of tumor suppression.

Healing of broken human chromosomes by the addition of telomeric repeats.

We have characterized and compared a series of naturally occurring chromosomal truncations involving the terminal region of the short arm of human chromosome 16 (16p13.3). All six broken chromosomes appear to have been stabilized by the direct addition of telomeric repeats (TTAGGG)n to nontelomeric DNA. In five of the six chromosomes, sequence analysis shows that the three of four nucleotides preceding the point of telomere addition are complementary to and in phase with the putative RNA template of human telomerase. Otherwise we have found no common structural features around the breakpoint regions. These findings, together with previously reported in vitro data, suggest that chromosome-healing events in man can be mediated by telomerase and that a small region of complementarity to the RNA template of telomerase at the end of a broken chromosome may be sufficient to prime healing in vivo.

Identification of an inversion 16 coexisting with an isochromosome 22q by in situ hybridization in a case of childhood AML M4e.

Rearrangements involving chromosome 16, including inv(16) (p13q22), del(16)(q22), and t(16;16)(p13;q22), are frequent findings in acute myeloblastic leukemia (AML). Each of these rearrangements can occur as the sole karyotypic change or in association with additional chromosomal abnormalities, including in decreasing order of frequency: trisomy 22, trisomy 8, and deletion of the long arm of chromosome 7. We report a pediatric case of de novo AML, M4e subtype, with a unique combination of inv(16) (p13q22) and i(22q) occurring within the same leukemic clone. The inv(16) was detected by fluorescence in situ hybridization (FISH) analysis with two cosmid probes specific for sequences flanking the inv(16) breakpoint on the long arm of chromosome 16. Use of a chromosome-22-specific painting probe unequivocally identified a small metacentric chromosome as an i(22q). This case illustrates a variation in the association of trisomy 22 with inv(16) and suggests that duplication of the long arm of chromosome 22 may contain critical gene(s) involved in the multistep process of evolution of leukemia with 16q22 abnormalities.