Prenatal detection of terminal 9p24.3 microduplication encompassing DOCK8 gene: A variant of likely benign.

ABSTRACT: Trisomy 9p is one of the most common chromosomal partial trisomies in newborns. However, reports on prenatal 9p microduplications are rare in the clinic. This study aimed to examine the genotype-phenotype correlation and assess the clinical significance of 9p24.3 microduplication encompassing the DOCK8 gene. Eight pregnant women underwent amniocentesis for cytogenetic and genetic testing for various indications for prenatal diagnosis from January 2019 to January 2020. Chromosomal karyotypic analysis was performed on G-band metaphases that were prepared from cultured amniotic fluid cells. Chromosomal microarray analysis was carried out to detect chromosomal copy number variations. We also performed a literature review on clinical data on similar 9p24.3 microduplications to determine the genotype-phenotype correlation. We detected 123-248-kb microduplications in the region of 9p24.3 (chr9: 208454-469022), involving part of or the entire DOCK8 gene. The indications for prenatal diagnosis mainly focused on the risk of maternal serum screening for trisomy 21/18, advanced maternal age, and increased nuchal translucency. No evident structural abnormalities were observed for all fetuses, except for case 5 who presented with increased nuchal translucency in prenatal ultrasound findings. Follow-up of postnatal health was performed and showed no apparent abnormalities for cases 1 to 6 after birth. The parents of case 7 chose to terminate the pregnancy while the parents of case 8 chose to continue the pregnancy. We propose that 9p24.3 microduplications that encompass part of or the entire DOCK8 gene are variants that might be benign. However, further large-scale studies are necessary to evaluate the clinical pathogenicity. For prenatal cases with 9p24.3 microduplication, postnatal health and growth should be followed up and assessed regularly from childhood to adulthood.

Genes, diabetes and cardiovascular risk prediction.

A region of chromosome 9p21 is linked to an increased risk of coronary artery disease in the general population. Variants of the same allele might also affect risk of cardiovascular disease in patients with type 2 diabetes mellitus, according to a new study.

Mitomycin C-induced pairing of heterochromatin reflects initiation of DNA repair and chromatid exchange formation.

Chromatid interchanges induced by the DNA cross-linking agent mitomycin C (MMC) are over-represented in human chromosomes containing large heterochromatic regions. We found that nearly all exchange breakpoints of chromosome 9 are located within the paracentromeric heterochromatin and over 70% of exchanges involving chromosome 9 are between its homologues. We provide evidence that the required pairing of chromosome 9 heterochromatic regions occurs in G(0)/G(1) and S-phase cells as a result of an active cellular process initiated upon MMC treatment. By contrast, no pairing was observed for a euchromatic paracentromeric region of the equal-sized chromosome 8. The MMC-induced pairing of chromosome 9 heterochromatin is observed in a subset of cells; its percentage closely mimics the frequency of homologous interchanges found at metaphase. Moreover, the absence of pairing in cells derived from XPF patients correlates with an altered spectrum of MMC-induced exchanges. Together, the data suggest that the heterochromatin-specific pairing following MMC treatment reflects the initiation of DNA cross-link repair and the formation of exchanges.

Reproductive follow-up of carriers of familial reciprocal balanced translocations involving chromosome 9 and comparison with predicted outcome.

Reproductive follow-up of carriers of familial reciprocal balanced translocations involving chromosome 9 and comparison with predicted outcome: Chromosome 9 is commonly implicated in reciprocal translocations (rcp). Twenty-seven families segregating rcp involving chromosome 9 were selected with the aim of comparing the theoretical risk of Mental Retardation with Congenital Anomalies (MCA/MR) calculated according to Human Cytogenetics Forum with the observed reproductive follow-up. The 27 families include 157 subjects. The reproductive follow-up showed that the majority of mothers underwent full-term pregnancies (88/130), and that there were 37 spontaneous and five voluntary abortions. Eighty-one subjects were karyotyped: 18 had a normal karyotype, 50 carried an rcp, ten had an unbalanced rcp-related karyotype and three an abnormal rcp-unrelated karyotype. Of the 88 live-born individuals, seven had an abnormal rcp-related karyotype with partial chromosome 9 trisomy (four cases) or partial 9p monosomy (three cases), and 48 were rcp carriers, two of whom also presented additional anomalies. The evaluation of reproductive outcomes in the 27 families studied revealed good concordance between the Human Cytogenetics Forum predictions and the observed follow-up in relation to the most probable mode of unbalance at birth, and the higher risk of MCA/MR in rcp carriers with unbalanced live-borns in comparison with those generating healthy progeny

Frequent loss of chromosome 9 in human primary non-small cell lung cancer.

We analyzed the pattern of allelic loss on chromosome 9 in 40 primary human non-small cell lung cancers including 16 squamous cell, 18 adeno-, and 6 large cell carcinomas. Using 24 polymorphic microsatellite markers spanning chromosome 9, we found that 27 of 40 (67.5%) of these neoplasms displayed loss of heterozygosity (LOH) on chromosome 9. Most tumors showed LOH for all informative markers on both chromosomal arms, whereas five tumors demonstrated partial LOH on chromosome 9. In four of these tumors, allelic loss was limited to the 9p arm, whereas in the remaining specimen, LOH extended from 9p21-22 to terminal 9q. These five tumors delineate a minimal area of loss at 9p21-22, which includes a previously defined tumor suppressor gene locus. We have identified a distinct region of loss on chromosome 9p commonly involved in non-small cell lung cancer tumorigenesis.

Two molecular pathways to transitional cell carcinoma of the bladder.

Noninvasive transitional cell carcinomas of the bladder can have two distinct morphologies suggesting they contain different genetic alterations. Papillary transitional cell carcinomas (T(a) tumors) are often multifocal and only occasionally progress, whereas flat tumors (carcinomas in situ, CIS), frequently progress to invasive disease. We examined 216 bladder tumors of various stages and histopathologies for two genetic alterations previously described to be of importance in bladder tumorigenesis. Loss of heterozygosity of chromosome 9 was observed in 24 of 70 (34%) T(a) tumors but was present in only 3 of 24 (12%) CIS and dysplasia lesions (P = 0.04). In contrast, only 1 of 36 (3%) T(a) tumors contained a p53 gene mutation compared to 15 of 23 (65%) CIS and dysplasias (P < 0.001), a frequency comparable to that observed in muscle invasive tumors (25 of 49; 51%). The presence of p53 mutations in CIS and dysplasia could explain their propensities to progress since these mutations are known to destabilize the genome. Analysis of several tumor pairs involving a CIS and an invasive cancer provided evidence that the chromosome 9 alteration may in some cases be involved in the progression of CIS to more invasive tumors, in addition to its role in the initiation of T(a) tumors. However, the CIS and secondary tumor were found to contain different genetic alterations in some patients suggesting divergent progression pathways. Bladder carcinogenesis may therefore proceed through two distinct genetic alteration pathways responsible for generating superficial tumors with differing morphologies and pathologies.

Síndrome de Turner 45,XO asociado con una inversión pericéntrica del cromosoma 13 / Turner's syndrome 45, XO associated with a pericentric inversion of chromosome 13

El propósito del presente trabajo es el de describir a una paciente con manifestaciones clínicas del síndrome de Turner, quien al realizarle los estudios cromosómicos en cultivo de linfocitos de sangre periférica, y con técnicas de bandas G, mostró un complemento cromosómico de 45, XO y además una inversión pericéntrica del cromosoma 13 con sus puntos de ruptura en las bandas pll y ql4. Los padres y el hermano de la propósita presentaron un cariotipo normal. Se discuten los mecanismos probables de origen de ambas anomalías y los pocos casos reportados en la literatura

Homozygous loss of the interferon genes defines the critical region on 9p that is deleted in lung cancers.

Cytogenetic analyses of non-small cell lung cancer have revealed deletions of the short arm of chromosome 9 with breakpoints at 9p11-pter in a significant proportion of tumors. Recent evidence suggests that homozygous loss of the interferon (IFN) and methylthioadenosine phosphorylase (MTAP) genes located on 9p and a tumor suppressor gene closely linked to them is associated with acute lymphoblastic leukemia and with gliomas. We have observed alterations of DNA sequences on 9p which include the IFN genes at a significant frequency in all types of human lung cancers (20 of 56 or 36%). The genetic alterations observed include homozygous or hemizygous deletions of the IFN genes as well as rearrangement of contiguous DNA sequences. In addition to these genomic alterations, 10 of 22 (45%) cell lines examined lacked MTAP enzyme activity. Overall, 24 of 56 (43%) lung cancer cell lines examined had hemizygous or homozygous loss of DNA sequences which include the IFN or MTAP genes. These findings suggest that the putative tumor suppressor gene at this locus contributes to the malignant process in lung cancers, as well as other types of human cancer.

Allelic loss of chromosome 17p distinguishes high grade from low grade transitional cell carcinomas of the bladder.

Forty-three transitional cell carcinomas of the bladder of differing grades and stages were examined for reduction to homozygosity for chromosomes 9q, 11p, and 17p. Allelic loss of chromosome 9q was seen in 24 of 38 informative grades II, III, and IV tumors providing further evidence for a bladder tumor suppressor gene on this chromosome. In contrast to the grade-independent involvement of chromosome 9q, allelic losses of chromosomes 11p and 17p were seen only in grade III and IV tumors. The results with chromosome 17p were particularly striking and showed that 0 of 10 grade II versus 20 of 31 grade III and IV tumors had allelic losses for this chromosome harboring the p53 tumor suppressor gene often mutated in other human cancers. The data suggest that cumulative genetic damage is sustained in transitional cell carcinomas and that one of the underlying molecular mechanisms distinguishing low grade from high grade tumors involves chromosome 17p.