Gain of 1q and loss of 9q21.3-q32 are associated with a less favorable prognosis in papillary thyroid carcinoma

In order to approach the genetic mechanisms behind initiation and progression of papillary thyroid carcinoma (PTC) tumorigenesis, we characterized numerical chromosomal imbalances in a panel of 25 PTCs with varying histopathological and clinical features using comparative genomic hybridization (CGH). The most frequently detected imbalance was gain of 9q33-qter, which was seen in close to 30% of the cases. The commonly occurring regions of loss were assigned to 22q (12%) and 9q21.3-q32 (12%), while gains preferentially involved the entire X chromosome (20%), 1q (16%), 17q (16%), and 22q (12%). The distribution of CGH alterations supports the idea of a progression of genetic events in the development of PTC, where gain of 9q33-qter would represent a relatively early event that is followed by loss of 22q and gain of X, 1q, 17q, and 22q. When the detected CGH alterations were compared with the clinical outcome and the histopathological features of the 25 PTC cases, several statistically significant correlations were revealed. The total number of genetic alterations was higher in tumors from patients with aggressive disease as compared to those without signs of aggressiveness. Gain of 1q and loss of 9q21.3-q32 were exclusively seen in tumors from patients with aggressive disease, and the presence of distant metastases was associated with gain of 1q. A sex-dependent distribution was also evident for one of the common alterations, with gain of X exclusively seen in male cases. Taken together, the findings identify several candidate locations for tumor suppressor genes and oncogenes that are potentially involved in the establishment and progression of papillary thyroid carcinogenesis.     

Clinical phenotype associated with terminal 2q37 deletion

Three children with deletions of the terminal portion of the long arm of chomosome 2 [del (2) (q37)] are described and their clinical findings compared to published cases of 2q terminal deletions. Common clinical findings include development delay, macrocephaly, frontal bossing, depressed nasal bridge and cardiac anomaly. Hypotonia and repetitive behavior are also seen during different times of development. The facial characteristics of children with 2q terminal deletions are not uniform, but development delay is a constant finding. Chromosomal analysis of such children using high resolution banding may uncover the diagnosis of a small chromosomal deletion.     

Interstitial deletion 5q14.3q21.3 with MEF2C haploinsufficiency and mild phenotype: when more is less

An 18-year-old female with mild mental disability (global IQ 69), febrile seizures with subsequent myoclonic/grand mal epilepsy, and subtle morphologic changes is described with del 5(q14.3q21.3) by karyotype and minimal DNA deletion of 21.08 Mb by array comparative genomic hybridization microarray analysis (arr chr5:83,592,798-104,671,993 X1) that encompasses at least 50 genes. Included in the deletion interval is the MEF2C gene that usually causes severe mental disability when haploinsufficient, illustrating the complexity of clinic-cytogenetic correlation even with defined segmental aneuploidy. Interaction of MEF2C with the deleted febrile seizure (FEB4) and juveline myoclonic epilepsy (EJM4) loci plus the G-protein receptor (GPR98/MASS1/Usher syndrome) gene may moderate the phenotype, perhaps through common regulation by calcium.     

Deletions of 2q14 that include the homeobox engrailed 1 (EN1) transcription factor are compatible with a normal phenotype

A novel transmitted 2-3 Mb deletion of 2q14.1-q14.2 was found in an affected boy from a consanguineous family with a possible diagnosis of PEHO syndrome (OMIM 260565). BAC FISH showed that the deletion included a minimum of 20 genes including the homeobox engrailed 1 gene (EN1). However, the same deletion was also found in his phenotypically normal father and brother (family 1). The phenotype of the proband may, therefore, have been coincidental to the deletion, a result of a recessive condition within or outside the deleted segment or possibly due to variable dosage compensation of EN1 by the paralogous EN2 gene at 7q36. BAC FISH also showed that this deletion overlapped with a previously reported transmitted deletion of 2q13-q14.1 that had no phenotypic consequences (family 2). The deleted regions contained a total of 32 genes and comprise the final 5.25 Mb of the ancestral chromosome 2B from which chromosome 2 was formed in man. These families provide further evidence that heterozygous deletions of regions of low gene density are compatible with a normal phenotype.     

Polycystic kidneys and del (4)(q21.1q21.3): further delineation of a distinct phenotype

A three year-old boy was evaluated because of growth and developmental delay, hypotonia and dysmorphic features. G-banding analysis revealed a small interstitial deletion of the long arm of chromosome four described as 46,XY,del (4)(q21.1q21.3). This patient's findings on physical exam included relative macrocephaly, frontal bossing, short fingers with clinodactyly and were consistent with the phenotypes of previously reported deletions involving the 4q21--> 4q22 band region (Am. J. Med. Genet. 68 (1997) 400-405). To date there are 10 reported live-born cases with such deletions and similar features. The case reported here delimits a minimal critical region for this phenotype to chromosomal region 4q21. Our patient was also found to have cysts in both his kidneys. The gene for type II polycystic kidney disease (PKD2) has been mapped to chromosomal region 4q21--> 4q23. FISH analysis, with a probe including the PKD2 gene, demonstrated hemizygosity at this locus. Thus the absence of one of the PKD2 alleles in the case reported here is associated with early bilateral cyst development. Kidney ultrasound/autopsy studies were reported in seven of the patients with the characteristic phenotype, and were positive for cysts in four cases including the one presented here (Clin. Genet. 31 (1987) 199-205; Am. J. Med. Genet. 68 (1997) 400-405; Am. J. Med. Genet. 40 (1991) 77-790. Our report supports the presence of a distinct phenotype associated with a deleted chromosomal region within 4q21. Hemizygosity for the PKD2 gene is likely in such deletions and may lead to renal cyst formation.     

Chromosome 9p21.3 genotype is associated with vascular dementia and Alzheimer's disease

Vascular risk factors have been implicated in the pathogenesis of vascular dementia and Alzheimer's disease. The identification of a novel vascular disease susceptibility locus at 9p21.3 has recently generated great interest. In the present study, we sought to determine whether a common genetic variant (tagged by rs1333049, G/C) in the 9p21.3 locus—that has been previously linked to an increased vascular risk—might influence the susceptibility to vascular dementia (VaD) and late-onset Alzheimer's disease (LOAD). A cohort of 200 VaD patients, 407 LOAD patients and 405 cognitively healthy controls were genotyped for rs1333049 using a fluorogenic 5′ nuclease assay. The frequency of the C allele of rs1333049 was significantly higher in VaD (62.2%, P = 0.005) and LOAD (60.7%, P = 0.004) patients than in controls (53.6%). After adjustment for the APOE ε4 carrier status and other vascular risk factors, the C allele of rs1333049 remained significantly associated with both VaD (OR 1.31, 95% CI 1.07-1.77, P < 0.01) and LOAD (OR 1.28, 95% CI 1.04-1.55, P < 0.01). Altogether, our data indicate for the first time that the C allele of rs1333049 in the vascular disease susceptibility locus is associated with VaD and LOAD, independent of traditional risk factors and the APOE ε4 genotype.     

TheMspI restriction fragment length polymorphism of human aldolase B gene on chromosome 9q21.3–q22.2

The probe containing the exon 9 of human aldolase B gene revealedMspI polymorphism involving two fragments 6.5 and 3.0 kb long with the high frequency of heterozygosity (21%). The two alleles can be distinguished efficiently by the DNA PCR-restriction fragment length polymorphism procedure.     

Additional case of de novo interstitial deletion del(17)(q21.3q23) and expansion of the phenotype

Khalifa MM, MacLeod PM, Duncan AMV. Additional case of de novo interstitial deletion del(17)(q21.3q23) and expansion of the phenotype. Clin Genet 1993: 44: 258–261. © Munksgaard, 1993
A child with multiple congenital abnormalities and a de novo interstitial deletion of the long arm of chromosome 17 is reported. This is the third case reported with this chromosome abnormality. The three cases present a peculiar phenotype, which is probably specific to the deletion.     

MBL2 gene polymorphisms protect against development of thrombocytopenia associated with severe dengue phenotype

Dengue disease can clinically evolve from an asymptomatic and mild disease, known as dengue fever (DF), to a severe disease known as dengue hemorrhagic fever (DHF). Recent evidence has shown how host genetic factors can be correlated with severe dengue susceptibility or protection. Many of these genes, such as CD209, TNF-a, vitamin D receptor, and FC gamma receptor IIA, are components of the innate immune system, suggesting that innate responses might have a role in dengue pathogenesis. MBL2 gene polymorphisms have been shown to modulate susceptibility or protection in many viral diseases. We investigated the involvement of MBL2 gene in the dengue clinical outcome through the analysis of MBL2 exon 1 polymorphisms (at codons 52, 54, and 57) known to be associated with reduced serum levels of the MBL protein. The genotypes of 110 well-characterized dengue-positive patients were statistically analyzed to establish possible correlations between MBL2 polymorphisms and parameters such as sex, type of infection (primary or secondary response), race/ethnicity, course of infection, and age. We found significant correlations between wild-type AA MBL2 genotype and age as associated risk factors for development of dengue-related thrombocytopenia.     

Acampomelic campomelic dysplasia with de novo 5q;17q reciprocal translocation and severe phenotype.

Campomelic dysplasia (CD) is a rare skeletal malformation syndrome caused by mutations in the SRY related gene SOX9, mapped to 17q24.3-q25.1. A small proportion of cases are associated with structural rearrangements involving 17q and it has been proposed that this subgroup have a milder phenotype and better prognosis compared to those with mutations in the SOX9 gene. We report a severely affected infant with the acampomelic form of campomelic dysplasia, who died at 11 days and was found to have a de novo reciprocal translocation, 46,XX,t(5;17)(q15;q25.1). This is the second reported case of severe campomelic dysplasia associated with a structural rearrangement involving 17q and suggests that this subgroup of patients may not significantly differ from those without chromosomal rearrangements with regards to phenotype or prognosis.     

Deletions of 17p are associated with transition from early to advanced colorectal cancer

Several chromosome defects parallel morphologic evolution in colorectal tumor progression. Allelic losses in the short arm of chromosome 17, the majority encompassing the 17p13.3 band, have been found in advanced cancer in the absence of TP53 mutations, suggesting that loss of genes in this chromosome region is relevant for tumorigenesis. The aim of this study was to investigate 17p13.3 deletions throughout the colorectal tumor progression using two-color fluorescence in situ hybridization. Histologic sections from 20 colorectal adenomas containing early invasive carcinoma were analyzed by interphase fluorescence in situ hybridization using a centromeric probe for chromosome 17 simultaneously with a subtelomeric probe mapping to the 17p13.3 band. Separate evaluation was made for sectors corresponding to adenoma tissue with low-grade dysplasia, high-grade dysplasia, and early cancer. The same technique was also used in 20 cases of advanced adenocarcinoma of the large bowel. Loss of one centromeric signal was observed in 20, 40, 50, and 10% of low-grade dysplasia, high-grade dysplasia, early cancer, and advanced cancer, respectively (P<0.02 early vs. advanced cancer). Subtelomeric 17p deletions were seen in 60% of advanced cancer and in 15% of early cancer (P<0.01). These findings indicate that loss of genes from the 17p13.3 chromosome region may play an important role in sustaining the transition from early to advanced cancer in colorectal tumor progression.