PlantPAN 4.0: updated database for identifying conserved non-coding sequences and exploring dynamic transcriptional regulation in plant promoters.

PlantPAN 4.0 (http://PlantPAN.itps.ncku.edu.tw/) is an integrative resource for constructing transcriptional regulatory networks for diverse plant species. In this release, the gene annotation and promoter sequences were expanded to cover 115 species. PlantPAN 4.0 can help users characterize the evolutionary differences and similarities among cis-regulatory elements; furthermore, this system can now help in identification of conserved non-coding sequences among homologous genes. The updated transcription factor binding site repository contains 3428 nonredundant matrices for 18305 transcription factors; this expansion helps in exploration of combinational and nucleotide variants of cis-regulatory elements in conserved non-coding sequences. Additionally, the genomic landscapes of regulatory factors were manually updated, and ChIP-seq data sets derived from a single-cell green alga (Chlamydomonas reinhardtii) were added. Furthermore, the statistical review and graphical analysis components were improved to offer intelligible information through ChIP-seq data analysis. These improvements included easy-to-read experimental condition clusters, searchable gene-centered interfaces for the identification of promoter regions' binding preferences by considering experimental condition clusters and peak visualization for all regulatory factors, and the 20 most significantly enriched gene ontology functions for regulatory factors. Thus, PlantPAN 4.0 can effectively reconstruct gene regulatory networks and help compare genomic cis-regulatory elements across plant species and experiments.

JustRNA: a database of plant long noncoding RNA expression profiles and functional network.

Long noncoding RNAs (lncRNAs) are regulatory RNAs involved in numerous biological processes. Many plant lncRNAs have been identified, but their regulatory mechanisms remain largely unknown. A resource that enables the investigation of lncRNA activity under various conditions is required because the co-expression between lncRNAs and protein-coding genes may reveal the effects of lncRNAs. This study developed JustRNA, an expression profiling resource for plant lncRNAs. The platform currently contains 1 088 565 lncRNA annotations for 80 plant species. In addition, it includes 3692 RNA-seq samples derived from 825 conditions in six model plants. Functional network reconstruction provides insight into the regulatory roles of lncRNAs. Genomic association analysis and microRNA target prediction can be employed to depict potential interactions with nearby genes and microRNAs, respectively. Subsequent co-expression analysis can be employed to strengthen confidence in the interactions among genes. Chromatin immunoprecipitation sequencing data of transcription factors and histone modifications were integrated into the JustRNA platform to identify the transcriptional regulation of lncRNAs in several plant species. The JustRNA platform provides researchers with valuable insight into the regulatory mechanisms of plant lncRNAs. JustRNA is a free platform that can be accessed at http://JustRNA.itps.ncku.edu.tw.

Polypill and Combination Therapy: Blood Pressure and Cardiovascular Risk Reduction.

PURPOSE OF REVIEW: The number of medications prescribed to patients has been progressively increasing, primarily driven by cardioprotective medications. The advent of pharmaceutical 3D printing technology holds the promise of reducing the burden of multiple pills by combining various medications with different release mechanisms into a single tablet. This development encourages a comprehensive review of the evidence supporting the use of combination pills. RECENT FINDINGS: Recent randomized studies have shown higher BP control rates in quadpill groups than in monotherapy groups and improved 6-month BP control rates with a low-dose triple fixed-dose combination (FDC) medication compared to usual care. Recent randomized controlled trials also support FDC use for primary and secondary prevention of cardiovascular disease. Three-dimensional printing technologies such as powder-based (PB) 3D printing, fused deposition modeling (FDM) 3D printing, and semisolid extrusion (EXT) 3D printing are examples of promising technologies that could be utilized to combine multiple medications with different release mechanisms into a single tablet. FDC therapy can provide patients with combination regimens with a reduced pill burden, which promotes improved adherence and efficacy. Recent randomized trials have shown that FDC can be used for primary and secondary prevention of cardiovascular disease with no significant difference in adverse events. Multidisciplinary approaches should be implemented to enhance long-term adherence, and further research on establishing affordable and effective initial dual antihypertensive therapy options is necessary. Pharmaceutical 3D printing technology may play an important role in enhancing the flexibility, affordability, and feasibility of clinical FDC utilization.

Low-level mosaic trisomy 7 at amniocentesis in a pregnancy associated with cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes, perinatal progressive decrease of the trisomy 7 cell line and a favorable fetal outcome.

OBJECTIVE: We present low-level mosaic trisomy at amniocentesis in a pregnancy associated with cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes, perinatal progressive decrease of the trisomy 7 cell line and a favorable fetal outcome. CASE REPORT: A 40-year-old, primigravid woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY in cultured amniocytes. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed the result of arr (7) × 2-3, (X,Y) × 1, consistent with 24% mosaicism for trisomy 7. Polymorphic DNA marker analysis on the DNA extracted from the uncultured amniocytes and parental bloods excluded uniparental disomy (UPD) 7. Prenatal ultrasound findings were normal. She was referred for genetic counseling at 19 weeks of gestation. No repeat amniocentesis was suggested, and continuing the pregnancy was advised. At 22 weeks of gestation, the result of soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) = 6.1 (normal < 38). She did not have preeclampsia. At 39 weeks of gestation, a 3346-g male baby was delivered without any phenotypic abnormality. aCGH analysis on the DNA extracted from cord blood and placenta revealed the result of arr (1-22) × 2, (X,Y) × 1 with no genomic imbalance in all tissues. When follow-up at age three months, the baby was normal in development and phenotype. The peripheral blood had a karyotype of 46,XY, and interphase fluorescence in situ hybridization (FISH) analysis using the bacterial artificial chromosome (BAC) probes of chromosome 7 showed disomy 7 cells in all 102/102 cells. CONCLUSION: Low-level mosaic trisomy 7 at amniocentesis can be associated with cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes, perinatal progressive decrease of the trisomy 7 cell line and a favorable fetal outcome.

Databases and prospects of dynamic gene regulation in eukaryotes: A mini review.

In eukaryotes, dynamic regulation enables DNA polymerases to catalyze a variety of RNA products in spatial and temporal patterns. Dynamic gene expression is regulated by transcription factors (TFs) and epigenetics (DNA methylation and histone modification). The applications of biochemical technology and high-throughput sequencing enhance the understanding of mechanisms of these regulations and affected genomic regions. To provide a searchable platform for retrieving such metadata, numerous databases have been developed based on the integration of genome-wide maps (e.g., ChIP-seq, whole-genome bisulfite sequencing, RNA-seq, ATAC-seq, DNase-seq, and MNase-seq data) and functionally genomic annotation. In this mini review, we summarize the main functions of TF-related databases and outline the prevalent approaches used in inferring epigenetic regulations, their associated genes, and functions. We review the literature on crosstalk between TF and epigenetic regulation and the properties of non-coding RNA regulation, which are challenging topics that promise to pave the way for advances in database development.

The Prevalence and Risk Factors of Hypokalemia in Pregnancy-Related Hospitalizations: A Nationwide Population Study.

BACKGROUND: There are no nationwide population studies conducted to analyze the prevalence and risk factors associated with hypokalemia during pregnancy in the U.S. METHOD: We retrieved data from the Nationwide Inpatient Sample (NIS) and the National Inpatient Sample of Healthcare Cost and Utilization Project (HCUP) for pregnant patients with hypokalemia from 2012 to 2014. We used a chi-squared test to analyze categorical variables and an adjusted Wald test to compare quantitative variables. We applied logistic regression models to calculate adjusted odds ratios (ORs) with 95% confidence intervals (95% CIs) to identify the risk factors for hypokalemia. We used a p value <0.05 as the cutoff for statistical significance. RESULT: Among 12,431,909 pregnancy-related discharges, females of younger age (mean age 27.0 ± 6.2 vs. 28.1 ± 6.0, p < 0.001), of African American race, using government-paid insurance, with an income level in the first quartile, and of a higher Charlson Comorbidity Index score (≥1) were found to have a higher likelihood of hypokalemia during pregnancy (p < 0.001). Gestational hypertension (GH) (including pre-eclampsia and eclampsia, aOR 2.03, 95% CI 1.94-2.12, p < 0.001), hyperemesis gravidarum (aOR 33.18, 95% CI 31.61-34.83, p < 0.001), and post-partum hemorrhage (aOR 1.42, 95% CI 1.31-1.53, p < 0.001) were found to be independently associated with a higher rate of hypokalemia during pregnancy. CONCLUSION: The prevalence of hypokalemia during pregnancy was less than 1% in this large, nationwide population-based study. There were significant differences between those patients who developed hypokalemia during pregnancy. Notably, those who had hypokalemia were younger, of African American race, and of a low-income level. Congestive heart failure, coronary artery disease, Cushing's syndrome, GH, and hyperemesis gravidarum were found to be associated with hypokalemia during pregnancy.

Epidemiology and the Impact of Acute Kidney Injury on Outcomes in Patients with Rhabdomyolysis.

BACKGROUND: Currently, no large, nationwide studies have been conducted to analyze the demographic factors, underlying comorbidities, clinical outcomes, and health care utilization in rhabdomyolysis patients with and without acute kidney injury (AKI). METHODS: We queried the National Inpatient Sample of Healthcare Cost and Utilization Project (HCUP) with patients with rhabdomyolysis from 2016 to 2018. The chi-squared test was used to compare categorical variables, and the adjusted Wald test was employed to compare quantitative variables. The logistic regression model was applied to calculate adjusted odds ratios (ORs) with 95% confidence intervals (95% CIs) to estimate the impact of AKI on outcomes in patients with rhabdomyolysis. RESULTS: Among 111,085 rhabdomyolysis-related hospitalizations, a higher prevalence of AKI was noticed in older patients (mean age ± SD, 58.2 ± 21.6 vs. 53.8 ± 22.2), Medicare insurance (48.5% vs. 43.2%), and patients with a higher Charlson Comorbidity Index score (CCI 3-5, 15.1% vs. 5.5%). AKI was found to be independently associated with higher mortality (adjusted odds ratio [aOR] 3.33, 95% CI 2.33-4.75), longer hospital stays (adjusted difference 1.17 days, 95% CI: 1.00-1.34), and higher cost of hospital stay (adjusted difference $11,315.05, 95% CI: $9493.02-$13,137.07). CONCLUSIONS: AKI in patients hospitalized with rhabdomyolysis is related to adverse clinical outcomes and significant economic and survival burden.

Novel Interleukin-10 Gene Polymorphism Is Linked to Gestational Diabetes in Taiwanese Population.

Objective: The association of interleukin-10 (IL-10) polymorphism with diabetes and its complication was recently established, while there were few researches considering the potential role of IL-10 in gestational diabetes (GDM). This study aimed to investigate the association between IL-10 gene rs1800896 (-1082 A/G), rs1800871 (-819 T/C), rs1800872 (-592 A/C), and rs3021094 (3388 A/C) single nucleotide polymorphisms (SNPs) and GDM susceptibility. Methods: This study included 72 GDM patients and 100 healthy pregnant women. Direct sequencing of the products from polymerase chain reactions of the extracted genomic DNA from study subjects were conducted for analyzing IL-10 gene polymorphism and further genotype frequencies were compared. Plasma IL-10 concentration was measured by ELISA method. Results: The results revealed no significant difference in -592 A/C, -819 T/C, and -1082 A/G genotypes. Significantly increased prevalence of A allele (P = 0.028, OR = 1.69, 95% CI = 1.081-2.64) and A/A genotype (P = 0.031, OR = 2.881, 95% CI = 1.145-7.250) at a previously un-characterized rs3021094 SNP were discovered in the GDM group. Increased IL-10 levels and insulin resistance were also related to the genotype of rs3021094. The risk of GDM was increased when IL-10 level was over 6.5 pg/ml. Conclusion: Our study demonstrated that A allele and A/A genotype of rs3021094 SNP in IL-10 gene were linked to increased risk for GDM, IL-10 plasma level and insulin resistance, which could be potential targets for early screening and detection of GDM.

Prenatal diagnosis of a 3.2-Mb 2p16.1-p15 duplication associated with familial intellectual disability.

OBJECTIVE: We present prenatal diagnosis of a 2p16.1-p15 duplication associated with familial intellectual disability, and we discuss the genotype-phenotype correlation. CASE REPORT: A 22-year-old, primigravid woman underwent amniocentesis at 22 weeks of gestation because of a family history of intellectual disability. The woman and her two sisters had intellectual disability but no behavioral disorders. The intellectual disability was noted in at least one paternal aunt and six paternal cousins of the woman. Cytogenetic analysis revealed the karyotype of 46,XX in the fetus and the two women. Array comparative genomic hybridization (aCGH) analysis on the DNAs extracted from cultured amniocytes and the bloods of the woman and the her sister revealed a 3.244-Mb duplication of 2p16.1-p15 or arr 2p16.1p15 (58,288,588-61,532,538) × 3.0 [GRCh37 (hg19)] encompassing eight Online Mendelian Inheritance in Man (OMIM) genes of VRK2, FANCL, BCL11A, PAPOLG, REL, PUS10, PEX13 and USP34 in the fetus and the two women. Prenatal ultrasound findings were unremarkable. The woman elected to continue the pregnancy. A 3244-g female baby was delivered at term with neither craniofacial dysmorphism nor structural abnormalities. CONCLUSION: aCGH is useful in prenatal diagnosis of inherited subtle chromosome imbalance in pregnancy with familial intellectual disability. Chromosome 2p16.1-p15 duplication can be associated with intellectual disability.

Prenatal diagnosis of a familial 15q11.2 (BP1-BP2) microdeletion encompassing TUBGCP5, CYFIP1, NIPA2 and NIPA1 in a fetus with ventriculomegaly, microcephaly and intrauterine growth restriction on prenatal ultrasound.

OBJECTIVE: We present prenatal diagnosis of a 15q11.2 (BP1-BP2) microdeletion encompassing TUBGCP5, CYFIP1, NIPA2 and NIPA1 in a fetus with ventriculomegaly, microcephaly and intrauterine growth restriction (IUGR) on prenatal ultrasound. CASE REPORT: A 30-year-old, gravida 3, para 2, woman was referred to the hospital for amniocentesis because of fetal ventriculomegaly on prenatal ultrasound. Her husband was 31 years old. The couple had two healthy daughters, and there was no family history of mental disorders and congenital malformations. Amniocentesis revealed a karyotype of 46,XX. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed a 451.89-kb 15q11.2 microdeletion or arr 15q11.2 (22,765,628-23,217,514) × 1.0 [GRCh37 (hg19)] encompassing TUBGCP5, CYFIP1, NIPA2 and NIPA1. The parental karyotypes were normal. aCGH analysis on the DNAs extracted from parental bloods revealed a 402-kb 15q11.2 microdeletion or arr 15q11.2 (22,815,577-23,217,514) × 1.0 (hg19) encompassing TUBGCP5, CYFIP1, NIPA2 and NIPA1 in the phenotypically normal father. The mother did not have any genomic imbalance. Level II ultrasound at 21 weeks of gestation revealed microcephaly and IUGR. The parents elected to terminate the pregnancy at 22 weeks of gestation, and a female fetus was delivered with a body weight of 448 g (10th centile) and a body length of 26 cm (3rd-10th centile) but no gross abnormalities. CONCLUSION: Fetuses with a 15q11.2 (BP1-BP2) microdeletion may present ventriculomegaly, microcephaly and IUGR on prenatal ultrasound, and aCGH is helpful for prenatal diagnosis under such a circumstance.

Prenatal diagnosis of a familial 5p14.3-p14.1 deletion encompassing CDH18, CDH12, PMCHL1, PRDM9 and CDH10 in a fetus with congenital heart disease on prenatal ultrasound.

OBJECTIVE: We present prenatal diagnosis of a familial 5p14.3-p14.1 deletion in a fetus with congenital heart disease on prenatal ultrasound. CASE REPORT: A 33-year-old woman underwent amniocentesis at 18 weeks of gestation because of fetal ventricular septal defect (VSD) and echogenic bowel on prenatal ultrasound. Amniocentesis revealed a karyotype of 46,XX,del (5) (p14p14). Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed a 5.589-Mb 5p14.3-p14.1 deletion or arr 5p14.3p14.1 (19, 497, 649-25,086,268) × 1.0 [GRCh37 (hg19)] encompassing CDH18, CDH12, PMCHL1, PRDM9 and CDH10. Cytogenetic and aCGH analyses of the parents showed that the phenotypically normal mother carried the 5p14.3-p14.1 deletion. The father did not have such a deletion. The parents elected to continue the pregnancy, and a 3426-g female baby was delivered at 38 weeks of gestation with no gross abnormalities. The infant postnatally manifested VSD, atrial septal defect and patent ductus areriosus, and underwent cardiac surgery to treat the congenital heart disease. When follow-up at age 1 year and 4 months, she had a body weight of 8.8 Kg (50th-75th centile), a body height of 75.6 cm (85th-95th centile) and normal psychomotor development. CONCLUSION: Fetuses with a 5p14.3-p14.1 deletion may present congenital heart disease on prenatal ultrasound, and aCGH is helpful for prenatal diagnosis under such a circumstance.

Prenatal diagnosis of a familial 1q21.1-q21.2 microdeletion in a fetus with polydactyly of left foot on prenatal ultrasound.

OBJECTIVE: We present prenatal diagnosis of a familial 1q21.1-q21.2 microdeletion in a fetus with polydactyly of left foot on prenatal ultrasound. CASE REPORT: A 30-year-old, gravida 2, para 1, woman underwent amniocentesis at 22 weeks of gestation because of fetal polydactyly of left foot and echogenic heart foci on prenatal ultrasound. She and her husband and the 2-year-old son were healthy, and there was no family history of mental disorders, skeletal abnormalities and congenital malformations. Amniocentesis revealed a karyotype of 46,XX. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed a 1.317-Mb 1q21.1-q21.2 microdeletion encompassing PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, GJA8 and GPR89B. aCGH analysis of the family members revealed that the phenotypically normal father and elder son carried the same 1q21.1-q21.2 microdeletion. The mother did not have such a deletion. The parents elected to continue the pregnancy, and a 3416-g female baby was delivered at 40 weeks of gestation with neither facial dysmorphism nor gross abnormalities except postaxial polydactyly of the left foot. CONCLUSION: Fetuses with a 1q21.1-q21.2 microdeletion may present polydactyly on prenatal ultrasound, and aCGH is helpful for prenatal diagnosis under such a circumstance.

Prenatal diagnosis of a 0.7-Mb 17p13.3 microdeletion encompassing YWHAE and CRK but not PAFAH1B1 in a fetus without ultrasound abnormalities.

OBJECTIVE: We present prenatal diagnosis and molecular cytogenetic characterization of 17p13.3 microdeletion encompassing YWHAE and CRK but not PAFAH1B1 in a fetus without ultrasound abnormalities. CASE REPORT: A 33-year-old woman underwent amniocentesis at 17 weeks of gestation because of a family history of spinocerebellar atrophy in the husband. Amniocentesis revealed a karyotype of 46,XX. Simultaneously array comparative genomic hybridization (aCGH) analysis (using 60,000 probes) revealed a 0.7-Mb 17p13.3 microdeletion or arr 17p13.3 (1,264,243-1,965,733) × 1 dn [GRCh37 (hg19)] encompassing YWHAE and CRK but not PAFAH1B1. Prenatal ultrasound findings were unremarkable. There were no structural abnormalities of the brain, heart, kidneys, skull, limbs and other internal organs. The parents elected to terminate the pregnancy, and a 268-g fetus was delivered at 19 weeks of gestation with mild facial dysmorphism. Postnatal high-resolution aCGH analysis of the placenta (using 630,000 probes) showed a 0.79-Mb 17p13.3 microdeletion or arr 17p13.3 (1,173,549-1,970,690) × 1 (hg19) encompassing TUSC5, YWHAE, CRK and HIC1 but not PAFAH1B1. Metaphase fluorescence in situ hybridization analysis using the 17p13.3-specific probe of RP11-818O24 revealed a 17p13.3 deletion. CONCLUSION: Fetus with 17p13.3 microdeletion without involving PAFAH1B1 may present no brain abnormalities on fetal ultra sound.

Retrospective cause analysis of troponin I elevation in non-CAD patients: Special emphasis on sepsis.

BACKGROUND: Troponin I is one of the most commonly tested biochemical markers in the emergency room (ER) and in the hospital setting. Besides coronary artery disease (CAD), demand ischemia with underlying tachycardia, anemia, hypertensive emergency, congestive heart failure, kidney disease, sepsis, and pulmonary embolism have also been reported to cause troponin I elevations. Few reports have excluded patients with CAD, and no study has summarized the proportion of these factors relative to an increased troponin I level. METHODS: The aim of this retrospective study was to investigate the level of contribution of causative factors in troponin I elevation. Charts of patients tested for troponin I during an ER visit or during hospitalization were collected. Patients with known CAD, abnormal stress tests, cardiac catheterizations, or discharge without an adequate cardiac evaluation were excluded. Logistic regression was used to identify predictors of elevated troponin I levels. RESULTS: A total of 586 patients were investigated in this study. Age, hemoglobin (Hb), heart rate (HR), glomerularfiltration rate, atrial fibrillation, congestive heart failure (CHF), and sepsis were significant predictors of elevated troponin I by analysis in univariate logistic regression (all P < .001). In multivariate logistic regression, sepsis, CHF, age, Hb, and HR were independent predictors of troponin I (all P < .01). A simple clinical scoring system was generated with 1 score on patients with age ≥ 60, Hb < 10 g/dL, and HR ≥ 100 beats per minute (bpm). The prevalence of elevated troponin I was 4%, 16%, 38%, and 50% for patients with scores of 0, 1, 2, and 3, respectively. In patients without sepsis and CHF, the chances of elevated troponin I were 2%, 11%, 28%, and 43%. CONCLUSIONS: Sepsis was found to be the strongest independent cause of elevated troponin I levels in non-CAD patients. The scoring system composed of age, hemoglobin (Hb), and heart rate (HR) can assist clinical evaluation of elevated troponin I test in non-CAD patients.

Prenatal diagnosis of low-level mosaicism for trisomy 13 at amniocentesis associated with a favorable outcome.

OBJECTIVE: We present prenatal diagnosis of low-level mosaicism for trisomy 13 at amniocentesis associated with a favorable outcome. CASE REPORT: A 35-year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XY,+13[5]/46,XY[20]. Oligonucleotide array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed arr [GRCh37] (13)×3 [0.10], (X,Y)×1 compatible with trisomy 13 mosaicism. Prenatal ultrasound was unremarkable. Repeat amniocentesis was performed at 21 weeks of gestation. Interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes revealed a mosaic trisomy 13 level of 10% (10/100 cells). aCGH analysis on uncultured amniocytes revealed a result of arr 13q12.11q34 (20,407,323-115,092,619)×2.1 with a log2 ratio of 0.06 compatible with a 10% level of mosaicism. Polymorphic DNA marker analysis excluded uniparental disomy 13. The parental karyotypes were normal. Conventional cytogenetic analysis using cultured amniocytes at repeat amniocentesis revealed a karyotype of 46,XY in 23/23 colonies. The pregnancy was carried to 37 weeks of gestation, and a 3600-g phenotypically normal male baby was delivered. When examined at 8 months of age, the infant was doing well and was normal in psychomotor and growth development. The peripheral blood had a karyotype of 46,XY, and interphase FISH analysis on uncultured urinary cells revealed a mosaic trisomy 13 level of 4.4% (2/45 cells). CONCLUSION: Low-level true mosaicism for trisomy 13 at amniocentesis without ultrasound abnormalities can be associated with a favorable fetal outcome.

Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from chromosome 16.

OBJECTIVE: We present prenatal diagnosis and molecular cytogenetic characterization of a small supernumerary marker chromosome (sSMC) derived from chromosome 16. CASE REPORT: A 28-year-old woman underwent amniocentesis at 17 weeks of gestation because of abnormal maternal serum screening for Down syndrome. Amniocentesis revealed a karyotype of 47,XY,+mar[5]/46,XY[9]. Parental karyotypes were normal. Prenatal ultrasound findings were unremarkable. Array comparative genomic hybridization (aCGH) analysis of cultured amniocytes revealed a de novo 16% gene dosage increase of 16q11.2-q22.1. Repeat amniocentesis at 21 weeks of gestation revealed a karyotype of 47,XY,+mar[10]/46,XY[31]. aCGH analysis of uncultured amniocytes revealed a result of arr 16q11.2q22.1 (46,492,626-68,867,969) × 2.20 with a log2 ratio of 0.15 encompassing RPGRIP1L, FTO, SLC6A2, BBS2 and CDH1. Interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes detected partial trisomy 16q in 36/137 (26.3%) of uncultured amniocytes. Polymorphic DNA marker analysis on amniocytes and parental bloods excluded uniparental disomy 16. Premature labor occurred at 25 weeks of gestation, and a 585-g male baby without craniofacial dysmorphism was delivered and survived. At age 1½ years, pediatric follow-ups revealed normal psychomotor development, normal body weight, short stature, congenital hypothyroidism, hearing impairment and hypospadias in the neonate, and the peripheral blood had a karyotype of 46,XY in 40 cultured lymphocytes. CONCLUSION: aCGH, interphase FISH and polymorphic DNA marker analyses of uncultured amniocytes are useful for confirmation of prenatally detected mosaic sSMCs at amniocentesis.

Molecular cytogenetic characterization of a duplication of 15q24.2-q26.2 associated with anencephaly and neural tube defect.

OBJECTIVE: We present molecular cytogenetic characterization of a duplication of 15q24.2-q26.2 associated with anencephaly and neural tube defect (NTD). CASE REPORT: A 35-year-old pregnant woman was found to have a fetus with anencephaly by prenatal ultrasound at 12 weeks of gestation. The pregnancy was subsequently terminated, and a malformed fetus was delivered with anencephaly. Cytogenetic analysis of the cultured placental tissues revealed a karyotype of 46,XX,dup(15) (q24.2q26.2). Parental karyotypes were normal. Array comparative genomic hybridization analysis of the placental tissues revealed a 20.36-Mb duplication of 15q24.2-q26.2 encompassing 100 Online Mendelian Inheritance of in Man (OMIM) genes including LINGO1, MTHFS, KIF7 and CHD2. Metaphase fluorescence in situ hybridization analysis using 15q25.1-specidic probe confirmed a duplication of 15q25.1. Polymorphic DNA marker analysis showed a maternal origin of the duplication. CONCLUSION: A duplication of chromosome 15q24.2-q26.2 can be associated with NTD.

Prenatal diagnosis and molecular cytogenetic characterization of low-level mosaic trisomy 12 at amniocentesis associated with a favorable pregnancy outcome.

OBJECTIVE: We present prenatal diagnosis of low-level mosaic trisomy 12. CASE REPORT: A 40-year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age, which revealed a karyotype of 47,XX,+12[5]/46,XX[24] consistent with 17.2% (5/29) mosaicism for trisomy 12. Repeat amniocentesis performed at 21 weeks of gestation revealed a karyotype of 47,XX,+12[4]/46,XX[6] consistent with 40% (4/10) mosaicism for trisomy 12. Interphase fluorescence in situ hybridization (FISH) on 112 uncultured amniocytes detected 23 cells with trisomy 12 consistent with 20.5% (23/112) mosaicism for trisomy 12. Polymorphic DNA marker analysis excluded uniparental disomy 12. Array comparative genomic hybridization (aCGH) on uncultured amniocytes revealed a result of arr 12p13.33q24.33 (230,451-133,773,499) × 2.2, 17p12 (14,191,925-15,442,037) × 1.0 consistent with 10-20% mosaic trisomy 12. The father carried the 17p12 microdeletion. The fetal ultrasound findings were unremarkable. A 3958-g female fetus was delivered at 37 weeks of gestation with no phenotypic abnormality. The cord blood had a karyotype of 46,XX. Postnatal interphase FISH on urinary cells revealed 7.14% (7/98) mosaicism for trisomy 12. CONCLUSION: Low-level mosaic trisomy 12 at amniocentesis can be associated with a favorable pregnancy outcome. Interphase FISH and aCGH on uncultured amniocytes are useful for confirmation of low-level mosaic trisomy 12 at amniocentesis.

Molecular cytogenetic characterization of Jacobsen syndrome (11q23.3-q25 deletion) in a fetus associated with double outlet right ventricle, hypoplastic left heart syndrome and ductus venosus agenesis on prenatal ultrasound.

OBJECTIVE: We present molecular cytogenetic characterization of Jacobsen syndrome (11q23.3-q25 deletion) in a fetus associated with double outlet right ventricle (DORV), hypoplastic left heart syndrome (HLHS), and ductus venosus (DV) agenesis on prenatal ultrasound. CASE REPORT: A 26-year-old woman underwent prenatal ultrasound examination at 22 weeks of gestation, which revealed intrauterine growth restriction, short femurs, DORV, HLHS, DV agenesis, single umbilical artery, and curly fourth toe of the left foot. The parents elected to terminate the pregnancy, and a 500-g female fetus was delivered at 23 weeks of gestation with facial dysmorphism, bilateral camptodactyly, and hammertoes. The parental karyotypes were normal. Cytogenetic analysis of the cord blood and umbilical cord revealed a karyotype of 46,XX,del(11)(q23). Array comparative genomic hybridization analysis of the DNA extracted from the umbilical cord revealed a 14.38-Mb deletion of 11q23.3-q25 encompassing BSX, ETS1, FLI1, and ARHGAP32. Metaphase fluorescence in situ hybridization analysis using the probes RP11-209L12 (11q25) and RP11-25M7 (11q11) showed a distal 11q deletion in the aberrant chromosome 11 in 17/17 cells examined. CONCLUSION: Prenatal diagnosis of DORV, HLHS, DV agenesis associated with intrauterine growth restriction and short limbs should include a differential diagnosis of Jacobsen syndrome.

Prenatal diagnosis of a 1.6-Mb 4p16.3 interstitial microdeletion encompassing FGFRL1 and TACC3 associated with bilateral cleft lip and palate of Wolf-Hirschhorn syndrome facial dysmorphism and short long bones.

OBJECTIVE: We present prenatal diagnosis of a 4p16.3 interstitial microdeletion associated with bilateral cleft lip and palate and short long bones on prenatal ultrasound, and we discuss the genotype-phenotype correlation. MATERIALS AND METHODS: A 32-year-old woman underwent amniocentesis at 22 weeks of gestation because of bilateral cleft lip and palate and short limbs on prenatal ultrasound. Conventional cytogenetic analysis was performed on cultured amniocytes and parental bloods. Oligonucleotide array comparative genomic hybridization (aCGH) was performed on the DNAs extracted from uncultured amniocytes, parental bloods and umbilical cord. Metaphase fluorescence in situ hybridization (FISH) was performed on cultured amniocytes. RESULTS: Amniocentesis revealed a karyotype of 46,XY. The parental karyotypes were normal. aCGH analysis on uncultured amniocytes revealed a 1.66-Mb interstitial microdeletion at 4p16.3 encompassing 23 Online Mendelian Inheritance of in Man (OMIM) genes including FGFRL1 and TACC3. The parents did not have such a deletion. The pregnancy was subsequently terminated, and a malformed fetus was delivered with typical Wolf-Hirschhorn syndrome (WHS) facial appearance and bilateral cleft lip and palate. aCGH analysis of the umbilical cord confirmed the prenatal diagnosis with a result of arr 4p16.3 (72,447-1,742,649) × 1.0 [GRCh37 (hg19)]. Metaphase FISH analysis of cultured amniocytes confirmed a 4p16.3 microdeletion. CONCLUSION: Haploinsufficiency of FGFRL1 and TACC3 at 4p16.3 can be associated with bilateral cleft lip and palate of WHS facial dysmorphism and short long bones. Prenatal diagnosis of facial cleft with short long bones should raise a suspicion of chromosome microdeletion syndromes.