Ming-Yi Chung

Prevalence and parental origin in tetralogy of Fallot associated with chromosome 22q11 microdeletion

Objective. Tetralogy of Fallot is a common cardiac anomaly that is associated with chromosome 22q11 microdeletion. In this study we examined the mode of transmission as well as the parental origin of microdeletion in patients with tetralogy of Fallot. Methods. Eighty-four children with sporadic tetralogy of Fallot (40 boys and 44 girls; mean age, 34 months) were analyzed for microdeletion at chromosome 22q11 by genotype analysis, using five microsatellite markers, D22S427, D22S941, D22S944, D22S264 and D22S311, and confirmed by quantitative polymerase chain reaction, using TUPLE1 and D22S264. All parents of these subjects consented to their own participation and their childs participation in the clinical evaluation and molecular study. To provide a molecular characterization of microdeletion, we isolated DNA from the parents and typed their DNA with each of the five polymorphic markers. Results. Sixty-six patients were associated with pulmonary stenosis; and 8 of these cases (12%) had microdeletion. Eighteen patients were associated with pulmonary atresia, and 6 (33%) of these cases had microdeletion. The parental origins of the 14 patients with microdeletion were paternal in 3 cases and maternal in 11 cases. The most common mode of transmission was de novo without parental hemizygosity (93%). Transmission by autosomal dominant heredity was uncommon (7%). Conclusions. Biased parental origin was consistently found in tetralogy of Fallot patients with chromosomal 22q11 microdeletion. Our results indicated a higher prevalence of microdeletion because of inheritance of maternal microdeletion (78%).

Monozygotic Twins with Chromosome 22q11 Microdeletion and Discordant Phenotypes in Cardiovascular Patterning

Abstract. Monozygotic twins with chromosome 22q11 microdeletions offer an ideal situation to observe the association of microdeletion and disrupted cardiovascular patterning. We report monozygotic twins concordant for 22q11.2 microdeletion but discordant for cardiovascular patterning. Both twins showed identical intracardiac defects including tetralogy of Fallot with pulmonary atresia. Nevertheless, their great vessel patternings were variable. These twins show that the mispatterning of the great vessels may not correlate with intracardiac morphogenesis. The discordant development of the great vessels, especially in the pulmonary vascular system, has clinical significance for prognosis. The phenotypic variability of cardiovascular anomalies seen in 22q11 microdeletion cannot be explained on the basis of genotypic difference.

Increased risk of attention-deficit/hyperactivity disorder associated with exposure to organophosphate pesticide in Taiwanese children

Attention‐deficit/hyperactivity disorder (ADHD) is male predominated, and the etiology of this disorder remains unclear. Past studies have assessed the association of low‐level organophosphate pesticide exposure with childhood ADHD cross‐sectionally and prospectively. However, the results have been inconsistent. A first case–control study was performed to investigate the relationship between organophosphate pesticide exposure and ADHD with adjusted covariates. We recruited 97 doctor‐diagnosed ADHD cases and 110 non‐ADHD controls who were 4–15 years of age. Exposure was assessed using urinary levels of dialkylphosphate metabolites, which are biomarkers of OP pesticide exposure. Blood lead levels and polymorphisms of two commonly verified dopaminergic‐related genes (the D4 dopamine receptor gene DRD4 and the dopamine transporter gene DAT1) were also analyzed. The sociodemographics and lifestyles of the children and of the mothers during pregnancy were collected using a questionnaire. The blood lead levels of both groups were similar (1.57 ± 0.73 vs. 1.73 ± 0.77 μg/dL, p = 0.15). Significant urinary concentration differences in one of the six dialkylphosphate metabolites, dimethylphosphate (DMP), were found between ADHD and control subjects (322.92 ± 315.68 vs. 224.37 ± 156.58 nmol/g cr., p < 0.01). A dose–response relationship was found between urinary concentrations of DMP and ADHD in both crude and adjusted analyses (p for trend<0.05). Children with higher urinary DMP concentrations may have a twofold to threefold increased risk of being diagnosed with ADHD. We report a dose–response relationship between child DMP levels and ADHD. Organophosphate pesticide exposure may have deleterious effects on childrens neurodevelopment, particularly the development of ADHD.

Molecular Characterization of Tetralogy of Fallot Within DiGeorge Critical Region of the Chromosome 22

Abstract. The purpose of this study was to determine whether the levels of heterozygosity and microdeletion of specific loci within the DiGeorge critical region (del22q11) are associated with different phenotypes of tetralogy of Fallot (TF). Examinations were conducted on 84 sporadic TF patients and their unaffected parents for del22q11, using the following 9 simple tandem repeat polymorphic microsatellite markers: D22S420, D22S427, D22S941, D22S944, D22S264, D22S311, D22S425, D22S303, D22S257. The microdeletions were confirmed using quantitative PCR with markers TUPLE1, exon 2 of the UFD1L gene, and D22S264; the boundaries of these microdeletions were estimated using genotypic analyses of the unaffected family members. The del22q11 was identified in 14 patients (16.6%). The boundary of the shortest region of deletion overlap (SRO) in these 14 TF patients was identified, proximally using D22S427 and distally using the TUPLE 1 gene. The deletion of exon 2 of the UFD1L gene and TUPLE1 gene was identified in 13 patients (13/14 cases; 93%). The SRO in TF patients with del22q11 was at or close to the ADU breakpoint and centromeric to the UFD1L gene. The level of heterozygosity for the marker D22S944 in TF patients without del22q11 (n= 70) was found to be significantly lower than expected. Overall, this study demonstrated the significantly low level of heterozygosity within DiGeorge critical region in TF patients with or without del22q11. Our results suggest that the genetic factors leading to DiGeorge/velocardiofacial syndrome might also be partly responsible for TF phenotypes.

Absence of mutations in human ubiquitin fusion-degradation protein gene in tetralogy of Fallot

Abstract Congenital defects in human chromosome 22q11 deletion syndromes are associated with the 3rd and 4th pharyngeal pouch during fetal development. In the cardiovascular system, these disorders are usually apparent as conotruncal heart defects and aortic arch anomalies. UFD1L, a gene that is downregulated in dHAND-deficient mice, expressed in the mouse embryo at the branchial arch and mapped to human chromosome 22q11, has recently been strongly suspected to be responsible for the phenotypes expressed in 22q11 deletion syndromes. Its putative causal role in relevant congenital cardiovascular malformations was studied by gene dosage analysis, mutation screening and sequence analyses. Sixty cases of tetralogy of Fallot with no detectable chromosome deletion at 22q11 or 10p13 were examined, including 51 cases of simple tetralogy of Fallot, and 9 cases of tetralogy of Fallot with pulmonary atresia. None of these patients revealed deletion limited to a portion of the UFD1L gene. Although mobility shift was found by heteroduplex analysis in 24 cases at exon 4 and flanking sequences, further sequence analysis demonstrated only two silent nucleotide variations and a single nucleotide polymorphism in intron 4. Our data suggest that, although the UFD1L gene is mapped to 22q11 and is expressed during early murine development at both cardiac and cranial neural crests, it is not responsible for the majority of tetralogy of Fallot cases in humans.

The interactions among organophosphate pesticide exposure, oxidative stress, and genetic polymorphisms of dopamine receptor D4 increase the risk of attention deficit/hyperactivity disorder in children

Objective The aim of this study was to clarify the association between organophosphate pesticides (OPs) and attention‐deficit/hyperactivity disorder (ADHD) related to oxidative stress and genetic polymorphisms. Methods This case‐control study enrolled 93 children with ADHD and 112 control children in north Taiwan. Six dialkyl phosphate (DAP) metabolites of OPs and oxidative stress biomarkers were analyzed. Polymorphisms of the dopamine receptor D4 gene (DRD4) were identified. Results Children with ADHD had significantly higher dimethylphosphate (DMP, 236.69 nmol/g cre. vs. 186.84 nmol/g cre., p value = 0.01) and 4‐hydroxy‐2‐nonenal‐mercapturic acid (HNE‐MA, 28.95 &mgr;g/g cre. vs. 16.55 &mgr;g/g cre., p value<0.01) concentrations than control children. Children who carried DRD4 GA/AA genotypes (rs752306) were less likely than those who carried the DRD4 GG genotype to have ADHD (odds ratio [OR]: 0.45, 95% CI: 0.24–0.84). The estimated value of the AP (attributable proportion due to interaction) was 0.59 (95% CI: 0.13–1.05), indicating that 59% of ADHD cases in DMP‐exposed children with the DRD4 GG genotype were due to the gene‐environment interaction. After adjustment for other covariates, children who carried the DRD4 GG genotype, had been exposed to high DMP levels (more than the median), and had high HNE‐MA levels had a significantly increased risk for developing ADHD (OR = 11.74, 95% CI: 2.12–65.04). Conclusion This study indicated a gene‐environment interaction in the risk of ADHD in children. The association between DMP and ADHD in children might relate to the mechanism of lipid peroxidation. Dose‐response relationships and the combined effects of OPs, oxidative stress, and genetic polymorphism on ADHD should not be neglected. HighlightsChildren with ADHD had high dimethylphosphate (DMP) and lipid peroxidation levels.An additive interaction between DRD4 polymorphism and DMP levels for ADHD existed.The combined effects of DRD4, DMP, and HNE‐MA increased the risk of developing ADHD.

DiGeorge syndrome with microdeletion of chromosome 22q11.2: report of one case.

DiGeorge syndrome (DGS) is a congenital anomaly involving developmental defects of the third and fourth pharyngeal pouches. Thymic aplasia or hypoplasia, parathyroid aplasia or hypoplasia, cardiac malformations, and dysmorphic facies are characteristics features. We present a case which had thymic aplasia, hypocalcemia, facial dysmorphism (hypertelorism, low set ears, cleft of soft palate, fish-like mouth and micrognathia) and congenital heart disease (ventricular septal defect, perimembranous type). The T-cell immunologic functions as a percentage of T-cell and phytohemagglutinin stimulation test were within normal range matched with age. Molecular study showed microdeletion of chromosome 22q11.2 by genotype analysis, but chromosome study of high-resolution cytogenetic analysis by G-banding technique was normal. To our knowledge, about 90% of DiGeorge syndrome patients show chromosome abnormalities, most involving chromosome 22 (monosomy of 22q11.2). In the past, most cases were proven by high-resolution cytogenetic analysis or fluorescence in situ hybridization(FISH). We report a case of DGS in Taiwan with microdeletion of chromosome 22q11.2 detected by genotype analysis.

Associations between urinary total arsenic levels, fetal development, and neonatal birth outcomes: A cohort study in Taiwan

BACKGROUND Arsenic exposure is a global health concern. Several studies have focused on chronic arsenic exposure in adults; however, limited data are available regarding the potential adverse effects of prenatal exposure on fetuses and neonates. OBJECTIVES To assess which time point maternal arsenic exposure may influence the fetus during pregnancy and birth outcomes. METHODS In this study, total arsenic concentrations were analyzed in urine samples collected from 130 women with singleton pregnancies (22-45years old) in Taiwan from March to December of 2010. All fetal biometric measurements in each trimester period and birth outcomes at delivery were obtained. We applied a generalized estimating equation model and multivariate regression models to evaluate the associations between maternal urinary total arsenic (UtAs) exposure during pregnancy, fetal biometric measurements, and neonatal birth outcomes. RESULTS We observed statistically significant correlations between maternal UtAs levels and the fetal biparietal diameter over all three trimesters (β=-1.046mm, p<0.05). Multiple regression analyses showed a negative association between maternal UtAs levels and chest circumference in the first trimester (β=-0.721cm, p<0.05), and second-trimester UtAs exposure was associated with decreases in birth weight (β=-173.26g, p<0.01), head circumference (β=-0.611cm, p<0.05), and chest circumference (β=-0.654cm, p<0.05). Dose-response relationships were also observed for maternal UtAs exposure and birth outcomes. CONCLUSIONS We identified a negative relationship between maternal UtAs levels during pregnancy, fetal development, and neonatal birth outcomes. These findings should be confirmed in future studies with large sample sizes.