22q11.2 deletion mosaicism in patients with conotruncal heart defects

BACKGROUND: Some patients with conotruncal heart defects (CTDs) have a chromosome 22q11.2 deletion, but we do not know whether patients with CTDs who are missing the peripheral blood-cell chromosome 22q11.2 deletion are also missing the 22q11.2 deletion in myocardial cells, and whether patients with the 22q11.2 deletion can show a different 22q11.2 deletion in peripheral blood cells and myocardial cells due to a postzygotic mutation during the embryonic period. METHODS: A total of 32 Chinese pediatric nonsyndromic CTD patients (21 with tetralogy of fallot [TOF], 9 with double outlet right ventricle [DORV], 1 with pulmonary artery atresia with ventricular septal defect [PAA/VSD], and 1 with congenitally corrected transposition of the great arteries [CCTGA]), 12 females and 20 males ranging in age from 5 months to 7 years, were included in our study. We used fluorescence in situ hybridization (FISH) to find the chromosome 22q11.2 deletion in peripheral blood cells and compared genotypes of 15 short tandem repeat (STR) markers within 22q11.2 between peripheral blood cells and myocardial cells to search for genetic mosaicism of the chromosome 22q11.2 deletion. RESULTS: Three patients, 2 with TOF and 1 with DORV, were determined to have the peripheral blood cell chromosome 22q11.2 deletion. There was no STR genotypic difference observed between peripheral blood cells and myocardial cells in patients with or without the chromosome 22q11.2 deletion. CONCLUSIONS: Genetic mosaicism may not play a major role in the etiology of isolated CTDs.     

Epidemiology of nonsyndromic conotruncal heart defects in Texas, 1999-2004

INTRODUCTION: Congenital heart defects (CHDs) are the most common structural birth defects, yet their etiology is poorly understood. As there is heterogeneity within the group of CHDs, epidemiologic studies often focus on subgroups, of conditions, such as conotruncal heart defects (CTDs). However, even within these subgroups there may be etiologic heterogeneity. The aim of the present study was to identify and compare maternal and infant characteristics associated with three CTDs: truncus arteriosus (TA), dextro‐transposition of the great arteries (d‐TGA), and tetralogy of Fallot (TOF). METHODS: Data for cases with nonsyndromic TA (n = 78), d‐TGA (n = 438), and TOF (n = 529) from the Texas Birth Defects Registry, 1999–2004, were used to estimate crude and adjusted prevalence ratios, separately for each condition, using Poisson regression. Polytomous logistic regression was used to determine whether the observed associations were similar across the two largest case groups (d‐TGA and TOF). RESULTS: In Texas, 1999–2004, the prevalence of nonsyndromic TA, d‐TGA, and TOF was 0.35, 1.98, and 2.40 per 10,000 live births, respectively. There was evidence of a significant linear increase in the risk of each condition with advancing maternal age (p < 0.01). Significant associations were observed for TA and maternal residence on the Texas‐Mexico border; d‐TGA and infant sex, maternal race/ethnicity, history of previous live birth, and birth year; and TOF and maternal race/ethnicity and education. Further, the associations with some, but not all, of the study variables were significantly different for d‐TGA and TOF. CONCLUSION: These findings add to our limited understanding of the epidemiology of CTDs. Birth Defects Research (Part A), 2010. © 2010 Wiley‐Liss, Inc.     

Socioeconomic measures,orofacial clefts,and conotruncal heart defects in California

OBJECTIVE : To examine the association of multiple measures of socioeconomic status (SES) with risks of orofacial clefts and conotruncal heart defects. DESIGN : Data were from a recent population‐based case‐control study conducted in California that included 608 patients with orofacial clefts, 277 patients with conotruncal heart defects, and 617 nonmalformed controls. RESULTS : The odds ratio for the worst versus best score on a household‐level SES index was strongest for cleft lip with or without palate, at 1.7 (95% confidence interval, 0.9–3.4); the odds ratios for this comparison were closer to 1 and less precise for the other defect groups. An index based on neighborhood‐level SES was also not associated with increased risk of the studied defects. CONCLUSIONS : This detailed analysis of SES and selected birth defects did not suggest worse SES was associated with increased risk of the studied defects, with the possible exception of cleft lip with or without cleft palate. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Lack of adenosine A3 receptors causes defects in mouse peripheral blood parameters

The role of the adenosine A₃ receptor in hematopoiesis was studied using adenosine A₃ receptor knockout (A₃AR KO) mice. Hematological parameters of peripheral blood and femoral bone marrow of irradiated and untreated A₃AR KO mice and their wild-type (WT) counterparts were investigated. Irradiation of the mice served as a defined hematopoiesis-damaging means enabling us to evaluate contingent differences in the pattern of experimentally induced hematopoietic suppression between the A₃AR KO mice and WT mice. Defects were observed in the counts and/or functional parameters of blood cells in the A₃AR KO mice. These defects include statistically significantly lower values of blood neutrophil and monocyte counts, as well as those of mean erythrocyte volume, mean erythrocyte hemoglobin, blood platelet counts, mean platelet volume, and plateletcrit, and can be considered to bear evidence of the lack of a positive role played by the adenosine A₃ receptor in the hematopoietic system. Statistically significantly increased values of the bone marrow parameters studied in A₃AR KO mice (femoral bone marrow cellularity, granulocyte/macrophage progenitor cells, and erythrocyte progenitor cells) can probably be explained by compensatory mechanisms attempting to offset the disorders in the function of blood elements in these mice. The pattern of the radiation-induced hematopoietic suppression was very similar in A₃AR KO mice and their WT counterparts.     

Lack of heat-shock response in preovulatory mouse oocytes

The response to heat (hs response) of preovulatory mouse oocytes was compared with that of mouse granulosa cells and characterized in regard to in vitro resumption of meiosis, amino acid incorporation into total protein, and qualitative analysis of protein synthesized before and after the shock. Granulosa cells displayed a hs response typical of other mammalian systems. When incubated at 43 degrees C for 20-40 min, these cells maintained a normal level of amino acid incorporation into total protein, responded to stress by new synthesis of 33- and 68-kDa heat-shock proteins (hsps), and enhanced synthesis of 70-kDa heat-shock cognate protein (hsc70) and of 89- and 110-kDa hsps. In contrast to granulosa cells, preovulatory mouse oocytes were very sensitive to hyperthermia. Incubation at 43 degrees C for 20-40 min strongly inhibited oocyte resumption of meiosis and protein synthesis and did not induce a new or enhanced synthesis of hsps. Unstressed preovulatory mouse oocytes constitutively synthesized 70- and 89-kDa polypeptides resembling hsc70 and hsp89 of granulosa cells.     

Chromosome anomalies in mouse oocytes after irradiation.

We investigated the cytogenetic effects of X-rays on unfertilized mouse oocytes. NMRI females received an irradiation with 0,22.2,66.6,200, and 600 R during the preovulatory phase 3 hrs after HCG (human chorionic gonadotrophin). This is a stage during oogenesis in which the oocytes pass from late dictyotene to diakinesis. Chromosome analysis was performed after ovulation at metaphase II. From these experiments we can draw the following conclusions: 1) X-rays induced during the preovulatory phase a high number of chromosome anomalies. Among these, structural anomalies prevail. 7 out of 144 ovulated oocytes in matched controls carried such an abnormality, whereas after irradiation we observed with 22.2, 66.6, 200, and 600 R, 11 out of 72, 34 out of 108, 89 out of 102, and 122 out of 124, respectively. 2) Irradiation seems also to affect the chromosome segregation during the 1. meiotic division, as we observed after 22.2, 66.6, and 200 R a total of 6 oocytes out of 204 with a supernummary chromosome. In controls, however, no hyperploidy was found in 143 ova. This increase, however, was not significant. 3) Chromosome anomalies, e.g. breaks and deletions that go back to a one-break event increased linearly with increasing dose. Exchanges, however, going back to two-break events fittest best to the linear-quadratic dose-response model. 4) The dose of 600 R seems to represents a kind of borderline in this experiment, because nearly all (122 out 124) carried at least one structural chromosome anomaly. It is also this dose after which the highest frequency of reciprocal translocations was observed in a hump-shaped slope in spermatocytes after irradiation of spermatogonia (Preston and Brewen, 1973). With an increasing dosage up to 1200 R the frequency of translocations decrease again. The elimination of cells, crossing this borderline, might be due to genetic or non-genetic effects. 5) The frequency of radiation-induced translocations per oocyte agrees with the frequency of translocations in human lymphocytes (Dolphin and Lloyd, 1974) after in vitro irradiation. 6) Significant, lower frequencies of structural chromosome anomalies were observed irradiating earlier stages of mouse oogenesis. These stages are dictyotene from females at the age of 3, or 6 weeks and prophase I-stages in female embryos on the 17th day of gestation. This result may be due to a lower sensitivity of these stages or to modifying events during the interval between irradiation and preparations.