Genetic Factors in Birth Defects

已从大约20个主要畸形中获得DNA，用于当前和未来的调查。此外，还选择了用于拷贝数变异研究的病例，并通过大规模拷贝数变异阵列检测分析了首批样本。 数据清理、编辑和分析的初始阶段已经开始。 与进行全基因组关联研究的财团合作，在病例和对照组中对样本进行了检测。 我们正在几项研究中提供受试者进行确证性基因分型。 我们关于先天性巨结肠和脐膨出的第一批出版物最近已经出版。 先天性巨结肠（HSCR）是由肠神经嵴细胞（ENCC）在胚胎肠道定植失败引起的;定植需要RET原癌基因（RET）信号传导。我们对RET进行测序，以确定基于人群的病例组中的编码和剪接位点变体，并检测HSCR与RET常见变体和候选基因（ASCL 1、同源框B5（HOXB 5）、L1细胞粘附分子（L1 CAM）、配对样同源框2b（PHOX 2B）、PROK 1和PROKR 1）之间的关联，因为它们参与动物模型中的ENCC增殖、迁移和分化。我们对304例HSCR病例和1215例对照进行了巢式病例对照研究。在38例（12.5%）有34个RET编码和剪接位点变异的病例中，有18个变异以前未报告。我们证实了HOXB 5和PHOX 2B中常见变异的相关性，但在多重比较调整后，与ASCL 1，L1 CAM和PROK 1中变异的相关性不显著。RET变异与HSCR密切相关（P值在10（-3）和10（-31）之间），但这因种族/民族而异：在非洲裔美国人中不存在相关性。我们基于人群的研究不仅在HSCR病例中发现了新的RET变异，而且表明常见的RET变异可能不会在所有种族/民族中导致HSCR。HOXB 5和PHOX 2B的发现提供了支持性证据，即调控ENCC增殖、迁移和分化的基因可能是HSCR的风险因素。 据报道，在怀孕期间服用含叶酸的维生素和食用富含叶酸的食物都可以降低脐膨出率。遗传因素在脐膨出的病因学上也很重要，我们的初步研究表明与叶酸代谢酶基因亚甲基四氢叶酸还原酶（MTHFR）有关。我们研究了1998年至2005年期间所有纽约州出生的169例非非整倍体脐膨出病例和761例未受影响的匹配对照，以寻找与已知对叶酸、维生素B12或胆碱代谢重要的单核苷酸多态性（SNP）的关联。在整个研究人群中，转钴胺素受体基因（TCblR）rs 2232775（p.Q8R）和MTHFR基因rs 1801131（c.1298A>C）的变异与脐膨出显著相关。在非裔美国人中，发现维生素B12转运蛋白（TCN 2）和维生素B12受体（TCblR）基因中的SNP具有显著相关性。同型半胱氨酸相关基因，甜菜碱同型半胱氨酸S-甲基转移酶（BHMT），rs3733890（p.R239Q）的SNP与非洲裔美国人和亚洲人的脐膨出显著相关。如果应用Bonferroni校正，则仅总群体中的TCblR关联保持统计学显著性。转钴胺素受体（TCblR）和转运体（TCN 2）SNP和BHMT SNP与脐膨出相关的发现表明，甲基化反应的破坏，其中叶酸，维生素B12和同型半胱氨酸起关键作用，可能是脐膨出的危险因素。如果得到证实，我们的数据表明，同时含有叶酸和维生素B12的补充剂可能有助于预防脐膨出。 其他几项病例对照研究的工作正在进行中，这些研究着眼于与重大出生缺陷相关的候选基因。

DNA has been obtained from approximately 20 major malformations for current and future investigations. In addition, cases have been selected for copy number variant studies and the first samples have been analyzed by large scale copy number variant array testing. The initial phase of data cleaning, editing and analysis is beginning. Samples have been tested in cases and controls in collaboration with consortia performing genome wide association studies. We are providing subjects for confirmatory genotyping in several studies. Our first publications on Hirshcsprung's disease and omphalocele have recently appeared in print. Hirschsprung's disease (HSCR) results from failed colonization of the embryonic gut by enteric neural crest cells (ENCCs); colonization requires RET proto-oncogene (RET) signaling. We sequenced RET to identify coding and splice-site variants in a population-based case group and we tested for associations between HSCR and common variants in RET and candidate genes (ASCL1, homeobox B5 (HOXB5), L1 cell adhesion molecule (L1CAM), paired-like homeobox 2b (PHOX2B), PROK1 and PROKR1) chosen because they are involved in ENCC proliferation, migration and differentiation in animal models. We conducted a nested case-control study of 304 HSCR cases and 1215 controls. Among 38 (12.5%) cases with 34 RET coding and splice-site variants, 18 variants were previously unreported. We confirmed associations with common variants in HOXB5 and PHOX2B but the associations with variants in ASCL1, L1CAM and PROK1 were not significant after multiple comparisons adjustment. RET variants were strongly associated with HSCR (P-values between 10(-3) and 10(-31)) but this differed by race/ethnicity: associations were absent in African-Americans. Our population-based study not only identified novel RET variants in HSCR cases, it showed that common RET variants may not contribute to HSCR in all race/ethnic groups. The findings for HOXB5 and PHOX2B provide supportive evidence that genes regulating ENCC proliferation, migration and differentiation could be risk factors for HSCR. Both taking folic acid-containing vitamins around conception and consuming food fortified with folic acid have been reported to reduce omphalocele rates. Genetic factors are etiologically important in omphalocele as well; our pilot study showed a relationship with the folate metabolic enzyme gene methylenetetrahydrofolate reductase (MTHFR). We studied 169 non-aneuploid omphalocele cases and 761 unaffected, matched controls from all New York State births occurring between 1998 and 2005 to look for associations with single nucleotide polymorphisms (SNPs) known to be important in folate, vitamin B12, or choline metabolism. In the total study population, variants in the transcobalamin receptor gene (TCblR), rs2232775 (p.Q8R), and the MTHFR gene, rs1801131 (c.1298A>C), were significantly associated with omphalocele. In African-Americans, significant associations were found with SNPs in genes for the vitamin B12 transporter (TCN2) and the vitamin B12 receptor (TCblR). A SNP in the homocysteine-related gene, betaine-homocysteine S-methyltransferase (BHMT), rs3733890 (p.R239Q), was significantly associated with omphalocele in both African-Americans and Asians. Only the TCblR association in the total population remained statistically significant if Bonferroni correction was applied. The finding that transcobalamin receptor (TCblR) and transporter (TCN2) SNPs and a BHMT SNP were associated with omphalocele suggests that disruption of methylation reactions, in which folate, vitamin B12, and homocysteine play critical parts, may be a risk factor for omphalocele. Our data, if confirmed, suggest that supplements containing both folic acid and vitamin B12 may be beneficial in preventing omphaloceles. Work is ongoing on several other case control studies looking at candidate genes for association with major birth defects.