High‐density single nucleotide polymorphism screen in a large multiplex neural tube defect family refines linkage to loci at 7p21.1–pter and 2q33.1–q35

Stamm, Demetra S.; Rampersaud, Evadnie; Slifer, Susan H.; Mehltretter, Lorraine; Siegel, Deborah G.; Xie, Jianzhen; Hu-Lince, Diane; Craig, David W.; Stephan, Dietrich A.; George, Timothy M.; Gilbert, John R.; Speer, Marcy C.; Aben, Joanna; Aylsworth, Arthur S.; Powell, Cynthia M.; Mackey, Joanne; Worley, Gordon; Brei, Timothy J.; Buran, Connie; Bodurtha, Joann; Sawin, Kathleen J.; Mack, Philip W.; Meeropol, Elli; Lasarsky, Nicole; McLone, David G.; Ito, Joy; Oakes, W. Jerry; Walker, Marion L.; Iskandar, Bermans

doi:10.1002/bdra.20272

Cited by 13 publications

(16 citation statements)

References 48 publications

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“…Because of the large size of the mapped Exen gene regions, it is premature to focus on particular candidate genes. A recent genome screen for human NTD loci, using 44 multiplex families, has identified regions of interest on chromosomes 7p, 10q, and 2q (Rampersaud et al, 2005; Stamm et al, 2006), none of which has homology with an Exen ‐gene region. The most likely homologous regions for the Exen loci are on human chromosomes 9q, 5p or 5q for Exen1 ; 7q for Exen2 ; 17q for Exen3 ; and 19q for Exen4 .…”

Section: Introductionmentioning

confidence: 99%

Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects

Harris

Juriloff

2006

Birth Defects Research

286

325

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BACKGROUND:The number of mouse mutants and strains with neural tube closure defects (NTDs) now exceeds 190, including 155 involving known genes, 33 with unidentified genes, and eight ''multifactorial'' strains. METHODS: The emerging patterns of mouse NTDs are considered in relation to the unknown genetics of the common human NTDs, anencephaly, and spina bifida aperta. RESULTS: Of the 150 mouse mutants that survive past midgestation, 20% have risk of either exencephaly and spina bifida aperta or both, parallel to the majority of human NTDs, whereas 70% have only exencephaly, 5% have only spina bifida, and 5% have craniorachischisis. The primary defect in most mouse NTDs is failure of neural fold elevation. Most null mutations (>90%) produce syndromes of multiple affected structures with high penetrance in homozygotes, whereas the ''multifactorial'' strains and several null-mutant heterozygotes and mutants with partial gene function (hypomorphs) have low-penetrance nonsyndromic NTDs, like the majority of human NTDs. The normal functions of the mutated genes are diverse, with clusters in pathways of actin function, apoptosis, and chromatin methylation and structure. The female excess observed in human anencephaly is found in all mouse exencephaly mutants for which gender has been studied. Maternal agents, including folate, methionine, inositol, or alternative commercial diets, have specific preventative effects in eight mutants and strains. CONCLUSIONS: If the human homologs of the mouse NTD mutants contribute to risk of common human NTDs, it seems likely to be in multifactorial combinations of hypomorphs and low-penetrance heterozygotes, as exemplified by mouse digenic mutants and the oligogenic SELH/Bc strain.

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Section: Introductionmentioning

confidence: 99%

Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects

Harris

Juriloff

2006

Birth Defects Research

286

325

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“…The Affymetrix version 2 SNP chip provides genotypes for approximately 11,500 SNPs that have an average heterozygosity of 0.37 and average spacing of one SNP every 210 Kb. Microarray handling and data acquisition methods are the same as previously reported (Stamm et al, 2006). All marker information from the genomic screen was databased using the PEDIGENE system (Haynes et al, 1995).…”

Section: Methodsmentioning

confidence: 99%

“…Further genetic analysis of family 8776 alone revealed similar evidence of linkage on chromosome 2, with both linkage regions in 7p21.1–pter and 2q33.1–q35 having nonparametric S pairs LOD* scores ∼3.0, assuming a broad phenotypic definition for NTDs in which all affected individuals with a broad spectrum of NTDs were considered affected (Stamm et al, 2006). The 2q and 7p linkage regions were confirmed by haplotype analysis, and we also determined that the 2q and 7p NTD associated haplotypes segregated in a pattern consistent with autosomal dominant inheritance with reduced penetrance.…”

Section: Introductionmentioning

confidence: 95%

Refinement of 2q and 7p loci in a large multiplex NTD family

Stamm

Siegel

Mehltretter

et al. 2008

Birth Defects Research

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This large NTD family has identified two genomic regions that may harbor NTD susceptibility genes. Ascertainment of another branch of family 8776 and additional fine mapping permitted a 9.1 Mb reduction of the NTD candidate interval on chromosome 7 and 37.3 Mb on chromosome 2 from previously published data. Identification of one or more NTD susceptibility genes in this family could provide insight into genes that may affect other NTD families.

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“…Considering these observations, some mutations on chromosomes which are involved in the pathogenesis of albinism or CAH may be responsible for the development of MMC [54, 55]. For example, mutations in the Macs gene in the mouse lead to exencephaly and other midline NTDs; its human homolog MACS has been localized to chromosome 6 [51], the same chromosome involved in the pathogenesis of CAH.…”

Section: Discussionmentioning

confidence: 99%

“…NTDs are associated with known genetic syndromes, whereas chromosome abnormalities, specifically aneuploidy, are found in 5–17% of cases with NTDs [51]. Recently, whole-genome-wide linkage screening in NTDs revealed regions of interest on chromosomes 2, 7 and 10 [54, 55]. …”

Section: Discussionmentioning

confidence: 99%

Nonneural Congenital Abnormalities Concurring with Myelomeningocele: Report of 17 Cases and Review of Current Theories

et al. 2008

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Objective: Meningomyelocele (MMC) is a common central nervous system birth defect. Various congenital and acquired abnormalities have been reported with MMC, some of which are secondary to the pathophysiology and some are morbidities of the underlying disease. The aim of this study was to discuss current possible theories explaining diverse anomalies/abnormalities seen in a series of 390 patients with MMC. Methods: A retrospective study was performed using the records of 390 patients with MMC at Children’s Hospital Medical Center in Tehran, Iran, from January 2001 to January 2007. A series of 17 cases of MMC with attributed organ anomalies, not explained by a causal effect of the underlying disorder, were compiled. There were 3 cardiac anomalies including ventricular septal defect, pulmonary artery atresia and tetralogy of Fallot, 4 musculoskeletal malformations, consisting of missing rib, polydactylia and complex distal limb anomaly, 4 urological anomalies such as bladder exstrophy, horseshoe kidney and dysplastic kidneys, 2 occipital encephaloceles, 2 congenital adrenal hyperplasia patients with ambiguous genitalia, 1 omphalocele, 1 albinism and 1 Klippel-Feil syndrome. A review of the literature and discussion explaining each of these observations, have been performed and some possible theories have been proposed.Conclusions: Although various organ anomalies with different embryological origin had been observed and reported with MMC, it is difficult to explain their development using one of the current theories of MMC formation. It could be attributed to a possible genetic defect or merely an incidental finding. A teratological insult during the embryogenic phase would be an alternative assumption.

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High‐density single nucleotide polymorphism screen in a large multiplex neural tube defect family refines linkage to loci at 7p21.1–pter and 2q33.1–q35

Cited by 13 publications

References 48 publications

Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects

Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects

Refinement of 2q and 7p loci in a large multiplex NTD family

Nonneural Congenital Abnormalities Concurring with Myelomeningocele: Report of 17 Cases and Review of Current Theories

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