Is gastroschisis truly a sporadic defect? Familial cases of gastroschisis in Utah, 1997 to 2008

Feldkamp, Marcia L.; Carey, John C.; Pimentel, Richard; Krikov, Sergey; Botto, Lorenzo D.

doi:10.1002/bdra.22844

Cited by 28 publications

(24 citation statements)

References 38 publications

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“…However, with studies of closely related family members, it is difficult to separate out genetic versus a shared environmental role in gastroschisis. Additional evidence of a genetic susceptibility is supported by the 30 high‐risk multiplex‐multigenerational Utah pedigrees which included between two and eight distantly‐related affected individuals with gastroschisis that had statistically significant evidence of clustering (more gastroschisis observed in the pedigree than expected based on the population prevalence) (Feldkamp, Carey, Pimentel, Krikov, & Botto, ). Unique to Utah, multigenerational pedigrees provide a rare opportunity to discover disease risk variants for any condition, including gastroschisis.…”

Section: Introductionmentioning

confidence: 99%

Shared genomic segments in high‐risk multigenerational pedigrees with gastroschisis

Feldkamp

Krikov

Gardner

et al. 2019

Birth Defects Research

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Objectives: Gastroschisis remains an etiologic dilemma. We posit that an underlying genetic susceptibility either separately or coupled with a periconceptional environmental exposure stimulates an inflammatory response resulting in gastroschisis. To investigate the genetic link, we applied shared genomic segment (SGS) analysis, a novel approach to discover chromosomal segments that inherit in high-risk multigenerational pedigrees. Methods: We studied pedigrees containing distantly related children with gastroschisis originating from a common ancestor. We used the Illumina OmniExpress genotyping array with >700,000 SNPs. Samples from 40 affected children in 13 pedigrees (≥3 affected children) were genotyped to generate the high-density SNP data necessary to perform SGS analysis. Assessment of significance in SGS was determined empirically using simulations based on precise pedigree structure and modeling linkage disequilibrium (LD) for SNPs in the general population to properly account for genetic architecture. The LD model was estimated from the 1000 Genome Project using the same set of SNPs. Genome-wide significance thresholds were determined for each pedigree. Results: We identified six pedigrees that contained genome-wide statistically significant SGS regions inherited from a common founder. These regions were different in each pedigree, all contained immune pathway genes. Discussion: The genome-wide significant regions support a genetic susceptibility for gastroschisis. The regions are compelling candidates for regionally focused genome sequencing, enabling the discovery of coding or noncoding (e.g., regulatory) risk variants, the latter of which are unlikely to be found using conventional exomic/genefocused approaches. This technique provides a comprehensive and focused genomic interrogation that will help to advance our understanding of gastroschisis. K E Y W O R D Sgastroschisis, genetics, high-risk multigenerational pedigrees

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Section: Introductionmentioning

confidence: 99%

Shared genomic segments in high‐risk multigenerational pedigrees with gastroschisis

Feldkamp

Krikov

Gardner

et al. 2019

Birth Defects Research

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“…Gastroschisis frequency has been inexplicably increasing around the world for several decades [Castilla et al, ]. Several studies of familial cases of gastroschisis have suggested an underlying genetic susceptibility for gastroschisis [Torfs et al, ; Kohl et al, ; Feldkamp et al, ]. However, given the recent increase in frequency, it is not likely that genetic variants are solely responsible for the occurrence of gastroschisis.…”

Section: Introductionmentioning

confidence: 99%

Gene variants as risk factors for gastroschisis

Padula

Yang

Schultz

et al. 2016

American J of Med Genetics Pt A

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In a population‐based case‐control study in California of 228 infants, we investigated 75 genetic variants in 20 genes and risk of gastroschisis with regard to maternal age, race/ethnicity, vitamin use, and smoking exposure. We hypothesized that genes related to vascular compromise may interact with environmental factors to affect the risk of gastroschisis. Haplotypes were constructed for 75 gene variants using the HaploView program. Risk for gastroschisis associated with each gene variant was calculated for both the homozygotes and the heterozygotes, with the homozygous wildtypes as the referent. Risks were estimated as odds ratios (ORs) with 95% confidence intervals (CIs) by logistic regression. We found 11 gene variants with increased risk and four variants with decreased risk of gastroschisis for heterozygous (ORh) or homozygous variants (ORv) genotypes. These included NOS3 (rs1036145) ORh = 0.4 (95% CI: 0.2–0.7); NOS3 (rs10277237) ORv = 2.7 (95% CI: 1.3–6.0); ADD1 (rs12503220) ORh = 2.9 (95% CI: 1.6–5.4), GNB3 (rs5443) ORh = 0.2 (95% CI: 0.1–0.5), ORv = 0.4 (95% CI: 0.2–0.9); ICAM1 (rs281428) ORv = 6.9 (95% CI: 2.1–22.9), ICAM1 (rs3093030) ORv = 2.6 (95% CI: 1.2–5.6); ICAM4 (rs281438) ORv = 4.9 (95% CI: 1.4–16.6), ICAM5 (rs281417) ORh = 2.1 (95% CI: 1.1–4.1), ORv = 4.8 (95% CI: 1.7–13.6); ICAM5 (rs281440) ORh = 23.7 (95% CI: 5.5–102.5), ORv = 20.6 (95% CI: 3.4–124.3); ICAM5 (rs2075741) ORv = 2.2 (95% CI: 1.1–4.4); NAT1 ORv = 0.3 (95% CI: 0.1–0.9). There were additional associations between several gene variants and gastroschisis among women aged 20–24 and among mothers with and without vitamin use. NOS3, ADD1, ICAM1, ICAM4, and ICAM5 warrant further investigation in additional populations and with the interaction of additional environmental exposures. © 2016 Wiley Periodicals, Inc.

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“…It is interesting that we have not found differences in the frequency of associated anomalies between the fraction of cases to adolescent mothers or with unplanned pregnancies, factors to which one might attribute a relation, at least with our particularly high prevalence of gastroschisis [Robledo‐Aceves et al, ]. The effect of the reported familial factors in gastroschisis [Feldkamp et al, ] seems to be having a negligible contribution for the occurrence of associated anomalies, based on its rarity in our cohort. Finally, this study highlights the importance of investigating the presence of any other secondary or primary anomalies when diagnosis of gastroschisis is made, as well as its proper pathogenic categorization.…”

Section: Discussionmentioning

confidence: 56%

Associated congenital anomalies in infants with isolated gastroschisis: A single‐institutional experience

Corona‐Rivera

Nieto-García

López-Marure

et al. 2015

American J of Med Genetics Pt A

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The aim of our study was to determine the frequency and type of associated congenital anomalies in patients with isolated gastroschisis born at the Dr. Juan I. Menchaca Civil Hospital of Guadalajara (Guadalajara, México), and to explore its possible association with the included outcome variables. One hundred-eight cases with isolated gastroschisis were reviewed from 2009 to 2014. The occurrence of intestinal and extraintestinal associated anomalies (either secondary or primary) was prospectively assessed. The type of gastroschisis, length of hospital stay (LOS), and in-hospital mortality were outcome variables for statistical analysis. Of infants with gastroschisis, 52 (48.1%) had one or more associated anomalies (AA), with increased odds in males (OR = 2.3, 95%CI: 1.1-5.0). AA classified, as secondary and primary were present in 34.3 and 5.6% of patients, respectively. Of secondary AA, 25.9% were intestinal anomalies, and 17.6% were extraintestinal. Primary AA were congenital heart disease (n = 3), meningomyelocele, and hydrocephaly and amniotic band sequence in one instance, respectively. Multivariate logistic regression showed that secondary AA (both intestinal and extraintestinal) were associated with complex gastroschisis, prolonged LOS, and in-hospital death, whereas primary AA were not related to a worse outcome. Our results highlight the pathogenic importance of properly investigating and categorizing the presence of others secondary or primary AA when diagnosis of gastroschisis is made.

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Is gastroschisis truly a sporadic defect? Familial cases of gastroschisis in Utah, 1997 to 2008

Cited by 28 publications

References 38 publications

Shared genomic segments in high‐risk multigenerational pedigrees with gastroschisis

Shared genomic segments in high‐risk multigenerational pedigrees with gastroschisis

Gene variants as risk factors for gastroschisis

Associated congenital anomalies in infants with isolated gastroschisis: A single‐institutional experience

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