Shared genomic segments in high‐risk multigenerational pedigrees with gastroschisis

Abstract

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

Fetal gastroschisis: Maternal and fetal methylation profile

“…46 Given that DNA methylation plays an important and dynamic role in gene expression regulation, development, genetic imprinting, and suppression of repetitive elements in a healthy organism, 27 14,21,49 Recently, an ancestry study involving six distantly related children with gastroschisis and a common ancestor identified regions of shared genomic segments where 33/103 (32%) of the genes participated in the immune-related pathways. 17 In this same study, each lineage had its own unique shared region and, in common with all other lineages, an involvement of immune-related genes.…”

“…In the present study, the absence of differences in methylation profile between the mothers in the gastroschisis group and the controls allow us to conclude that the methylation pattern of the fetuses with gastroschisis was not inherited, reinforcing its low recurrence rate. 17 embryos. [50][51][52] Therefore, we propose that the hypermethylation in cases with gastroschisis might have occurred previously to the inflammation processes in the amniotic fluid due to the bowels exposure.…”

“…10,11 However, genetic studies are still controversial and have been unable to provide enough data on the etiopathology of gastroschisis (Table 1). [11][12][13][14][15][16][17][18][19][20][21][22] Different molecular methods of investigation were used (sequencing, polymerase chain reaction with restriction fragment length polymorphism, panel, array comparative genomic hybridization, shared genomic segment, and whole exome sequencing) and different genes were related. These findings, however, have not been replicated, preventing confirmation of the involvement of such genes in gastroschisis.…”

“…These findings, however, have not been replicated, preventing confirmation of the involvement of such genes in gastroschisis. [12][13][14][15][16][17][18][19][20][21][22] Recent studies have shown that, when deregulated, deoxyribonucleic acid (DNA) methylation may be associated with several diseases such as cancer, type 2 diabetes, neurological disorders, obesity, and autoimmune diseases. [23][24][25][26][27] To the best of our knowledge, the gastroschisis methylation profile has not been researched to date.…”

Shared genomic segment analysis with equivalence testing

“…For statistical significance, a long run in a candidate region was compared with run lengths in the rest of the genome. This approach was recently applied to multigenerational pedigrees with gastroschisis (Feldkamp et al, 2019).…”