Genome‐wide association studies of structural birth defects: A review and commentary

Abstract

Background While there is strong evidence that genetic risk factors play an important role in the etiologies of structural birth defects, compared to other diseases, there have been relatively few genome‐wide association studies (GWAS) of these conditions. We reviewed the current landscape of GWAS conducted for birth defects, noting novel insights, and future directions. Methods This article reviews the literature with regard to GWAS of structural birth defects. Key defects included in this review include oral clefts, congenital heart defects (CHDs), biliary atresia, pyloric stenosis, hypospadias, craniosynostosis, and clubfoot. Additionally, other issues related to GWAS are considered, including the assessment of polygenic risk scores and issues related to genetic ancestry, as well as utilizing genome‐wide single nucleotide polymorphism array data to evaluate gene–environment interactions and Mendelian randomization. Results For some birth defects, including oral clefts and CHDs, several novel susceptibility loci have been identified and replicated through GWAS, including 8q24 for oral clefts, DGKK for hypospadias, and 4p16 for CHDs. Relatively common birth defects for which there are currently no published GWAS include neural tube defects, anotia/microtia, anophthalmia/microphthalmia, gastroschisis, and omphalocele. Conclusions Overall, GWAS have been successful in identifying several novel susceptibility genes and genomic regions for structural birth defects. These findings have provided new insights into the etiologies of these phenotypes. However, GWAS have been underutilized for understanding the genetic etiologies of several birth defects.

Whole-Exome Sequencing of Discordant Monozygotic Twin Families for Identification of Candidate Genes for Microtia-Atresia

“…Pedigree studies demonstrate both autosomal-dominant and autosomal-recessive patterns of inheritance (Brown et al, 2013;Piceci et al, 2017;Chen et al, 2018;Lupo et al, 2019; FIGURE 2 | Protein-to-protein interactions of candidate genes with known microtia-atresia associated pathways. (A) HOXA4 directly interacts with RARA of the RA pathway, detected in three families (II, III, V); (B) TBX10 interacts directly or indirectly with WINT11 of the Wnt pathway; (C) AMER1 interacts indirectly with WINT3A of the Wnt pathway.…”

Prevalence rates study of selected isolatednon‐Mendeliancongenital anomalies in the Hutterite population of Alberta, 1980–2016

“…There is evidence of high heritability, as high as 70–90%, in certain types of congenital heart anomalies (Cripe, Andelfinger, Martin, Shooner, & Benson, 2004; Hinton et al, 2007; McBride et al, 2005). Genome wide association and whole exome sequencing studies have identified hundreds of genes and candidate genes/loci involved with isolated CHD (Lalani & Belmont, 2014; Li et al, 2017; Lupo, Mitchell, & Jenkins, 2019; Page et al, 2019) however, most genes account for a small percentage of cases and there remains a significant number with no confirmed genetic etiology.…”

Omphalocele—What should we tell the prospective parents?

“…ES, which provides sequence information from the coding regions of known genes in the human genome, also holds promise for improving the rate of genetic diagnosis. Since most of the conditions associated with omphalocele may not be included in specific gene panels, ES may be effective in identifying a diagnosis in cases with normal karyotype and/or CMA 51 . Recent studies looking at prenatal exomes do not specifically report cases of omphalocele, therefore the exact utility of using ES in cases of omphalocele remains unclear 52 …”