Discovering Genotype Variants in an Infant with VACTERL through Clinical Exome Sequencing: A Support for Personalized Risk Assessment and Disease Prevention

Abstract

Congenital anomalies may have an increased risk of noncommunicable diseases (NCDs) We performed a clinical exome analysis in an infant affected by “Vertebral, Anorectal, Cardiac, Tracheoesophageal, Genitourinary, and Limb” (VACTERL) malformation association to identify potential biomarkers that may be helpful for preventing malignancy risk or other chronic processes. Among the variants, six variants that may be linked with VACTERL were identified in the exome analysis. The variants c.501G>C on OLR1 and c.-8C>G on PSMA6 were previously associated with myocardial infarction. The variants c.1936A>G on AKAP10 and c.575A>G on PON1 are linked to defects in cardiac conduction and artery disease, respectively. Alterations in metabolism were also suggested by the variants c.860G>A on EPHX2 and c.214C>A on GHRL. In addition, three variants associated with colon cancer were discovered. Specifically, the reported variants were c.723G>A on CCND1 and c.91T>A on AURKA proto-oncogenes as well as c.827A>C in the tumor suppressor PTPRJ. A further inspection identified 15 rare variants carried by cancer genes. Specifically, these mutations are located on five tumor suppressors (SDHA, RB1CC1, PTCH1, DMBT1, BCR) and eight proto-oncogenes (MERTK, CSF1R, MYB, ROS1, PCM1, FGFR2, MYH11, BRCC3) and have an allele frequency lower than 0.01 in the Genome Aggregation Database (GnomAD). We observed that the cardiac and metabolic phenotypic traits are linked with the genotype of the patient. In addition, the risk of developing neoplasia cannot be excluded a priori. Long-term surgical issues of patients with VATER syndrome could benefit from the clinical exome sequencing of a personalized risk assessment for the appearance of further disease in pubertal timing and adult age.

Determining oncogenic patterns and cancer predisposition through the transcriptomic profile in Mitchell–Riley syndrome with heterotopic gastric mucosa and duodenal atresia: a case report

“…The GHRL gene, encoding ghrelin and obestatin prepropeptide, is associated with insulin secretion and downregulated. Our research group has already observed in a previous work that an infant with VACTERL and esophageal atresia carried a missense mutation on GHRL linked to metabolic syndrome [ 40 ]. In addition, the role of GHRL seems to be crucial in cell proliferation, migration, and invasion, as well as in inflammation in many cancers.…”

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

“…It may well be that other factors, such as additional low risk CRC alleles and/or gene-environment interactions, obscure its link to heritable CRC ( Terradas et al, 2020 ). Since reports connecting PTPRJ variants to colon cancer risk continue to appear ( Pelizzo et al, 2021 ) we may hope that meta-analyses in a perhaps far future could settle the issue.…”

The Role of Sonic Hedgehog in Human Holoprosencephaly and Short-Rib Polydactyly Syndromes

“…Mouse models with deficiencies in hedgehog or ciliary function show some features similar to human VACTERL association, but it is probably multifactorial and includes different entities [ 78 ]. A study of exome sequencing in a case of VACTERL revealed multiple genetic variants [ 79 ].…”