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PMID:31682389
Abstract

About one half of people living with congenital anomalies have not had a specific cause or diagnosis identified based on their clinical presentation or examination of environmental causes. Such individuals are given a label of “unexplained developmental delay”, and it is not uncommon for them to be subjected to multiple diagnostic tests venturing on what some refer to as the ‘diagnostic odyssey’. Genetic sequencing has the potential to alleviate these diagnostic odysseys and provide definitive diagnoses otherwise undetectable by clinical history, physical examination, and biochemical or metabolic tests, or to do so sooner than current practice. Next generation sequencing technologies, like chromosomal microarray (CMA) and whole exome sequencing (WES), require patients to undergo a standard blood draw that is sent off to a laboratory for analysis. The sequencing, analysis and interpretation of these technologies, however, is situated within complex bioclinical collectives made up of highly specialized professionals such as molecular analysts, bioinformaticians, and laboratory geneticists. While the sequencing itself is automated, and algorithms do exist to help identify notable mutations, these collectives must collaboratively interpret sequencing results to connect phenotype to genotype and establish whether identified variants should be considered pathogenic. For technologies like WES and CMA, pathogenicity is labeled along a scale from pathogenic to benign. For example, the American College of Medical Genetics (ACMG) has developed and standardized five descriptive reporting categories: pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, or benign. Interpretations are based on known phenotypic associations as documented in open access databases (e.g., Online Mendelian Inheritance in Man, Human Gene Mutation Database) as well as group discussions around natural history and clinical presentation. Unlike single gene or gene panel sequencing methods that focus on single or small sets of genetic material information, next-generation sequencing reads millions of fragments of genetic information in parallel. This makes the process substantially faster, but it also requires those within the bioclinical collective to be broadly familiar with potential genetic variations. This also has the effect of increasing the amounts of variants returned that may be causally relevant to the person’s condition (i.e., VUS), but cannot be determined with certainty. Test results and subsequent interpretations of pathogenicity confirmed, they are then returned to the clinic and shared with patients and their families who necessarily find ways of incorporating them into their lived worlds. The purpose of this report is to identify and describe families’ and clinicians’ experiences with, and perspectives on, using genetic testing when seeking clarity on a person’s unexplained developmental delay or multiple congenital anomalies.

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