Newborn Genome Sequencing Project Identifies Unexpected Disease Risks

Recent advances in genome-scale sequencing have enabled complete genome sequencing of newborns to be performed shortly after birth. Analysis of this sequence enables the detection of deleterious variants associated with monogenic diseases. Although such screening tools are currently available, there are several ethical, evidentiary, and cost-related issues.

Recent American Journal of Human Genetics A study investigated medical conditions in infants with unanticipated monogenic disease risk (uMDR) and mapped them to a standardized semi-quantitative scale. potential action.

study: Feasibility of Unexpected Single-Gene Disease Risk in Newborn Genomic Screening: Findings from the BabySeq Project. Image credit: metamorworks / Shutterstock

What is the Baby Seek Project?

The BabySeq project includes a series of neonatal clinical trials funded by the National Institutes of Health (NIH). These clinical trials relate to newborn screening using genome sequencing (GS) and provide empirical data on consent mechanisms, disclosure methods, gene curation, and variant interpretation. Additionally, these trials focus on behavioral, medical, and economic outcomes.

Initially, the BabySeq project recruited both healthy and sick infants for the study. Healthy infants were collected from the neonatal nursery (NBN) and sick infants from the intensive care unit (ICU). These candidates were randomly assigned to receive either standard-of-care newborn screening (NBS) or NBS plus GS.

Infants assigned to GS underwent whole-exome sequencing. Here, exomes were annotated, filtered, and the results analyzed to identify pathogenic or potentially pathogenic variants (PLPV). Clinical data of PLPV for all genetic disorders have been described.

These data were associated with genetic conditions that may be expressed in childhood and are highly penetrant or manageable in childhood and are moderately penetrant. It has been noted that penetrance is most likely to be underestimated when the genetic disease exhibits mild or subclinical features. The concept of penetrance is based on which specific phenotype is analyzed over how long. In epidemiological studies, hereditary cardiomyopathy penetrance is described as asymptomatic thickening of the cardiac septum.

research result

A total of 325 newborns were initially enrolled in the BabySeq project. Her 159 out of 325 were randomized to her GS treatment arm, of which 11.3% were associated with her PLPV. However, she is the only infant with PLPV and is at risk for a monogenic disorder that may be retrospectively associated with clinical manifestations. Of the 159 infants, 17 had her PLPV characterized as her uMDR.

Sequencing results were shared with the participants’ parents during counseling sessions. Disclosure letters were provided to parents and neonatal clinicians. In her 17 infants with uMDR, her PLPV was found in 13 unique genes of inheritance. In addition, two carried a pathogenic variant in her BRCA2 and one in her MSH2.

The BabySeq project was involved in a feasibility analysis identifying the clinical severity of underlying conditions. Available interventions were then graded based on ClinGen’s semi-quantitative feasibility index (CASQM). A visual representation of these scores for each infant was generated.

Outcome-intervention pairs evaluated by CASQM consist of four dimensions: severity, likelihood, efficacy, and nature of intervention. In the context of visual representation of data, the perfect diamond shape represents the most favorable viable state. Here the authors assessed viability throughout life rather than assessing viability specifically in childhood or adulthood.

All infants at risk for uMDR were referred for monitoring, specialist consultation, and treatment. Of her 17 infants with uMDR, 3 had an unrecognized phenotype and uMDR was not considered a risky variant. However, they turned out to be penetrant with mild or subclinical features. This finding demonstrates the difficulty of detecting the true penetrance of most single-gene conditions. It is also important to detect differences in gene expression over time.

The BabySeq project focused only on genetic variants strongly associated with disease expression with high penetrance irrespective of practicality and moderate evidence of penetrance but high practicality in childhood or adolescence. . The concept of actionability is difficult to explain. In some cases, actionability enhances surveillance and even enables knowledge-based prediction of disease. However, some scientists explain that the utility is an effective treatment that can slow the progression of the disease or improve the prognosis of the disease.

The most actionable symptoms of the condition are represented by full diamonds with a score of 3 in each domain. However, alternative geometries show signal variability and may be expected to have lower penetrance or be more burdensome to treat. This visual dashboard helps policy makers, parents and clinicians intuitively understand the effectiveness of their chosen interventions for specific genetic diseases.

the importance of studying

In the BabySeq project, the majority of infants identified with uMDR underwent rapid specialist evaluation and follow-up procedures, which could be a life-saving approach. Therefore, the importance of warning families about the possibility of inherited disorders can be very beneficial.