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Unique outcomes from curated genome sequencing for newborn screening: Challenging results from the Early Check project 

Health Services and Implementation
  • Primary Categories:
    • Health services and Implementation
  • Secondary Categories:
    • Health services and Implementation
Introduction:
A current challenge facing newborn screening programs is if and if so, how to further incorporate genetic testing and sequencing technologies. Early Check is a voluntary, consented newborn sequencing research program available to infants who have received standard newborn screening (NBS) in North Carolina. The goals of this study include: 1) informing policy and possible transition to standard newborn screening and 2) assessing the outcomes and impact of this sequencing and confirmatory testing on infants and their families. Sequencing has been ongoing since September 2023. Genomic sequencing results can be complex, requiring genetics expertise and time intensive follow-up to elucidate clinical implications.

 

Methods:
Early Check offers a standard panel of genes associated with ~200 treatable monogenic conditions for all consented participants. Additionally, parents can opt in to receive results for ~40 additional monogenic conditions with potential treatments and/or a genetic risk score for type 1 diabetes (T1D). Genome sequencing (GS) is performed in a commercial, CLIA laboratory on residual dried blood spots remaining after standard NBS.  Positive genomic screening results for Early Check are limited to pathogenic (P) and likely pathogenic (LP) variants according to the inheritance pattern associated with each condition.

 

Results:
As of fall 2024, close to 3,000 infants have been sequenced, with a screen positive rate of 2.7%.  Results that are challenging to interpret are not uncommon. Notably, there have been several results for which appropriate interpretation, communication, and family focused follow up has required both variant interpretation expertise as well as nuanced genetic counseling. We will present on novel cases that represent these challenges:

  1. Genes with both autosomal recessive and autosomal dominant inheritance (e.g., POU1F1)

  2. Genomic sequencing results discordant with standard NBS results (e.g., PAH)

  3. Mosaicism (e.g., RB1)

  4. Identification of P/LP variants in unaffected parents (e.g., MECP2)

  5. Genes with a broad clinical spectrum and unclear genotype-phenotype correlations (e.g. SCN1A)

  6. Off-target results (e.g., MITF melanoma variant)

  7. Potential secondary findings (e.g., Trisomy 21)




Conclusion:
Reminiscent of the introduction of tandem mass spectrometry to NBS in the early 1990’s, programs that implement GS must anticipate and addressed complex challenges associated with screening a predominantly healthy population.  Newborn sequencing results in increased complexity- even when strict standards conscribe the condition-gene targets and permissible screen positive outcomes (e.g. variant classification uncertainty, phasing, penetrance, variable expressivity).  Development of standard procedures to manage these complexities is necessary to minimize burden on both the genetic workforce and families as well as improve accuracy and reporting efficiency in the future. Finally, it should be recognized that GS in NBS extends the “patients in waiting” phenomena – when newborns are under medical attention with uncertainty about if, how, and to what extent a child may develop symptoms associated with their GS based NBS result.  This situation is more likely when there is no orthogonal method for confirmatory testing and should be considered when weighing the benefits versus harms of utilizing this technology in NBS and selecting which gene-condition pairs to include.

 

Agenda

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