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Page 2 of 15 Pintos-Morell et al. Rare Dis Orphan Drugs J 2024;3:12 https://dx.doi.org/10.20517/rdodj.2023.52

Keywords: Newborn screening, inborn errors of metabolism, inherited metabolic disorders, rare diseases,
biomarkers, genomics, genome sequencing

INTRODUCTION
The International Rare Diseases Research Consortium (IRDiRC) is a global collaborative initiative on rare
diseases research launched in 2011 by the European Commission (EU) and the United States of America
National Institutes of Health (NIH) to accomplish the vision to enable all people living with a rare disease to
receive an accurate diagnosis, care, and available therapy within one year of coming to medical attention.
The Newborn Screening (NBS) Initiative was launched in June 2022 to tackle the increasing interest in NBS
for identifying rare diseases at an early stage, but also to highlight the challenges that exist in implementing
the screening programs across different regions of the world. While next-generation sequencing (NGS)
offers the opportunity to screen for genetic disorders through a single test, there are still challenges in terms
of overall cost and accessibility to complex and appropriate equipment.

The remarkable advancements in NGS technology have facilitated the discovery of novel inherited
metabolic disorders (IMDs) or inborn errors of metabolism, irrespective of the presence of conventional
blood, urine, or cerebrospinal fluid markers. Indeed, the latest International Classification of IMDs
(ICIMD) aims to include any primary genetic condition in which alteration of a biochemical pathway is
intrinsic to specific biochemical, clinical, and pathophysiological features, regardless of whether laboratory
[1,2]
biochemical tests are currently available . Rare genetic diseases may go unrecognized for weeks, months,
or even years until clinical manifestations are evident, and often when it is too late to establish an adequate
outcome with optimal treatment . However, the increasing use of techniques such as metabolomics with
[3]
[4]
tandem mass spectrometry (MS/MS) and NGS has expanded the possibilities of diagnosing patients .
[5,6]
Still, the complex clinical picture of IMDs, in combination with their rarity, makes the early clinical
[7,8]
recognition of these rare conditions challenging .
The establishment of an IMD diagnosis is generally supported by clinical suspicion and biochemical
investigations. Currently, NGS technology has grown as an essential tool for rapid and effective diagnostics
even prior to complex functional studies (i.e., enzyme activities). Targeted NGS approaches are currently
being implemented in clinical practice, and a clinical exome strategy has facilitated the simultaneous
assessment of different IMD phenotypes and the study of undiagnosed clinical problems for which a genetic
disease is considered [9,10] .

NBS represents a vital public health preventative intervention that allows the early diagnosis of a broad
spectrum of genetic diseases. The primary goal of NBS programs is to screen for genetic diseases with the
purpose of promptly diagnosing pediatric diseases for which specific effective therapeutic interventions are
available. For those IMDs with available treatment (e.g., nutritional, pharmacologic, organ transplant,
genetic), pre-symptomatic identification is very beneficial, and this is the main reason for newborn
screening. NBS, based on metabolic biomarkers, was initially started with a single amino acid,
phenylalanine, for phenylketonuria [11,12] . The resounding success of this first approach resulted in a rapid
expansion of the biochemical NBS in dried blood spots (DBS), which has been increasingly introduced in
the last few years in many countries as a public health program [13,14] . However, there is a group of IMDs
without reliable biochemical markers in DBS (e.g., some urea cycle disorders or citrin deficiency), while
other IMDs may need different methods than MS/MS (e.g., galactosemia, biotinidase deficiency), such as