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Over ten years of newborn screening for LSDs in Tuscany (Italy): Epidemiology, novel variants, and the
Sabrina Malvagia1, Marta Daniotti2, Rodolfo Tonin3
1Newborn Screening, Biochemistry and Clinical Pharmacy Lab, Meyer Children's Hospital IRCCS, 50139 Florence, Italy; Department of Neuroscience and Human Genetics, Meyer Children's Hospital IRCCS, 50139 Florence, Italy.
Insights
Newborn screening effectively identifies lysosomal storage disorders (LSDs) like Pompe disease and Fabry disease, but challenges remain with pseudodeficiencies and variants of uncertain significance. Robust second-tier testing is crucial for accurate diagnosis in diverse populations.
Area of Science:
- Medical Genetics
- Biochemistry
- Public Health
Background:
- Lysosomal storage disorders (LSDs) are inherited metabolic diseases requiring early diagnosis to prevent severe complications.
- Newborn screening (NBS) is vital for timely identification and intervention in LSDs.
Purpose of the Study:
- To evaluate the 10-year effectiveness of NBS for Fabry disease (FD), Pompe disease (PD), and mucopolysaccharidosis type I (MPS I).
- To analyze epidemiological data, molecular characteristics, and clinical impact in a multiethnic newborn population.
Main Methods:
- Analysis of 234,642 newborns screened over 10 years in Tuscany, Italy.
- Utilized tandem mass spectrometry and digital microfluidics-based assays for LSD detection.
- Included molecular characterization of confirmed cases and genetic variant analysis.
Main Results:
- Identified 170 confirmed positive screens out of 422 initial positives (0.18% recall rate).
- Confirmed 17 late-onset PD cases (1:13,802) and 24 FD cases (1:9776 total).
- Detected 19 novel variants across GAA, GLA, and IDUA genes, with evidence of founder effects for specific GLA variants.
Conclusions:
- NBS is effective for LSDs but faces challenges with pseudodeficiencies and variants of uncertain significance (VUS).
- High prevalence of pseudodeficiency alleles in MPS I screening necessitates improved second-tier testing strategies.
- Importance of robust diagnostic strategies in ethnically diverse populations for accurate NBS interpretation.
Background:
Lysosomal storage disorders (LSDs) comprise a heterogeneous group of inherited metabolic diseases that lead to severe, irreversible complications if diagnosis is delayed. Newborn screening (NBS) provides a crucial opportunity for early identification and timely initiation of disease-modifying interventions.
Methods:
We analyzed 234,642 newborns screened over a 10-year period in Tuscany, Italy, for Fabry disease (FD), Pompe disease (PD), and mucopolysaccharidosis type I (MPS I), using evolving methodologies, including tandem mass spectrometry and digital microfluidics-based assays. We report the epidemiological data, molecular characterization, and the clinical impact of our screening program. Approximately 18% of screened newborns were of non-Italian origin, predominantly from Chinese, North African, and sub-Saharan African communities, providing unique insights into the genetic landscape of LSDs in a multiethnic population.
Results:
We identified 422 initial positive screens (recall rate 0.18%), of which 170 were confirmed on second dried blood spot (DBS). Molecular analysis revealed 17 late-onset PD individuals (incidence 1:13,802), 24 FD individuals, including five classical and 19 late-onset phenotypes (incidence 1:9776 total, 1:46,928 classical). No MPS I cases were confirmed, despite 45 positive initial screens. Nineteen novel variants were detected across the three genes: 4 in GAA, 5 in GLA, and 10 in IDUA. Evidence of regional founder effects emerged for the GLA variants c.335G > A and c.640-823 T > C.
Conclusions:
Our 10-year experience demonstrates the effectiveness of NBS for LSDs while highlighting important challenges, particularly the high burden of pseudodeficiencies and variants of uncertain significance (VUS). In MPS I screening, the substantial prevalence of pseudodeficiency alleles underscores the need for robust second-tier testing strategies to improve positive predictive value, especially in ethnically diverse populations.
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