Molecular genetics and metabolism · 2026
Over ten years of newborn screening for LSDs in Tuscany (Italy): Epidemiology, novel variants, and the pseudodeficiency burden.
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Malvagia Sabrina, Daniotti Marta, Tonin Rodolfo, Ferri Lorenzo, Ombrone Daniela, Forni Giulia, Scolamiero Emanuela, Funghini Silvia, Rinaldi Marina, Falliano Silvia, Paoli Antonella, Mura Massimo, Raspini Francesca, Poggiali Sara, Scaturro Giusi, Sacchini Michele, Donati Maria Alice, Procopio Elena, Guerrini Renzo, Morrone Amelia, la Marca Giancarlo
Аннотация
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.
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.