M Rebecca Heiner-Fokkema

PubMed2026

Next-generation newborn screening: feasibility of combined genetic and biochemical testing for 95 treatable inherited metabolic disorders.

INTRODUCTION: Next-generation sequencing (NGS) is gaining attention in newborn screening (NBS) for its ability to detect treatable genetic disorders, especially those without a biochemical footprint. However, NGS-NBS requires interpreting variants without phenotype information or family trio analysis. Biochemical tests, preferably in dried blood spots (DBS), are therefore useful to confirm the pathogenicity of variants identified by NGS-NBS and increase its specificity and sensitivity. OBJECTIVES: We aimed to explore the potential of combined genetic-biochemical testing for 95 treatable Inherited Metabolic Disorders (IMD) considered eligible for NGS-NBS (100 genes) previously identified by our research group. METHODS: We reviewed the Collaborative Laboratory Integrated Reports (CLIR) and carried out systematic literature reviews in PubMed and Embase to identify biochemical tests for 95 IMD. Biochemical tests conducted on DBS were differentiated from tests that require referral. RESULTS: We identified DBS-biochemical tests for 72 of the 95 IMD (77/100 genes). DBS-based biochemical tests for 55 IMD (60 genes) are already implemented in NBS. For the other 23 IMD, biochemical tests in non-DBS specimens are reported, although some are less sensitive when measured at neonatal age in presymptomatic infants. CONCLUSION: We present a comprehensive overview of current biochemical tests for 95 IMD. These tests can be used to confirm inconclusive NGS-NBS results, and combined genetic-biochemical testing is expected to improve both the negative and positive predictive values of NBS programs.

Humans↗

PubMed2026

Proteomics profiling of serum and liver in GSD Ia and Ib patients: insights into complication mechanisms and circulation biomarkers.

BACKGROUND: Glycogen Storage Disease (GSD) Types Ia and Ib are rare metabolic diseases caused by gene variants in G6PC1 and SLC37A4, respectively. Although life-threatening fasting hypoglycemia can be controlled by a strict diet, patients often suffer from multiple metabolic abnormalities and severe long-term complications. However, the underlying mechanisms remain incompletely understood, and there is a lack of effective monitoring biomarkers. Therefore, the aims of this study are to investigate the pathological mechanisms of the disease and disease complications in GSD I and identify potential protein biomarkers. METHODS: Comprehensive untargeted proteomics was performed on 18 GSD Ia and 8 GSD Ib sera samples from patients with 21 matched control sera, complemented by liver 3 GSD Ia samples and 1 GSD Ib sample from patient liver tissues, compared to 10 donor liver samples. RESULTS: We identified 415 proteins in total. Significantly changed (FDR < 0.05) were observed in 158 (38%) proteins for GSD Ia vs Control, 116 (28%) for GSD Ib vs. Control, and 151 (36%) for GSD Ia vs. Ib. Pathway analysis revealed distinct alterations in serum/plasma, with 58, 32, and 29 significantly changed biological processes (FDR < 0.05) in these three comparisons, respectively. The coagulation pathway was the most significantly changed one in the GSD Ia patients. Immune response-associated proteins, especially immunoglobulins, were increased in GSD Ib specifically. Proteins related to liver injury, cholesterol, and amyloidosis were altered in two subtypes, though more pronounced in GSD Ia. Potential biomarkers with significant alterations both in the circulation and in the liver tissue were identified specifically for monitoring GSD I subtypes and prognosing liver deterioration, namely APOC1 and CD5L to distinguish between GSD Ia and Ib and ALDOB for the presence of hepatocellular carcinoma (HCC) in GSD Ia patients. CONCLUSIONS: These findings provide new insights into the differences between the two GSD I subtypes and the pathogenesis of GSD I-related complications, as well as highlighting the potential of protein circulating biomarkers for monitoring complication progression in GSD I and assessing HCC risk in GSD Ia patients.

Humans↗