Though heterogeneity of cancers is recognized and has been much discussed in recent years, the concept often remains overlooked in different routine examinations. Indeed, in clinical or biological articles, reviews, and textbooks, cancers and cancer cells are generally presented as evolving distinct entities rather than as an independent heterogeneous cooperative cell population with its self-oriented biology. There are, therefore, conceptual gaps which can mislead the interpretations/diagnostic and therapeutic approaches. In this short review, we wish to summarize and discuss various aspects of this dynamic evolving heterogeneity and its biological, pathological, clinical, diagnostic, and therapeutic implications, using thyroid carcinoma as an illustrative example.

The rapid development of therapies for severe and rare genetic conditions underlines the need to incorporate first-tier genetic testing into newborn screening (NBS) programs. A workflow was developed to screen newborns for 165 treatable pediatric disorders by deep sequencing of regions of interest in 405 genes. The prospective observational BabyDetect pilot project was launched in September 2022 in a maternity ward of a public hospital in the Liege area, Belgium. In this ongoing observational study, 4,260 families have been informed of the project, and 3,847 consented to participate. To date, 71 disease cases have been identified, 30 of which were not detected by conventional NBS. Glucose-6-phosphate dehydrogenase deficiency was the most frequent disorder detected, with 44 positive individuals. Of the remaining 27 cases, 17 were recessive disorders. We also identified one false-positive case in a newborn in whom two variants in the AGXT gene were identified, which were subsequently shown to be located on the maternal allele. Nine heterozygous variants were identified in genes associated with dominant conditions. Results from the BabyDetect project demonstrate the importance of integrating biochemical and genomic methods in NBS programs. Challenges must be addressed in variant interpretation within a presymptomatic population and in result reporting and diagnostic confirmation.

Background: Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH. Materials and methods: We sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test. Results: In 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls. Conclusion: Our study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.

As genomic newborn screening (gNBS) progresses toward broader implementation, questions arise regarding conditions to include on first-tier sequencing panels. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common monogenic disorder worldwide, is inconsistently screened in Europe despite its established role in neonatal hyperbilirubinemia and hemolytic crises. Using data from the Belgian BabyDetect pilot, one of the first European programs to include the evaluation of genomic and biochemical newborn screening in the same cohort, together with international evidence, we assessed the readiness of G6PD deficiency for inclusion in gNBS. In BabyDetect, genomic screening identified 94 newborns carrying pathogenic or likely pathogenic G6PD variants, including 17 neonates not detected by routine biochemical screening, demonstrating the complementary value of sequencing. However, identifying additional moderately deficient infants introduces uncertainty regarding penetrance, follow-up burden, healthcare impact and cost-effectiveness. Screening readiness was evaluated using an adapted NEXUS 2015 semi-quantitative framework, where G6PD deficiency scored 17/21, reflecting strong clinical benefit, high feasibility and ethical favorability, with moderate analytic validity, population impact, and evidence strength. Published economic modeling suggests the principal value of screening derives from reducing severe hyperbilirubinemia complications and later hemolytic crises, with additional benefits from improved pharmacovigilance and risk mitigation for subsequent siblings within affected families. Given the minimal marginal cost of adding G6PD to existing gNBS workflows, available evidence indicates that G6PD deficiency is well-suited for inclusion in gNBS when paired with confirmatory testing and proportionate, pediatric-led follow-up.

Genomic newborn screening (gNBS) may complement conventional newborn screening by identifying treatable genetic disorders before symptom onset. However, implementation at the population scale raises unresolved questions regarding variant interpretation, reporting thresholds and management of low-penetrance findings. BabyDetect was a prospective, population-based first-tier gNBS study conducted in Liege, Belgium, between September 2022 and June 2025. Newborns were screened using a targeted panel of 405 genes associated with severe, treatable childhood-onset disorders. Screening performance, clinical outcomes, false-positive and false-negative findings, and reporting challenges were evaluated across the complete cohort. Among 6,824 screened newborns, parental uptake reached 90.8%. A total of 134 infants (1.96%) had reportable findings; 131 were confirmed as true positives and three as false positives. Two false-negative cases were identified during follow-up. Thirty-nine confirmed diagnoses were detected exclusively by gNBS, including 20 conditions not amenable to biochemical screening and 19 missed by conventional newborn screening. Findings enabled presymptomatic treatment, emergency planning, dietary intervention or structured surveillance. Reassessment of MYH7 and MYBPC3 variants revealed that reporting heterozygous dominant cardiomyopathy-associated variants would have generated 37 additional findings without clear newborn-period clinical utility, prompting revision of reporting criteria. Population-scale first-tier gNBS is feasible, highly accepted and clinically informative. Long-term success will depend on rigorous variant curation and carefully defined reporting frameworks that prioritize childhood actionability while minimizing overdiagnosis and unnecessary follow-up.