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We recently investigated the role of the cerebellum during development, reporting that children with genetic slow-progressive ataxia (SlowP) show worse postural control during quiet stance and gait initiation compared to healthy children (H). Instead, children with genetic non-progressive ataxia (NonP) recalled the behavior of H. This may derive from compensatory networks, which are hindered by disease progression in SlowP while free to develop in NonP. In the aim of extending our findings to intra-limb postural control, we recorded, in 10 NonP, 10 SlowP and 10 H young patients, Anticipatory Postural Adjustments (APAs) in the proximal muscles of the upper-limb and preceding brisk index finger flexions. No significant differences in APA timing occurred between NonP and H, while APAs in SlowP were delayed. Indeed, the excitatory APA in Triceps Brachii was always present but significantly delayed with respect to both H and NonP. Moreover, the inhibitory APAs in the Biceps Brachii and Anterior Deltoid, which are normally followed by a late excitation, could not be detected in most SlowP children, as if inhibition was delayed to the extent where there was overlap with a late excitation. In conclusion, disease progression seems to be detrimental for intra-limb posture, supporting the idea that inter- and intra-limb postures seemingly share the same control mechanism.

Joubert syndrome (JS) is a genetically heterogeneous neurodevelopmental ciliopathy. Despite exome sequencing (ES), several patients remain undiagnosed. This study aims to increase the diagnostic yield by uncovering cryptic variants through targeted ES reanalysis. We first focused on 26 patients in whom ES only disclosed heterozygous pathogenic coding variants in a JS gene. We reanalyzed raw ES data searching for copy number variants (CNVs) and intronic variants affecting splicing. We validated CNVs through real-time PCR or chromosomal microarray, and splicing variants through RT-PCR or minigenes. Cryptic variants were then searched in additional 44 ES-negative JS individuals. We identified cryptic “second hits” in 14 of 26 children (54%) and biallelic cryptic variants in 3 of 44 (7%), reaching a definite diagnosis in 17 of 70 (overall diagnostic gain 24%). We show that CNVs and intronic splicing variants are a common mutational mechanism in JS; more importantly, we demonstrate that a significant proportion of such variants can be disclosed simply through a focused reanalysis of available ES data, with a significantly increase of the diagnostic yield especially among patients previously found to carry heterozygous coding variants in the KIAA0586 , CC2D2A and CPLANE1 genes.

Background/Objectives: The pathogenetic role of 15q11.2 Copy Number Variations (CNVs) remains contentious in the scientific community, as microdeletions and microduplications in this region are linked to neurodevelopmental disorders with variable expressivity. This study aims to explore the diagnostic utility of Exome Sequencing (ES) in a cohort of pediatric patients with 15q11.2 CNVs. Methods: We enrolled 35 probands with 15q11.2 microdeletions or microduplications from two genetic centers between January 2021 and January 2023. Chromosomal Microarray Analysis (CMA) and ES were performed with written consent obtained from all parents. Pathogenic variants were classified according to ACMG guidelines. Results: CMA identified additional pathogenic CNVs in 3 of 35 children (9%). Subsequent ES revealed likely pathogenic or pathogenic variants in 11 of 32 children (34%). Notably, a higher percentage of isolated autism spectrum disorder (ASD) diagnoses was observed in patients without other CNVs or point mutations (p = 0.019). Conclusions: The ES analysis provided a diagnostic yield of 34% in this pediatric cohort with 15q11.2 CNVs. While the study does not dismiss the contribution of the CNV to the clinical phenotype, the findings suggest that ES may uncover the underlying causes of neurodevelopmental disorders. Continuous monitoring and further genetic testing are recommended for all 15q11.2 CNV carriers to optimize clinical management and familial counseling.

Background: Hormone-receptor-positive (HR+)/HER2-negative (HER2−) breast cancer (BC) is characterized by low immunogenicity and an immunosuppressive microenvironment. These features likely contribute to the inconsistent clinical activity of immune checkpoint inhibitors (ICIs) in this BC subtype. We conducted a systematic review of clinical trials evaluating ICIs in HR+/HER2− BC patients, focusing on potential biomarkers of response and resistance to these drugs. Methods: We systematically searched in Medline via PubMed, EMBASE, and CENTRAL for phase II/III clinical trials published between 2013 and 2023, testing ICIs alone or in combination with other agents in HR+/HER2− BC patients at any stage. All the searches were performed up to 27 January 2024. Data on study characteristics, clinical outcomes, and biomarker profiles were extracted, and due to study heterogeneity, a narrative synthesis was performed, without risk-of-bias assessment or meta-analysis. Results: Twenty-five studies were included, with 3298 patients enrolled overall. Eighteen of these trials enrolled patients with advanced disease. All trials investigated ICI combination regimens, more frequently with chemotherapy, CDK4/6 inhibitors, or other immunotherapeutic agents. Most of the studies enrolling patients with advanced disease failed to show a significant clinical activity of ICIs. In the early setting, neoadjuvant chemo-immunotherapy with nivolumab or pembrolizumab increased the rate of complete responses compared to chemotherapy alone. Moreover, high programmed death-ligand 1 (PD-L1) expression, low ER (estrogen receptor), and high tumor-infiltrating lymphocyte (TIL) levels correlated with improved outcomes. Consistently, markers indicating enhanced immune activation, such as the MammaPrint High 2 (MP2) genomic signature, were associated with increased ICI sensitivity. Discussion: Despite the limited overall efficacy, ICIs may represent a viable therapeutic option for a selected subset of HR+/HER2− BC patients. However, this systematic review is limited by study heterogeneity and the inclusion of ongoing or immature trials, which prevents quantitative analysis and may affect future conclusions on ICIs in HR+/HER2− breast cancer. Finally, optimized combination strategies could enhance tumor immunogenicity, while predictive biomarkers such as PD-L1, TILs, or specific genomic signatures could identify responsive patients.

This study aimed to identify the clinico-pathological variables predictive of radiologic complete response (rCR) to first-line anti-HER2 therapy in patients with HER2-positive metastatic breast cancer. Patients were selected from the database of the GIM14 study and classified according to the best radiologic response obtained to first-line anti-HER2 therapy and upon time-to-treatment-discontinuation (TTD). A total of 545 patients were included in the analysis. Eighty patients experienced a rCR to first-line anti-HER2 therapy with a TTD > 3 months and HER2 Immunohistochemistry score 3+, presence of non-visceral metastases and 1 metastatic site were significantly associated with higher odds of obtaining a CR. Of the 80 patients achieving a rCR, 56 experienced a CR with a TTD > 18 months, with anti-HER2 therapy being the only variable significantly associated with a higher probability of achieving such sustained CR.