Background: Autosomal dominant intellectual developmental disorder 51 (MIM #617788) is caused by pathogenic variants in KMT5B, a histone methyltransferase essential for transcriptional repression and central nervous system development. The disorder manifests as a complex neurodevelopmental syndrome with variable neurological and systemic features. Methods: Two adolescents with nonsense KMT5B variants underwent detailed clinical, neuropsychological, and neuroimaging evaluations, including MRI and ¹⁸FDG PET/CT, analyzed with Statistical Parametric Mapping against matched controls. RNA sequencing was performed, and the literature was reviewed to assess genotype–phenotype correlations. Results: Both patients showed global developmental delay, progressing to autism spectrum disorder (ASD) and developmental coordination disorder (DCD), without intellectual disability (ID). The MRI was normal, but neuropsychological testing revealed executive function impairment, expressive language deficits, and behavioral disturbances. PET/CT consistently demonstrated cerebellar and temporal lobe hypometabolism, correlating with symptom severity. RNA sequencing identified shared dysregulated pathways, notably DDIT4 upregulation, linked to synaptic dysfunction and neuronal atrophy in animal models. Conclusions: The findings highlight cerebellar involvement in DCD and ASD, medial temporal lobe contribution to ASD and executive dysfunction, and DDIT4 as a possible molecular signature of KMT5B loss-of-function. An integrative multimodal approach refined genotype–phenotype correlations and revealed novel brain regions and pathways implicated in KMT5B-related disorders.

Haemoglobinopathies are an increasing health concern in Europe due to changing population demographics. In Italy, however, newborn screening (NBS) for haemoglobinopathies is not yet included in the national mandatory screening panel. The primary aim of this study was to estimate the prevalence of haemoglobinopathies in a population-based neonatal cohort from the Piedmont region; a secondary exploratory objective was to characterise neonatal HbA₀ distribution and its association with molecular findings in selected samples. We conducted a retrospective, multicentre study of 2002 anonymised dried blood spot samples collected from term newborns 48–72 h after birth. Haemoglobin fractions were analysed by high-performance liquid chromatography (HPLC). HbA₀ distribution was characterised in newborns without structural haemoglobin variants using descriptive statistics. Molecular analysis was performed in an intentionally selected subset of samples with HbA₀ < 12%. HPLC identified 29 structural haemoglobin variants (22 HbS and 7 other variants), corresponding to a prevalence of 1.4%. After exclusion of these cases, HbA₀ distribution was analysed in 1973 newborns. Mean HbA₀ was 16.1% (SD 5.3), median HbA₀ was 15.5% (Q1–Q3: 12.3–19.1), and the distribution showed moderate positive skewness. Overall, 448/1973 newborns (22.7%) had HbA₀ < 12%. Among 12 selected newborns with HbA₀ < 12% who underwent molecular testing, detectable β-globin gene mutations were identified in five. DNA extracted from stored dried blood spots was suitable for molecular analysis. Structural haemoglobin variants were identified in a non-negligible proportion of newborns in this Northern Italian cohort. HPLC provided effective first-line identification of the variants observed, whereas neonatal HbA₀ showed substantial variability and an asymmetric distribution, supporting cautious interpretation of fixed absolute thresholds for suspected β-thalassaemia carrier status. Larger, systematically genotyped cohorts are required to assess the diagnostic performance of candidate HbA₀ thresholds.