Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

Background: Lysosomal storage disorders (LSDs) are rare, chronic, progressive multisystem diseases implying severe medical issues and psychological burden. Some of these disorders are susceptible to a treatment, which is administered weekly or every other week, in a hospital. During the COVID-19 (Corona Virus Disease 2019) pandemic lockdown, patients with LSDs on enzyme replacement therapy (ERT) missed their scheduled access to the Day Hospital to get their treatment. Methods: Based on the feeling that our patients were experiencing profound distress, we designed a structured telephone interview with the aim to evaluate how, and to which extent, the pandemic outbreak was changing their behavior and feelings about their chronic disease, the impact on therapies, and future expectations. The same interview was administered to an age-matched control group. Results: All interviewed people experienced an increase of anxiety, worries, and uncertainty fostered by incessant media updates. Moreover, a striking similarity emerged between the groups regarding forced home reclusion and the profound feeling to be excluded by normal life, well-known to those affected by a chronic rare disease. Conclusions: Although no statistically significant difference was found compared to controls, we felt that the reactions were qualitatively different, underlining the fragility and isolation of such patients.

The expanded newborn screening for selected inborn errors of metabolism (IEM) in Sicily was introduced in 2007 by a Regional project entitled “Early detection of congenital metabolic diseases: expanded neonatal screening”. It established two newborn screening laboratories, for Western and Eastern Sicily, which started their activity in 2011. Here we present the results of expanded screening (excluding phenylketonuria (PKU)) of the Eastern laboratory from January 2011 to December 2017. Our data highlight the importance of the expanded newborn screening as a basic health program to avoid the underestimation of rare diseases and the need of further investigations even when there are no textbook alterations of the metabolic profiles. We performed our analysis on dried blood spot by tandem mass spectrometry, according to Italian guidelines. A total of 196 samples from 60,408 newborns gave positive screening results (recall rate 0.32%) while 12 babies were true positive, including 2 newborns whose mothers resulted in being affected by a metabolic disease. The overall frequency of IEM found in the screening panel was 1:6041 (mothers excluded) or 1:5034 (mothers included). The introduction of MS/MS technology in Sicily has significantly increased the detection of inherited metabolic disorders, including those not previously covered, with a predictable improved outcome for several disorders.

The 8p inverted duplication/deletion is a rare chromosomal rearrangement clinically featuring neurodevelopmental delay, mild to severe cognitive impairment, heart congenital defects and brain abnormalities. Patients affected also present typical facial dysmorphisms and skeletal malformations, and it is thought that the composite clinical picture may fall into the chromosomal rearrangement architecture. With the major aim of better framing its related clinical and diagnostic paths, we describe a patient carrying a de novo invdupde[8p] whose clinical features have not been described so far. Hence, through an extensive genotype–phenotype correlation analysis and by reviewing the dedicated scientific literature, we compared our patient’s features with those reported in other patients, which allows us to place our proband’s expressiveness in an intermediate area, widening the scope of the already known invdupde[8p] genotype–phenotype relationship.

Background: Phenylketonuria (PKU) poses significant challenges for maternal and neonatal outcomes, requiring strict adherence to dietary protocols to maintain optimal maternal phenylalanine (Phe) levels during pregnancy. This study retrospectively analyzed outcomes of pregnancies in PKU-affected women and conducted a systematic review on the timing of dietary management and its impact on outcomes. Methods: This retrospective study included data from nine PKU-affected women and 14 pregnancies followed at the Regional Reference Center for Metabolic Diseases in Catania. Women were categorized based on the timing of dietary intervention: preconception (pcD), during pregnancy (pD), or never (nD). Maternal Phe levels were classified as in-target (tP+) or non-target (tP−). A systematic review of the literature was conducted using PRISMA methodology, including 77 studies reporting maternal Phe levels, dietary timing, and clinical/auxological offspring outcomes. Results: In the retrospective study, pcD and tP+ groups had significantly better neonatal outcomes, with lower rates of congenital heart disease (CHD), facial dysmorphisms, intrauterine growth restriction (IUGR), and microcephaly. Systematic review data from 1068 PKU-affected women and 2094 pregnancies revealed that pcD with tP+ resulted in the lowest rates of miscarriage (0.14%) and adverse neonatal outcomes, while tP− and nD groups showed the highest rates of CHD, microcephaly, and intellectual disability. Conclusions: Early dietary intervention, ideally preconceptionally, and achieving target maternal Phe levels are critical in reducing adverse outcomes in pregnancies of PKU-affected women. These findings emphasize the importance of metabolic control and adherence to dietary protocols in maternal PKU management.