Background: We report on a 20-week-old female fetus with a diaphragmatic hernia and other malformations, all of which appeared after the first-trimester ultrasound. Methods and Results: Whole trio exome sequencing (WES) on cell-free fetal DNA (cff-DNA) revealed a de novo frameshift variant of the X-linked STAG2 gene. Loss-of-function (LoF) STAG2 variants cause either holoprosencephaly (HPE) or Mullegama–Klein–Martinez syndrome (MKMS), are de novo, and only affect females, indicating male lethality. In contrast, missense mutations associate with milder forms of MKMS and follow the classic X-linked recessive inheritance transmitted from healthy mothers to male offspring. STAG2 has been reported to escape X-inactivation, suggesting that disease onset in LoF females is dependent on inadequate dosing for at least some of the transcripts, as is the case with a part of the autosomal dominant diseases. Missense STAG2 variants produce a quantity of transcripts, which, while resulting in a different protein, leads to disease only in hemizygous males. Similar inheritance patterns are described for other escapee genes. Conclusions: This study confirms the advantage of WES on cff-DNA and emphasizes the role of the type of the variant in X-linked disorders.

Background/Objectives: Pediatric hypertrophic cardiomyopathy (HCM) is the most common genetic myocardial disorder in children and a leading cause of sudden cardiac death (SCD) among the young. Its phenotypic variability, driven by incomplete penetrance and variable expressivity, presents significant challenges in diagnosis and clinical management. Methods: In this study, we report a unique case of a 16-month-old female diagnosed with HCM caused by a rare genetic deletion. Molecular analysis was performed using a multigene panel and chromosomal microarray analysis (CMA). Results: Molecular tests identified a 30 kb deletion encompassing the MYH6 and MYH7 genes. These genes are critical components of sarcomeric architecture, with known associations to HCM and other cardiomyopathies. Conclusions: This case underscores the clinical and genetic heterogeneity of HCM, highlighting the importance of considering genomic deletions involving key sarcomeric genes in the diagnostic evaluation.

Introduction: Multiple sclerosis (MS) is a persistent neurological condition impacting the central nervous system (CNS). The precise cause of multiple sclerosis is still uncertain; however, it is thought to arise from a blend of genetic and environmental factors. MS diagnosis includes assessing medical history, conducting neurological exams, performing magnetic resonance imaging (MRI) scans, and analyzing cerebrospinal fluid. While there is currently no cure for MS, numerous treatments exist to address symptoms, decelerate disease progression, and enhance the quality of life for individuals with MS.Methods: This paper introduces a novel machine learning (ML) algorithm utilizing decision trees to address a key objective: creating a predictive tool for assessing the likelihood of MS development. It achieves this by combining prevalent demographic risk factors, specifically gender, with crucial immunogenetic risk markers, such as the alleles responsible for human leukocyte antigen (HLA) class I molecules and the killer immunoglobulin-like receptors (KIR) genes responsible for natural killer lymphocyte receptors.Results: The study included 619 healthy controls and 299 patients affected by MS, all of whom originated from Sardinia. The gender feature has been disregarded due to its substantial bias in influencing the classification outcomes. By solely considering immunogenetic risk markers, the algorithm demonstrates an ability to accurately identify 73.24% of MS patients and 66.07% of individuals without the disease.Discussion: Given its notable performance, this system has the potential to support clinicians in monitoring the relatives of MS patients and identifying individuals who are at an increased risk of developing the disease.

Neurodevelopmental disorders (NDDs) are a heterogeneous group of conditions characterised by impairments in cognition, motor function, behaviour, and social interaction. Their genetic basis is highly diverse, and next-generation sequencing has become central to improving diagnostic yield. We retrospectively analysed 94 paediatric patients (0–18 years) with NDDs referred to the Paediatric and Rare Diseases Clinic, Microcitemico Hospital “A. Cao,” between January 2019 and July 2024. Each patient underwent detailed clinical evaluation and whole-exome sequencing (WES). Variants were prioritised according to ACMG guidelines. Gene burden analysis of rare predicted loss-of-function variants was performed using the Cohort Allelic Sums Test to detect enrichment in NDD cases relative to controls. WES identified 12 pathogenic variants, 16 likely pathogenic variants, and 10 variants of uncertain significance. Autosomal dominant disorders were the most frequent (n = 35 patients), while autosomal recessive and X-linked dominant conditions were identified in a single case each. The findings of this study further highlight the importance of WES in identifying novel genetic variants and in providing explanations for previously unexplained NDD cases. Moreover, the Cohort Allelic Sums Test (CAST) demonstrated that rare variants are enriched in genes implicated in neuronal development in affected individuals.

Background: Houge-Janssens syndrome 1 is a condition with onset in early childhood caused by heterozygous pathogenic variants in the PPP2R5D gene, which encodes a B56 regulatory subunit of the serine/threonine protein phosphatase 2A (PP2A). There is evidence that the PP2A-PPP2R5D complex is involved in regulating the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway, which is crucial for several cellular processes, including the pathogenesis and progression of haemangiomas. Case presentation: We report the first PPP2R5D-related neurodevelopmental disorder case from Sardinia, a child with transient hypoglycaemia, facial dysmorphisms, and multiple haemangiomas. Whole Exome Sequencing analysis confirmed the clinical suspicion, detecting the presence of the de novo missense variant c.592G>A in the PPP2R5D gene. Conclusions: Haemangiomas have never been linked to the syndromic phenotype of the PPP2R5D-associated disorder. The close correlation between the PP2A enzyme and the PI3K/AKT signalling pathway suggests the possible correlation between its dysfunction and activation of haemangiogenesis. Our report highlights a possible link between the PPP2R5D-related disorder and altered angiogenesis, characterizing diffuse haemangiomas as a possible novel phenotypic trait of this condition.