Background/Objectives: The FARSA gene encodes for the catalytic α subunit of Cytoplasmic phenylalanine-tRNA synthetase (FARS1), an essential enzyme for protein biosynthesis in transferring its amino acid component to tRNAs. Biallelic pathogenic variants have been associated with a multisystemic condition, characterized by variable expressivity and incomplete penetrance. Here, we report the case of an 11 year-old girl presenting interstitial lung disease, supratentorial leukoencephalopathy with brain cysts, hepatic dysfunction, hypoalbuminemia, skin and joint hyperlaxity, growth retardation, and dysmorphic features. In addition, our patient also developed two clinical features never reported before: hypergammaglobulinemia and myopic chorioretinitis. Methods: NGS analysis of the patient’s skin-derived DNA revealed two novel biallelic variants in FARSA gene (NM_004461.3) never described before: the maternal nonsense variant, c.799C>T [p.(Gln267Ter)], and the paternal missense variant, c.737T>C [p.(Met246Thr)], both predicted as deleterious. Results: From a therapeutic perspective, this young girl has been enrolled in a clinical trial with Nintedanib, in order to treat the severe pulmonary fibrosis, with interesting initial results. Conclusions: Our findings expand the clinical and molecular spectrum of the FARSA-related phenotype and introduce new cues on lung fibrosis treatment in pediatric age.

Background/Objectives: PKP2 (MIM *602861) is the most commonly gene associated with Arrhythmogenic Cardiomyopathy (ACM), an inherited cardiac muscle disorder. The aim of this study was to characterize the phenotypical effect of a heterozygous pathogenic c.2443_2448delAACACCinsGAAA variant in PKP2 gene (NM_004572), detected in two Italian families. Methods: Next Generation Sequencing (NGS) analysis was carried out on two probands, testing a multigenic targeted panel. Segregation analysis through Sanger sequencing detected other three and six positive members, in Family 1 and 2, respectively. Thus, eleven positive patients were identified overall. A deep clinical evaluation was performed according to age groups and clinical parameters (symptoms, electrocardiogram, imaging, and devices). To investigate the molecular effect of the identified variant on PKP2 expression level, total RNA was isolated from peripheral blood mononuclear cells (PBMCs) and quantitative RT-polymerase chain reaction was performed. PKP2 expression at the protein level was analyzed on PBMCs by Western blot analysis. Results: PKP2 transcriptional levels resulted to be reduced by 48% in cells carrying c.2443_2448delAACACCinsGAAA variant compared to WT cells (p = 0.00015). Importantly, Western blot confirmed the reduced level of PKP2 protein in two heterozygous carriers of the variant, confirming the haploinsufficiency effect. Conclusions: The clinical onset of ACM can be Sudden Cardiac Death, and hence, it is recommended to perform a segregation test on first-degree relatives of pathogenic variant carriers, even if they are asymptomatic, with the purpose of promptly detecting those at risk.

Background: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders characterized by variable degrees of inflammation and fibrosis affecting the pulmonary interstitium. Advances in molecular biology and genetics have greatly expanded our understanding of ILD pathogenesis, uncovering novel mechanisms and supporting precision medicine approaches. Genetic Insights: Genetic factors play a pivotal role in ILD heterogeneity, influencing disease onset, severity, and progression. To date, more than 30 genes with different inheritance patterns (autosomal dominant, recessive, or X-linked) have been associated with ILDs. These genes are primarily involved in surfactant metabolism, telomere maintenance, immune regulation, and epithelial repair. Emerging evidence also implicates genes encoding aminoacyl-tRNA synthetases. This review summarizes the main genetic alterations underlying ILD pathogenesis and discusses their impact on diagnostic and therapeutic approaches, highlighting how identification of disease-causing variants can improve diagnostic accuracy, refine prognostic assessment, and inform recurrence risk. Methods: A narrative review was conducted through targeted PubMed and Embase searches using disease- and gene-related keywords. Studies were prioritized based on predefined conceptual criteria, including clinical relevance, strength and replication of genetic associations, and availability of functional or translational evidence. Conclusions: This synthesis brings together the latest genetic insights into pediatric ILDs and their clinical implications. Integrating genomic data into clinical practice may enable earlier diagnosis, tailored follow-up, individualized therapeutic strategies, and more informed genetic counseling. However, important challenges remain, including incomplete genotype–phenotype correlations and limited functional validation for several disease-associated genes, which currently constrain full clinical translation.

Background: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders characterized by variable degrees of inflammation and fibrosis affecting the pulmonary interstitium. Advances in molecular biology and genetics have greatly expanded our understanding of ILD pathogenesis, revealing novel mechanisms and supporting the development of precision medicine approaches. Genetic insights: Genetic factors play a pivotal role in ILD heterogeneity, influencing disease onset, severity, and progression. To date, more than 30 genes with different inheritance patterns (autosomal dominant, recessive, or X-linked) have been associated to ILDs. These genes are primarily involved in surfactant metabolism, telomere mainte-nance, immune regulation, and epithelial repair. Recent evidence also implicates genes encoding aminoacyl-tRNA synthetases. This review summarises the main genetic al-terations underlying ILD pathogenesis and discusses their impact on diagnostic and therapeutic approaches, highlighting how identification of disease-causing variants can improve diagnostic accuracy, refine prognostic assessment, and inform recurrence risk. Methods: A narrative review was conducted through targeted PubMed and Embase searches using disease- and gene-related keywords. Eligible publications included narrative and systematic reviews, meta-analyses, case series, prospective studies, society guidelines, and peer-reviewed editorials. Conclusions: This synthesis brings together the latest genetic insights into pediatric ILDs and their clinical implications. Integrating genomic data into clinical practice may enable earlier diagnosis, tailored follow-up, individualized therapeutic strategies, and more informed genetic counseling. Collectively, these advances hold promise for better out-comes in children affected by ILDs.