Obesity represents a global medical and social challenge characterized by pathological accumulation of adipose tissue as a result of complex interactions among genetic, environmental, and epigenetic factors. Recent studies have highlighted the pivotal role of epigenetic mechanisms in the pathogenesis of this condition, including abnormal DNA methylation of metabolic genes, dysregulation of microRNAs, and chromatin remodeling. These modifications are reversible and can be modulated by dietary, behavioral, and pharmacological interventions. This review provides a comprehensive analysis of tissue-specific epigenetic alterations identified not only in adipocytes and hepatocytes but also in peripheral blood cells, offering promising opportunities for the development of novel diagnostic biomarkers and targeted epigenetic therapeutic strategies.

We report a case of SYNE1-associated autosomal recessive spinocerebellar ataxia (SCAR8) presenting with a complex multisystemic phenotype, including highly elevated creatine kinase levels and lower-leg muscle atrophy. In addition to identifying two novel pathogenic variants in the SYNE1 gene, whole-exome sequencing revealed three variants of uncertain significance in the DYSF gene. Electromyography and muscle magnetic resonance imaging indicated a neurogenic pattern of muscle involvement. These findings, along with the segregation analysis of the variants, allowed us to exclude DYSF-associated muscular dystrophy; however, we cannot entirely rule out the possibility that the DYSF gene variants may act as modifiers of the patient’s phenotype.

Obesity represents a global medical and social challenge characterized by pathological accumulation of adipose tissue as a result of complex interactions among genetic, environmental, and epigenetic factors. Recent studies have highlighted the pivotal role of epigenetic mechanisms in the pathogenesis of this condition, including aberrant DNA methylation of metabolic genes, dysregulation of microRNAs, and chromatin remodeling. These modifications are reversible and can be modulated by dietary, behavioral, and pharmacological interventions. This review provides a comprehensive analysis of tissue-specific epigenetic alterations identified not only in adipocytes and hepatocytes but also in peripheral blood cells, offering promising opportunities for the development of novel diagnostic biomarkers and targeted epigenetic therapeutic strategies.

Reverse transcription quantitative PCR (RT-qPCR) is widely used to quantify circulating microRNAs, but reliable interpretation depends on appropriate data normalization. In obesity research, selecting reference RNAs for measurements in whole blood, blood cells, plasma, and serum is challenging because of biological heterogeneity and preanalytical variability. This review summarizes normalization strategies used in RT-qPCR studies of blood-derived samples from participants with overweight or obesity. We examine commonly used endogenous reference RNAs, including U6 snRNA and miR-16-5p, and assess the rationale for their selection and the available validation evidence in relation to sample matrix and cohort characteristics. The review evaluates normalization practices and the quality and reporting of reference-RNA validation in obesity-related studies, with particular attention to the biological comparison being made. No candidate, algorithmic ranking, or fixed panel size is considered universally applicable. Candidate selection, the number of references, and the normalization scale should be justified for the intended comparison. The review provides practical guidance for designing and reporting validation of reference small non-coding RNAs and process controls in study cohorts with overweight or obesity, with recommendations qualified by the available evidence.

Background: ARCN1-related syndrome (short stature-micrognathia syndrome, SSMG; OMIM #617164) is an autosomal dominant disorder caused by loss-of-function variants in the ARCN1 gene, which encodes the δ-COP (COPD) subunit of the COPI coatomer complex. The condition is classically characterized by intrauterine growth restriction (IUGR), short stature with rhizomelic shortening, microcephaly, micrognathia, facial dysmorphism, and global developmental delay. Methods: Clinical examination, blood tests and genetic analysis were performed. Whole-exome sequencing and Sanger analysis were conducted, followed by bioinformatics analysis and ACMG-based variant interpretation to identify and characterize the pathogenic variant. Results: We report a male proband with a previously undescribed variant in the ARCN1 gene, presenting with an atypical phenotype. Notably, the patient lacked the classical syndromic features, including short stature, microcephaly, IUGR, and developmental delay. The predominant clinical manifestation was transient hepatic dysfunction occurring during febrile episodes, which resolved between acute events. On physical examination, rhizomelic shortening and dysmorphic facial features, including mild micrognathia, were found. Overall, identified symptoms were mild in severity, which may be associated with the variant’s location within the gene. Conclusions: We describe a novel likely pathogenic variant in the ARCN1 gene associated with a mild phenotype of SSMG. This case expands the phenotypic spectrum of ARCN1-related syndrome and highlights the importance of considering this diagnosis in patients with unexplained recurrent liver injury, even in the absence of classical syndromic features.

Background/Objectives: Bardet–Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy caused by variants in genes encoding components of the BBSome complex. Interpretation of rare variants in the BBS7 gene remains challenging, particularly for variants of uncertain significance. This study aimed to provide clinical and molecular genetic characterization of two siblings with a BBS phenotype harboring compound heterozygous variants in BBS7, including a previously undescribed missense variant. Methods: Two siblings (aged 11 and 8 years) presenting with obesity, postaxial polydactyly, retinal dystrophy, and cystic renal dysplasia were clinically evaluated. Whole-exome sequencing was performed in the proband, followed by segregation analysis within the family. Variant classification was conducted according to ACMG/AMP guidelines, integrating allele frequency data, in silico predictions, segregation evidence, and structural modeling. Results: Two heterozygous variants in the BBS7 gene (NM_176824.3) were identified in trans: a previously reported pathogenic frameshift variant, c.1967_1968delinsC, p.(Leu656ProfsTer18), and a missense variant, c.454T>C, p.(Cys152Arg), which, to the best of our knowledge, has not been previously reported in patients with Bardet–Biedl syndrome. The variant was extremely rare in population databases. Structural analysis suggested steric and electrostatic disruptions, including loss of a disulfide bond. Based on ACMG/AMP criteria, the variant was classified as likely pathogenic. Conclusions: This case supports the likely pathogenic classification of the c.454T>C, p.(Cys152Arg) variant. The findings highlight the importance of integrating clinical, genetic, and structural data for the interpretation of rare variants in BBS-associated genes.