Sabrina Busciglio

Nephronophthisis type 20 (NPHP20; MIM #617271) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in MAPKBP1. Although traditionally considered a kidney-restricted disorder, recent findings suggest that MAPKBP1-related disease may be associated with a broader spectrum of extrarenal manifestations. However, the available evidence remains fragmented across gene-discovery studies, family reports, diagnostic sequencing cohorts, and functional investigations. This systematic review aimed to characterize the extrarenal manifestations of MAPKBP1-related disease and estimate their frequency. A secondary objective was to describe the spectrum of pathogenic or likely pathogenic MAPKBP1 variants and integrate clinical findings with current mechanistic models. Studies were eligible if they reported at least one patient with biallelic MAPKBP1 variants and provided clinical information relevant to the phenotype. PubMed, Embase, ClinVar, and Google Scholar were systematically searched from inception to August 2026. The methodological quality and risk of bias of included reports were assessed using the appropriate Joanna Briggs Institute (JBI) critical appraisal tools. All included reports were judged to be of high or moderate methodological quality. Only one paper was considered at high risk of bias, while the remaining articles or database entries had a moderate or low risk of bias. ClinVar entries were evaluated separately, with additional information obtained from the respective submitters when required. Clinical and molecular data were extracted and descriptively synthesized across included reports. The frequency of individual extrarenal manifestations was calculated based on the total number of identified patients while considering possible reporting biases. The search identified 154 records, including duplicates. After deduplication, 100 records underwent title and abstract screening and 32 full-text reports were assessed for eligibility. Nine articles met the inclusion criteria, comprising 16 patients; three additional patients were identified through ClinVar, yielding a total of 19 patients with MAPKBP1-related nephronophthisis included in the analysis. Most patients presented with at least one extrarenal manifestation, predominantly involving the skeletal system. Scoliosis was the most frequently reported extrarenal feature, occurring in eight of 19 genetically eligible patients. Other reported manifestations included short stature, patellar subluxation, long fingers or feet, craniofacial dysmorphisms, and cardiovascular abnormalities. The identified pathogenic or likely pathogenic MAPKBP1 variants were predominantly stop-gain, splice-site, and frameshift variants. The evidence was limited by the rarity of MAPKBP1-related disease, the small number of reported patients, heterogeneity in clinical assessment and reporting, and the predominance of observational and case-based evidence. This systematic review supports an expanding extrarenal phenotypic spectrum of MAPKBP1-related nephronophthisis, with skeletal abnormalities (e.g., scoliosis) representing a prominent feature. Further systematic phenotyping and genotyping of affected individuals are warranted to formally suggest multidisciplinary surveillance, to clarify genotype–phenotype correlations and to investigate the mechanisms underlying extrarenal disease. Registration: The review was prospectively registered in PROSPERO (CRD420261429078).

Brunner syndrome is a rare X-linked neurodevelopmental disorder caused by loss-of-function (LOF) variants in the monoamine oxidase A gene (MAOA), which encodes monoamine oxidase A, a key enzyme involved in the degradation of monoamine neurotransmitters such as serotonin, norepinephrine, and epinephrine. Impaired MAOA activity leads to abnormal monoamine accumulation and disruption of monoaminergic signalling, resulting in intellectual disability and behavioural dysregulation. Here, we systematically summarize the molecular landscape and report a genotype-driven diagnosis of MAOA deficiency in a patient presenting with intellectual disability and no reported family history. Clinical exome sequencing (cES) identified a novel splice-site variant in the MAOA gene that had not been detected by first-line diagnostic approaches. Functional analysis of patient-derived mRNA demonstrated intron 8 retention leading to a premature stop codon, consistent with a LOF mechanism. Based on the molecular diagnosis, the patient received treatment with serotonin antagonist and reuptake inhibitor (SARI) class medication, which was associated with improvement in social behaviour and sleep disturbances. Notably, to the best of our knowledge, this represents the first reported use of SARI therapy in MAOA deficiency. Although SARI therapy in this condition remains off-label, this observation provides preliminary evidence suggesting a potential therapeutic benefit. Our findings expand the mutational spectrum of the MAOA gene and highlight the importance of molecular diagnosis driving personalized management in rare neurogenetic disorders.

Neurofibromatosis type 1 (NF1) predisposes to a spectrum of peripheral nerve sheath tumors, ranging from benign plexiform neurofibromas (PN) to atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBP) and malignant peripheral nerve sheath tumors (MPNST). Tumorigenesis follows a multistep molecular cascade initiated by biallelic NF1 inactivation, followed by CDKN2A loss and disruption of the Polycomb Repressive Complex 2 (PRC2). These events guide chromatin remodeling, widespread epigenetic dysregulation, and activation of oncogenic pathways such as RAS/MAPK and PI3K/AKT. Here, we integrate genomic, transcriptomic, and epigenomic studies to delineate the molecular trajectories underlying tumor progression and to define promising biomarkers for the early detection of malignant transformation. Emerging liquid biopsy approaches, based on circulating tumor DNA (ctDNA) analyses, reveal distinctive copy number variations (CNVs) and methylation patterns that mirror tissue-derived profiles, enabling the detection of malignant transformation. Together, these findings support a model in which cumulative genetic and epigenetic alterations drive the PN–ANNUBP–MPNST continuum. They also underscore the value of multi-omics and liquid biopsy-based strategies to improve early diagnosis, patient risk stratification, and personalized management of NF1-associated tumors, thereby advancing precision medicine in this complex disease spectrum.

Darier′s disease (DD) is a rare, autosomal dominant genodermatosis caused by pathogenic variants in the ATP2A2 gene, which encodes the SERCA2 protein, an endoplasmic reticulum ATPase Ca²⁺ transporter. These mutations impair the intracellular calcium homeostasis leading to increased protein misfolding, endoplasmic reticulum (ER) stress response, and the activation of the unfolded protein response (UPR), culminating in keratinocyte apoptosis and anomalies in interfollicular epidermal stratification. Clinically, the disease is characterized by the presence of skin lesions with hyperkeratotic papules and an increased susceptibility to inflammatory reactions, bacterial and viral infections. The histological hallmarks include acantholysis, dyskeratosis, and increased apoptotic keratinocytes, referred to as “corp ronds”. The SERCA2b isoform is expressed not only in the epidermis but it is present ubiquitously in all tissues, suggesting that its alteration may have multi-organ effects. The review aims to provide a broad overview of the pathology, from intracellular dysfunction to the clinical manifestations, elucidating the molecular effects of SERCA2 variants found in DD patients and exploring the potential cell signaling pathways that may contribute to disease progression. Beginning with an examination of the cellular alterations, our work then shifts to exploring their impact in an organ-specific context, providing insights into new potential therapeutic strategies tailored to clinical manifestations.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder characterized by the predisposition to develop tumors such as malignant peripheral nerve sheath tumors (MPNSTs) which represents the primary cause of death for NF1-affected patients. Regardless of the high incidence and mortality, the molecular mechanisms underneath MPNST growth and metastatic progression remain poorly understood. In this proof-of-concept study, we performed somatic whole-exome sequencing (WES) to profile the genomic alterations in four samples from a patient with NF1-associated MPNST, consisting of a benign plexiform neurofibroma, a primary MPNST, and metastases from lung and skin tissues. By comparing genomic patterns, we identified a high level of variability across samples with distinctive genetic changes which allow for the definition of profiles of the early phase with respect to the late metastatic stages. Pathogenic and likely pathogenic variants were abundant in the primary tumor, whereas the metastatic samples exhibited a high level of copy-number variations (CNVs), highlighting a possible genomic instability in the late phases. The most known MPNST-related genes, such as TP53 and SUZ12, were identified in CNVs observed within the primary tumor. Pathway analysis of altered early genes in MPNST pointed to a potential role in cell motility, division and metabolism. Moreover, we employed survival analysis with the TCGA sarcoma genomic dataset on 262 affected patients, in order to corroborate the predictive significance of the identified early and metastatic MPNST driver genes. Specifically, the expression changes related to the mutated genes, such as in RBMX, PNPLA6 and AGAP2, were associated with reduced patient survival, distinguishing them as potential prognostic biomarkers. This study underlines the relevance of integrating genomic results with clinical information for early diagnosis and prognostic understanding of tumor aggressiveness.