eliana salvo

Scopus Publications

Chromothriptic Translocation t(1;18): A Paradigm of Genomic Complexity in a Child with Normal Intellectual Development and Pyridoxine-Dependent Epilepsy
Raffaele Falsaperla, Eliana Salvo, Annamaria Sapuppo, Chiara Barberi, Vincenzo Sortino, Gaia Fusto, Roberta Rizzo, Xena Giada Pappalardo, Giovanni Corsello, Martino Ruggieri, Catia Romano, Lucia Saccuzzo, Marco Fichera, Maria Clara Bonaglia
Genes, 2025
Background: Pyridoxine-dependent epilepsy (PDE) is a rare disorder characterized by seizures resistant to conventional treatments but responsive to pyridoxine therapy. Typically caused by biallelic variants in ALDH7A1, PNPO, or PLPBP, a few patients present a similar clinical phenotype but without confirmed molecular diagnoses. We report a child with a 13-year PDE diagnosis and normal intellectual development, whose seizures recurred after pyridoxine withdrawal but resolved with reintroduction, despite unremarkable whole-exome sequencing results. Methods: Following negative results from WES, optical genome mapping (OGM) and whole-genome sequencing (WGS) were performed to highlight any potential structural variants involving known PDE-associated genes. Results: OGM and WGS revealed a recurrent 16p11.2 BP4-5 duplication, inherited from his healthy father, along with a de novo chromothripsis-type unbalanced t(1;18)(p22.3;q12.3), affecting several genes not currently associated with epilepsy (RIT2, PIK3C3, COL24A1, LRRC8D, DIPK1A, and DPYD), with RIT2 being a plausible candidate for the neurological phenotype due to its neuron-specific expression along with a likely reshuffling of topologically associating domains (TADs) involving SYT4, an epilepsy-candidate gene. Discussion: While the molecular data do not pinpoint a single gene or locus as the cause of seizures in this case, a key aspect of our patient’s phenotype is true pyridoxine dependence, rather than just pyridoxine responsiveness. We propose that the genomic complexity associated with the chromothriptic t(1;18) and the 16p11.2 BP4-5 duplication may create a unique metabolic environment in which pyridoxine-dependent pathways are disrupted through unconventional mechanisms. The preservation of cognitive function in our case has been observed in small groups of PDE patients, especially those diagnosed and treated early. This may indicate a distinct phenotypic subgroup that warrants further genetic investigation.
Constitutional copy number amplifications: rare or under-evaluated? Revisiting a 25-year-old cold case
Eliana Salvo, Romano Tenconi, Roberto Giorda, Sara Bertuzzo, Luca Cesana, Roberta Murru, Sabrina Giglio, Mana M. Mehrjouy, Niels Tommerup, Orsetta Zuffardi, Maria Clara Bonaglia
European Journal of Human Genetics, 2025
We reanalyzed through a cytogenomics approach a case published 20 years ago, describing a girl with developmental delay and epilepsy. Karyotype and FISH analysis showed a de novo 2.3 Mb terminal inverted-duplication at 8q24.3. The interpretation was inconsistent with the absence of a more distal deletion as expected for distal inverted duplications, and it was inconceivable to highlight rearrangements smaller than 5–10 Mb at that time. Chromosomal microarray (CMA), optical genome mapping (OGM), and short-read whole genome sequencing (srWGS) identified a complex configuration at 8q24.3, which resembles events like chromoanasynthesis or DUP-TRP/INV-DUP (duplication-triplication/inverted-duplication), both characterized by clustered duplications and triplications, some of which are inverted. In the EBV-line genes located in the amplified regions were overexpressed. Despite a more precise definition of the imbalance, we were unable to provide a clear-cut explanation for the proband’s clinical features.
Small Complex Rearrangement in HINT1-Related Axonal Neuropathy
Alessandra Tessa, Mariapaola Schifino, Eliana Salvo, Rosanna Trovato, Luca Cesana, Silvia Frosini, Rosa Pasquariello, Giada Sgherri, Roberta Battini, Maria Clara Bonaglia, Filippo Maria Santorelli, Guja Astrea
Genes, 2024
Background: Autosomal recessive inherited pathogenetic variants in the histidine triad nucleotide-binding protein 1 (HINT1) gene are responsible for an axonal Charcot-Marie-Tooth neuropathy associated with neuromyotonia, a phenomenon resulting from peripheral nerve hyperexcitability that causes a spontaneous muscle activity such as persistent muscle contraction, impaired relaxation and myokymias. Methods: Herein, we describe two brothers in whom biallelic HINT1 variants were identified following a multidisciplinary approach. Results: The younger brother came to our attention for clinical evaluation of moderate intellectual disability, language developmental delay, and some behavioral issues. His elder brother presented mild intellectual disability, hyperactivity, tiptoe walking, and gait ataxia. At first evaluation, motor impairment with frequent falls, pes cavus, and distal hyposthenia with reduced osteotendinous reflexes were found in both. Grip myotonic phenomenon was also noted. Blood tests revealed mildly elevated creatine kinase, and neurophysiology investigations revealed predominantly axonal polyneuropathy. Muscle MRI highlighted fibro-adipose infiltration, prevalent in the lower limbs. Gene panel testing detected a heterozygous HINT1 variant (c.355C>T/p.(Arg119Trp)) on the paternal allele. A further in-depth analysis using Integrative Genomics Viewer and Optical Genome Mapping led us to identify an additional variant in HINT1 represented by a complex rearrangement located in the region 5′UTR-exon 1-intron 1, not previously described. Conclusions: This complex rearrangement could have been overlooked if the clinical picture had not been evaluated as a whole (from a clinical, neurophysiological, and neuroimaging point of view). Neuropsychiatric manifestations (intellectual disability, hyperactivity, etc.) are part of the picture of HINT1-related neuromyotonia.
Case Report: Decrypting an interchromosomal insertion associated with Marfan’s syndrome: how optical genome mapping emphasizes the morbid burden of copy-neutral variants
Maria Clara Bonaglia, Eliana Salvo, Manuela Sironi, Sara Bertuzzo, Edoardo Errichiello, Teresa Mattina, Orsetta Zuffardi
Frontiers in Genetics, 2023
Optical genome mapping (OGM), which allows analysis of ultra-high molecular weight (UHMW) DNA molecules, represents a response to the restriction created by short-read next-generation-sequencing, even in cases where the causative variant is a neutral copy-number-variant insensitive to quantitative investigations. This study aimed to provide a molecular diagnosis to a boy with Marfan syndrome (MFS) and intellectual disability (ID) carrying a de novo translocation involving chromosomes 3, 4, and 13 and a 1.7 Mb deletion at the breakpoint of chromosome 3. No FBN1 alteration explaining his Marfan phenotype was highlighted. UHMW gDNA was isolated from both the patient and his parents and processed using OGM. Genome assembly was followed by variant calling and annotation. Multiple strategies confirmed the results. The 3p deletion, which disrupted ROBO2, (MIM*602431) included three copy-neutral insertions. Two came from chromosome 13; the third contained 15q21.1, including the FBN1 from intron-45 onwards, thus explaining the MFS phenotype. We could not attribute the ID to a specific gene variant nor to the reshuffling of topologically associating domains (TADs). Our patient did not have vesicular reflux-2, as reported by missense alterations of ROBO2 (VUR2, MIM#610878), implying that reduced expression of all or some isoforms has a different effect than some of the point mutations. Indeed, the ROBO2 expression pattern and its role as an axon-guide suggests that its partial deletion is responsible for the patient’s neurological phenotype. Conclusion: OGM testing 1) highlights copy-neutral variants that could remain invisible if no loss of heterozygosity is observed and 2) is mandatory before other molecular studies in the presence of any chromosomal rearrangement for an accurate genotype-phenotype relationship.
Case Report: A Novel Homozygous Missense Variant of FBN3 Supporting It Is a New Candidate Gene Causative of a Bardet–Biedl Syndrome–Like Phenotype
Maria Luce Genovesi, Barbara Torres, Marina Goldoni, Eliana Salvo, Claudia Cesario, Massimo Majolo, Tommaso Mazza, Carmelo Piscopo, Laura Bernardini
Frontiers in Genetics, 2022
Fibrillin proteins are extracellular matrix glycoproteins assembling into microfibrils. FBN1, FBN2, and FBN3 encode the human fibrillins and mutations in FBN1 and FBN2 cause connective tissue disorders called fibrillinopathies, affecting cardiovascular, dermal, skeletal, and ocular tissues. Recently, mutations of the less characterized fibrillin family member, FBN3, have been associated in a single family with Bardet–Biedl syndrome (BBS). Here, we report on a patient born from two first cousins and affected by developmental delay, cognitive impairment, obesity, dental and genital anomalies, and brachydactyly/syndactyly. His phenotype was very similar to that reported in the previous FBN3-mutated family and fulfilled BBS clinical diagnostic criteria, although lacking polydactyly, the most recurrent clinical feature, as the previous siblings described. A familial SNP-array and proband’s WES were performed prioritizing candidate variants on the sole patient’s runs of homozygosity. This analysis disclosed a novel homozygous missense variant in FBN3 (NM_032447:c.5434A&gt;G; NP_115823:p.Ile1812Val; rs115948457), inherited from the heterozygous parents. This study further supports that FBN3 is a candidate gene for a BBS-like syndrome characterized by developmental delay, cognitive impairment, obesity, dental, genital, and skeletal anomalies. Anyway, additional studies are necessary to investigate the exact role of the gene and possible interactions between FBN3 and BBS proteins.
Investigating microbial indicators of anthropogenic marine pollution by 16S and 18S High-Throughput Sequencing (HTS) library analysis
Maria Antonietta Buccheri, Eliana Salvo, Manuela Coci, Grazia M Quero, Luca Zoccarato, Vittorio Privitera, Giancarlo Rappazzo
FEMS Microbiology Letters, 2019
High-Throughput Sequencing technologies are providing unprecedented inventories of microbial communities in aquatic samples, offering an invaluable tool to estimate the impact of anthropogenic pressure on marine communities. In this case study, the Mediterranean touristic site of Aci Castello (Italy) was investigated by High-Throughput Sequencing of 16S and 18S rRNA genes. The sampling area falls within a Marine Protected Area and, notwithstanding, features an untreated urban wastewater discharge. Seawater samples were collected close to the wastewater output (COL) and at a second station about 400 m further off (PAN), before and after a summer increase in population. Prokaryotic communities clustered according to stations, rather than to seasons. While PAN showed a typical, not impacted, marine microbial composition, COL was consistently enriched in Epsilonproteobacteria and Firmicutes. Protist communities showed a peculiar clustering, as COL at springtime stood alone and was dominated by Ciliophora, while the other samples were enriched in Dinophyta. Analysis of alternative, detectable by High-Throughput Sequencing, microbial indicators, including both faecal- and sewage-associated, allowed uncovering the different sources of pollution in coastal and anthropogenically impacted marine ecosystems, underpinning the relevance of High-Throughput Sequencing-based screening as rapid and precise method for water quality management.
Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy
Marco Fichera, Pinella Failla, Lucia Saccuzzo, Martina Miceli, Eliana Salvo, Lucia Castiglia, Ornella Galesi, Lucia Grillo, Francesco Calì, Donatella Greco, Carmelo Amato, Corrado Romano, Maurizio Elia
Human Genetics, 2019
Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene (NM_016188:c.820C>T;p.Gln274*) coding for a subunit of the neuron-specific chromatin remodeling complex nBAF. To further support these findings, a targeted ACTL6B sequencing assay was performed on a cohort of 85 unrelated DEE individuals, leading to the identification of a homozygous missense variant (NM_016188:c.1045G>A;p.Gly349Ser) in a patient. This variant did not segregate in the unaffected siblings in this family and was classified as deleterious by several prediction softwares. Interestingly, in both families, homozygous patients shared a rather homogeneous phenotype. Very few patients with ACTL6B gene variants have been sporadically reported in WES cohort studies of patients with neurodevelopmental disorders and/or congenital brain malformations. However, the limited number of patients with incomplete clinical information yet reported in the literature did not allow to establish a strong gene–disease association. Here, we provide additional genetic and clinical data on three new cases that support the pathogenic role of ACTL6B gene mutation in a syndromic form of DEE.
Endosymbionts of entomopathogenic nematodes from south Italy: A phenotypic study
GIANCARLO RAPPAZZO, ELIANA SALVO, EUSTACHIO TARASCO, GIULIO PETRONIO PETRONIO, MARIA ANTONIETTA BUCCHERI, PIO MARIA FURNERI, VIRGINIA FUOCHI, MIRELLA CLAUSI
Redia, 2018
We examined different Xenorhabdusstrains (five of X. bovieniiand two of X. kozodoii), obtained from EPNisolates belonging to the genus Steinernema(S. feltiae, S. ichnusae, S. apuliae, S. vulcanicum) of different geographicorigin by both genotypic and phenotypic analysis. Common laboratory assays were done for traits such as antibioticresistance, haemolytic activity, lactose utilisation, biofilm production, chosen as the least selectable traits for EPN life-cycle, and thus as (presumably) neutral traits. As selective marker, the activity of the endosymbiont’s toxins was verified inan in vivoassay on G. mellonellalarvae. Genotyping done by 16S partial sequencing was used for identification purposes.Xenorhabdusbovieniiisolates showed a broad phenotypic spectrum; on the other hand, X. kozodoiishowed a less degreeof phenotypic variation, reduced ability of biofilm production and conspicuous β-galactosidase activity. However, all thestrains were able to kill G. mellonellalarvae with high efficiency.
Heme oxygenase-2/adiponectin protein-protein interaction in metabolic syndrome
Luca Vanella, Giovanni Li Volti, Salvatore Guccione, Giancarlo Rappazzo, Eliana Salvo, Morena Pappalardo, Stefano Forte, Michal L. Schwartzman, Nader G. Abraham
Biochemical and Biophysical Research Communications, 2013
Insulin resistance with adipose tissue dysfunction and dysregulation in the production and secretion of adipokines is one of the hallmarks of metabolic syndrome. We have previously reported that increased levels of the heme oxygenase (HO) system, HO-1/HO-2 results in increased levels of adiponectin. Despite documentation of the existence of the anti-inflammatory axis HO-adiponectin, a possible protein-protein interaction between HO and adiponectin has not been examined. Here, we investigated the existence of protein interactions between HO-2 and adiponectin in the maintenance of adipocyte function during metabolic syndrome by integrating phenotypic and in silico studies. Compared to WT animals, HO-2 null mice displayed an increase in both visceral and subcutaneous fat content and reduced circulating adiponectin levels. The decrease in adiponectin was reversed by upregulation of HO-1. HO-2 depletion was associated with increased adipogenesis in cultured mesenchymal stem cells (MSCs) and decreased adiponectin levels in the culture media. In addition, HO-1 siRNA decreased adiponectin release. HO-2 was found to bind to the monomeric form of adiponectin, according to poses and calculated energies. HO-2-adiponectin interactions were validated by the two-hybrid system assay. In conclusion, protein-protein interactions between HO-2 and adiponectin highlight the role of HO-2 as a molecular chaperone for adiponectin assembly, while HO-1 increases adiponectin levels. Thus, crosstalk between HO-2 and HO-1 could be manipulated in a therapeutic approach to ameliorate the deleterious effects of obesity and the metabolic syndrome.