sara bertuzzo

Scopus Publications

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, et al.
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.
Further evidence supporting the role of GTDC1 in glycine metabolism and neurodevelopmental disorders
Edoardo Errichiello, Mauro Lecca, Chiara Vantaggiato, Zoraide Motta, Nicoletta Zanotta, et al.
European Journal of Human Genetics, 2024
Copy number variants (CNVs) represent the genetic cause of about 15–20% of neurodevelopmental disorders (NDDs). We identified a ~67 kb de novo intragenic deletion on chromosome 2q22.3 in a female individual showing a developmental encephalopathy characterised by epilepsy, severe intellectual disability, speech delay, microcephaly, and thin corpus callosum with facial dysmorphisms. The microdeletion involved exons 5-6 of GTDC1, encoding a putative glycosyltransferase, whose expression is particularly enriched in the nervous system. In a previous study, a balanced de novo translocation encompassing GTDC1 was reported in a male child with global developmental delay and delayed speech and language development. Based on these premises, we explored the transcriptomic profile of our proband to evaluate the functional consequences of the novel GTDC1 de novo intragenic deletion in relation to the observed neurodevelopmental phenotype. RNA-seq on the proband’s lymphoblastoid cell line (LCL) showed expression changes of glycine/serine and cytokine/chemokine signalling pathways, which are related to neurodevelopment and epileptogenesis. Subsequent analysis by ELISA (enzyme-linked immunosorbent assay) and HPLC (high-performance liquid chromatography) revealed increased levels of glycine in the proband’s LCL and serum compared to matched controls. Given that an increased level of glycine has been observed in the plasma samples of individuals with Rett syndrome, a condition sharing epilepsy, microcephaly, and intellectual disability with our proband, we proposed that the GTDC1 downregulation is implicated in neurodevelopmental impairment by altering glycine metabolism. Furthermore, our findings expanded the phenotypic spectrum of the novel GTDC1-related condition, including microcephaly and epilepsy among relevant clinical features.
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, et al.
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.
Targeted next-generation sequencing identifies the disruption of the SHANK3 and RYR2 genes in a patient carrying a de novo t(1;22)(q43;q13.3) associated with signs of Phelan-McDermid syndrome
Maria Clara Bonaglia, Sara Bertuzzo, Anna Maria Ciaschini, Giancarlo Discepoli, Lucia Castiglia, et al.
Molecular Cytogenetics, 2020
Background It has been known for more than 30 years that balanced translocations, especially if de novo, can associate with congenital malformations and / or neurodevelopmental disorders, following the disruption of a disease gene or its cis-regulatory elements at one or both breakpoints. Case presentation We describe a 10-year-old girl with a non-specific neurodevelopmental disorder characterized by moderate intellectual disability (ID), gross motor clumsiness, social and communication deficits. She carries a de novo reciprocal translocation between chromosomes 1q43 and 22q13.3, the latter suggesting the involvement of SHANK3. Indeed, its haploinsufficiency associates with Phelan-McDermid Syndrome, whose main symptoms are characterized by global developmental delay and absent or severely delayed expressive speech. A deep molecular approach, including next-generation sequencing of SHANK3 locus, allowed demonstrating the breakage of RYR2 and SHANK3 on the derivative chromosomes 1 and 22 respectively, and the formation of two fusion genes SHANK3-RYR2 and RYR2-SHANK3 with concomitant cryptic deletion of 3.6 and 4.1 kilobases at translocation junction of both derivatives chromosomes 22 and 1, respectively. Conclusions Although the interruption of SHANK3 accounts for the patient’s psychomotor retardation and autism-like behavior, we do not exclude that the interruption of RYR2 may also have a role on her disorder, or result in further pathogenicity in the future. Indeed, RYR2 that has a well-established role in the etiology of two autosomal dominant adulthood cardiac disorders (#600996 and #604772) is also expressed in the brain (cerebellum, hippocampus, and cerebral cortex) and about half of RYR2 mutation carriers present late onset primary generalized epilepsy without cardiac arrhythmogenic disorders. Moreover, RYR2 variants have also been sporadically reported in individuals with early onset schizophrenia or ID, and its constraint values suggest intolerance to loss-of-function. This study not only confirms the usefulness of the molecular mapping of de novo balanced rearrangements in symptomatic individuals, but also underscores the need for long-term clinical evaluation of the patients, for better evaluating the pathogenicity of the chromosomal breakpoints.
Assigning single clinical features to their disease-locus in large deletions: The example of chromosome 1q23-25 deletion syndrome
Marco Fichera, Lucia Saccuzzo, Sara Bertuzzo, Susan Marelli, Anna Cavallini, et al.
Journal of Translational Genetics and Genomics, 2020
Aim: Assigning a disease-locus within the shortest regions of overlap (SRO) shared by deleted/duplicated subjects presenting this disease is a robust mapping approach, although the presence of different malformation traits and their attendance only in a part of the affected subjects can hinder the interpretation. To overcome the problem of incomplete penetrance, we developed an algorithm that we applied to the deletion region 1q23.3-q25, which contains three SROs, each contributing to the abnormal phenotype without clearly distinguishing between the different malformations. We describe six new subjects, including a healthy father and his daughter, with 1q23.3-q25 deletion of different sizes. The aim of this study was to correlate specific abnormal traits to the haploinsufficiency of specific gene/putative regulatory elements. Methods: Merging cases with those in the literature, we considered four traits, namely intellectual disability (ID), microcephaly, short-hands/feet, and brachydactyly, and conceived a mathematical model to predict with what probability the haploinsufficiency of a specific portion of the deletion region is associated with one of the four
De novo unbalanced translocations have a complex history/aetiology
Maria Clara Bonaglia, Nehir Edibe Kurtas, Edoardo Errichiello, Sara Bertuzzo, Silvana Beri, et al.
Human Genetics, 2018
Chromothripsis and ring chromosome 22: A paradigm of genomic complexity in the Phelan-McDermid syndrome (22q13 deletion syndrome)
Nehir Kurtas, Filippo Arrigoni, Edoardo Errichiello, Claudio Zucca, Cristina Maghini, et al.
Journal of Medical Genetics, 2018
IntroductionPhelan-McDermid syndrome (PMS) is caused bySHANK3haploinsufficiency. Its wide phenotypic variation is attributed partly to the type and size of 22q13 genomic lesion (deletion, unbalanced translocation, ring chromosome), partly to additional undefined factors. We investigated a child with severe global neurodevelopmental delay (NDD) compatible with her distal 22q13 deletion, complicated by bilateral perisylvian polymicrogyria (BPP) and urticarial rashes, unreported in PMS.MethodsFollowing the cytogenetic and array-comparative genomic hybridization (CGH) detection of a r(22) withSHANK3deletion and two upstream duplications, whole-genome sequencing (WGS) in blood and whole-exome sequencing (WES) in blood and saliva were performed to highlight potential chromothripsis/chromoanagenesis events and any possible BPP-associated variants, even in low-level mosaicism.ResultsWGS confirmed the deletion and highlighted inversion and displaced order of eight fragments, three of them duplicated. The microhomology-mediated insertion of partialAlu-elements at one breakpoint junction disrupted the topological associating domain joiningNFAM1to the transcriptional coregulatorTCF20. WES failed to detect BPP-associated variants.ConclusionsAlthough we were unable to highlight the molecular basis of BPP, our data suggest thatSHANK3haploinsufficiency andTCF20misregulation, both associated with intellectual disability, contributed to the patient’s NDD, whileNFAM1interruption likely caused her skin rashes, as previously reported. We provide the first example of chromoanasynthesis in a constitutional ring chromosome and reinforce the growing evidence that chromosomal rearrangements may be more complex than estimated by conventional diagnostic approaches and affect the phenotype by global alteration of the topological chromatin organisation rather than simply by deletion or duplication of dosage-sensitive genes.
Partial deletion of DEPDC5 in a child with focal epilepsy
Maria Clara Bonaglia, Roberto Giorda, Roberta Epifanio, Sara Bertuzzo, Susan Marelli, et al.
Epilepsia Open, 2016
We report on a child, aged 47/12 years, with borderline intelligence quotient, normal brain magnetic resonance imaging, and focal epilepsy. The polysomnographic electroencephalogram recording revealed asynchronous central spikes at both brain hemispheres resembling the features observed in focal idiopathic epileptic syndromes. Array comparative genomic hybridization analysis revealed a 32‐kb partial deletion of the DEP domain‐containing protein 5 (DEPDC5) gene, involved in a wide spectrum of inherited focal epileptic syndromes. The parental origin of the deletion could not be fully ascertained because the pregnancy had been achieved through anonymous egg donation and insemination by intracytoplasmic sperm injection. However, we demonstrate that the deletion, shared by all alternatively spliced isoforms of DEPDC5, produces a transcript presumably generating a DEPDC5 protein missing the entire DEP domain. Our findings suggest that partial deletion of DEPDC5 may be sufficient to cause the focal epilepsy in our patient, highlighting the importance of the DEP domain in DEPDC5 function. This study expands the phenotypic spectrum of DEPDC5 to sporadic forms of focal idiopathic epilepsy and underscores the fact that partial deletions, albeit probably very rare, are part of the genetic spectrum of DEPDC5 mutations.
Genotype-phenotype relationship in a child with 2.3Mb de novo interstitial 12p13.33-p13.32 deletion
Isabella Fanizza, Sara Bertuzzo, Silvana Beri, Elisabetta Scalera, Angelo Massagli, et al.
European Journal of Medical Genetics, 2014
8q12 microduplication including CHD7: Clinical report on a new patient with Duane retraction syndrome type 3
Anna Baroncini, Sara Bertuzzo, Rita Quarantini, Paolo Ricciardelli, Roberto Giorda, et al.
Molecular Cytogenetics, 2013
Background A novel multiple congenital anomalies syndrome has been recently identified in four patients carrying a 8q12 microduplication sharing the smallest region of overlap (SRO, size 1.6 Mb) including five genes CA8, ASPH, RAB2B, CLVS1 and CDH7. The phenotype is mainly characterized by neurodevelopmental delay, heart defects, facial features and Type 1 Duane anomaly. Increasing dosage of CDH7 was proposed to be responsible for the recurrent pattern of MCA. Results High resolution array-CGH analysis identified a 4.2 Mb de novo interstitial duplication of the 8q12.1-q12.3 chromosome region in a boy with developmental delay, dysmorphic features, type 3 Duane anomaly. This duplication includes several genes and spans the SRO. Discussion The present case represents a further patient with an interstitial duplication of chromosome 8q12 and several shared clinical features. Although more cases are needed to delineate the full-blown phenotype of 8q12 duplication syndrome, published data and present observations suggest that it results in a clinically recognizable phenotype. The presence of Duane anomaly in four out of five described patients with a 8q12 duplication definitely rules against the possibility of its being a chance finding unrelated to the imbalance and points toward a pathogenic role. Gene content analysis of the duplicated region and review of the literature suggest that gain-of-dosage of the CHD7 gene may be a good candidate for the main clinical features of the syndrome.