Laura Pignata

University of Campania "Luigi Vanvitelli"

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Andrea Riccio

University of Campania "Luigi Vanvitelli"

Angela Sparago

University of Campania "Luigi Vanvitelli"

Flavia Cerrato

University of Campania "Luigi Vanvitelli"

Maria Vittoria Cubellis

University of Naples Federico II

Massimo Carella

Casa Sollievo della Sofferenza

Orazio Palumbo

Casa Sollievo della Sofferenza

Ankit Verma

Wellcome/Cancer Research UK Gurdon Institute

Silvia Russo

IRCCS Istituto Auxologico Italiano

Rosita Del Prete

Toscana Life Sciences

Luciano Calzari

IRCCS Istituto Auxologico Italiano

Cooperative Institutions

University of Naples Federico II

Federico II University Hospital

Istituti di Ricovero e Cura a Carattere Scientifico

University of Campania "Luigi Vanvitelli"

Karolinska Institutet

Copenhagen University Hospital

Rigshospitalet

Washington Center

University of Washington

University of Copenhagen

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Mosaic Segmental and Whole-Chromosome Upd(11)mat in Silver-Russell Syndrome

Genes (2021)

Laura Pignata Angela Sparago Orazio Palumbo Elena Andreucci Elisabetta Lapi

Molecular defects altering the expression of the imprinted genes of the 11p15.5 cluster are responsible for the etiology of two congenital disorders characterized by opposite growth disturbances, Silver–Russell syndrome (SRS), associated with growth restriction, and Beckwith–Wiedemann syndrome (BWS), associated with overgrowth. At the molecular level, SRS and BWS are characterized by defects of opposite sign, including loss (LoM) or gain (GoM) of methylation at the H19/IGF2:intergenic differentially methylated region (H19/IGF2:IG-DMR), maternal or paternal duplication (dup) of 11p15.5, maternal (mat) or paternal (pat) uniparental disomy (upd), and gain or loss of function mutations of CDKN1C. However, while upd(11)pat is found in 20% of BWS cases and in the majority of them it is segmental, upd(11)mat is extremely rare, being reported in only two SRS cases to date, and in both of them is extended to the whole chromosome. Here, we report on two novel cases of mosaic upd(11)mat with SRS phenotype. The upd is mosaic and isodisomic in both cases but covers the entire chromosome in one case and is restricted to 11p14.1-pter in the other case. The segmental upd(11)mat adds further to the list of molecular defects of opposite sign in SRS and BWS, making these two imprinting disorders even more specular than previously described.

Uniparental disomy

Beckwith–Wiedemann syndrome

Genomic Imprinting

10.3390/genes12040581

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Citations (7)

Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance

Clinical Epigenetics (2020)

Maria Vittoria Cubellis Laura Pignata Ankit Verma Angela Sparago Rosita Del Prete

Abstract Background PADI6 is a component of the subcortical maternal complex, a group of proteins that is abundantly expressed in the oocyte cytoplasm, but is required for the correct development of early embryo. Maternal-effect variants of the subcortical maternal complex proteins are associated with heterogeneous diseases, including female infertility, hydatidiform mole, and imprinting disorders with multi-locus imprinting disturbance. While the involvement of PADI6 in infertility is well demonstrated, its role in imprinting disorders is less well established. Results We have identified by whole-exome sequencing analysis four cases of Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance whose mothers are carriers of PADI6 variants. In silico analysis indicates that these variants result in loss of function, and segregation analysis suggests they act as either recessive or dominant-negative maternal-effect mutations. Genome-wide methylation analysis revealed heterogeneous and extensively altered methylation profiles of imprinted loci in the patients, including two affected sisters, but not in their healthy siblings. Conclusion Our results firmly establish the role of PADI6 in imprinting disorders. We report loss-of-function maternal-effect variants of PADI6 that are associated with heterogeneous multi-locus imprinting disturbances in the progeny. The rare finding of two siblings affected by Beckwith-Wiedemann syndrome suggests that in some cases, familial recurrence risk of these variants may be high. However, the heterogeneous phenotypes of the other pedigrees suggest that altered oocyte PADI6 function results in stochastic maintenance of methylation imprinting with unpredictable consequences on early embryo health.

Imprinting (psychology)

Genomic Imprinting

Beckwith–Wiedemann syndrome

Pedigree chart

Loss function

10.1186/s13148-020-00925-2

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Citations (50)

MOESM7 of The phenotypic variations of multi-locus imprinting disturbances associated with maternal-effect variants of NLRP5 range from overt imprinting disorder to apparently healthy phenotype

Figshare (2019)

Angela Sparago Ankit Verma Maria Grazia Patricelli Laura Pignata Silvia Russo

Additional file 7: Table S3. Methylation levels of imprinted DMRs in individuals with maternal NLRP5 variants.

Imprinting (psychology)

Genomic Imprinting

10.6084/m9.figshare.11358134

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Citations (0)

Epigenetics: An opportunity to shape innate and adaptive immune responses

Immunology (2022)

Antonietta Liotti Anne Lise Ferrara Stefania Loffredo Maria Rosaria Galdiero Gilda Varricchi

Epigenetics connects genetic and environmental factors: it includes DNA methylation, histone post-translational modifications and the regulation of chromatin accessibility by non-coding RNAs, all of which control constitutive or inducible gene transcription. This plays a key role in harnessing the transcriptional programs of both innate and adaptive immune cells due to its plasticity and environmental-driven nature, piloting myeloid and lymphoid cell fate decisions with no change in their genomic sequence. In particular, epigenetic marks at the site of lineage-specific transcription factors and maintenance of cell type-specific epigenetic modifications, referred to as 'epigenetic memory', dictate cell differentiation, cytokine production and functional capacity following repeated antigenic exposure in memory T cells. Moreover, metabolic and epigenetic reprogramming occurring during a primary innate immune response leads to enhanced responses to secondary challenges, a phenomenon known as 'trained immunity'. Here, we discuss how stable and dynamic epigenetic states control immune cell identity and plasticity in physiological and pathological conditions. Dissecting the regulatory circuits of cell fate determination and maintenance is of paramount importance for understanding the delicate balance between immune cell activation and tolerance, in healthy conditions and in autoimmune diseases.

Reprogramming

Cell fate determination

Innate lymphoid cell

10.1111/imm.13571

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Citations (25)

Beckwith-Wiedemann syndrome and twinning: case report and brief review of literature

The Italian Journal of Pediatrics/Italian journal of pediatrics (2023)

Pierandrea Elefante Beatrice Spedicati Flavio Faletra Laura Pignata Flavia Cerrato

Abstract Background Beckwith-Wiedemann syndrome (BWS, OMIM #130,650) is a pediatric overgrowth disorder involving a predisposition to tumor development. Although the clinical management of affected patients is well established, it is less clear how to handle with the cases of siblings of affected patients, since the prevalence of the condition in twins (1:1000) is ten times higher than in singletones (1:10000). Case presentation We report the case of a premature twin patient who during her follow-up develops a clinical phenotype compatible with BWS, genetically confirmed in blood. However, the methylation alteration characteristic of the condition was also found in the almost phenotypically normal sibling, making it challening her management. Conclusion Through our case report we highlight how the diagnosis of BWS can be made without any prenatal suspicion and we propose a review of the literature on how to manage siblings of affected patients in twinning situation.

Beckwith–Wiedemann syndrome

Clinical phenotype

10.1186/s13052-023-01530-8

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Citations (1)

MOESM8 of The phenotypic variations of multi-locus imprinting disturbances associated with maternal-effect variants of NLRP5 range from overt imprinting disorder to apparently healthy phenotype

Figshare (2019)

Angela Sparago Ankit Verma Maria Grazia Patricelli Laura Pignata Silvia Russo

Additional file 8: Table S4. Sex and age information of controls.

Imprinting (psychology)

Genomic Imprinting

10.6084/m9.figshare.11358143

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Citations (0)

Understanding the Variability of 22q11.2 Deletion Syndrome: The Role of Epigenetic Factors

Genes (2024)

Francesca Cillo Emma Coppola Federico Habetswallner Francesco Cecere Laura Pignata

Initially described as a triad of immunodeficiency, congenital heart defects and hypoparathyroidism, 22q11.2 deletion syndrome (22q11.2DS) now encompasses a great amount of abnormalities involving different systems. Approximately 85% of patients share a 3 Mb 22q11.2 region of hemizygous deletion in which 46 protein-coding genes are included. However, the hemizygosity of the genes of this region cannot fully explain the clinical phenotype and the phenotypic variability observed among patients. Additional mutations in genes located outside the deleted region, leading to “dual diagnosis”, have been described in 1% of patients. In some cases, the hemizygosity of the 22q11.2 region unmasks autosomal recessive conditions due to additional mutations on the non-deleted allele. Some of the deleted genes play a crucial role in gene expression regulation pathways, involving the whole genome. Typical miRNA expression patterns have been identified in 22q11.2DS, due to an alteration in miRNA biogenesis, affecting the expression of several target genes. Also, a methylation epi-signature in CpG islands differentiating patients from controls has been defined. Herein, we summarize the evidence on the genetic and epigenetic mechanisms implicated in the pathogenesis of the clinical manifestations of 22q11.2 DS. The review of the literature confirms the hypothesis that the 22q11.2DS phenotype results from a network of interactions between deleted protein-coding genes and altered epigenetic regulation.

DiGeorge syndrome

TBX1

10.3390/genes15030321

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Citations (4)

Clinical and molecular characterization of patients affected by Beckwith‐Wiedemann spectrum conceived through assisted reproduction techniques

Clinical Genetics (2022)

Diana Carli Matteo Operti Silvia Russo Guido Cocchi Donatella Milani

The prevalence of Beckwith-Wiedemann spectrum (BWSp) is tenfold increased in children conceived through assisted reproductive techniques (ART). More than 90% of ART-BWSp patients reported so far display imprinting center 2 loss-of-methylations (IC2-LoM), versus 50% of naturally conceived BWSp patients. We describe a cohort of 74 ART-BWSp patients comparing their features with a cohort of naturally conceived BWSp patients, with the ART-BWSp patients previously described in literature, and with the general population of children born from ART. We found that the distribution of UPD(11)pat was not significantly different in ART and naturally conceived patients. We observed 68.9% of IC2-LoM and 16.2% of mosaic UPD(11)pat in our ART cohort, that strongly differ from the figure reported in other cohorts so far. Since UPD(11)pat likely results from post-fertilization recombination events, our findings allows to hypothesize that more complex molecular mechanisms, besides methylation disturbances, may underlie BWSp increased risk in ART pregnancies. Moreover, comparing the clinical features of ART and non-ART BWSp patients, we found that ART-BWSp patients might have a milder phenotype. Finally, our data show a progressive increase in the prevalence of BWSp over time, paralleling that of ART usage in the last decades.

Beckwith–Wiedemann syndrome

10.1111/cge.14193

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Citations (9)

Additional file 1 of Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance

Figshare (2020)

Maria Vittoria Cubellis Laura Pignata Ankit Verma Angela Sparago Rosita Del Prete

Additional file 1: Table S1. Pathogenic variants of PADI6 and corresponding clinical phenotype.

Imprinting (psychology)

Beckwith–Wiedemann syndrome

Loss function

10.6084/m9.figshare.12956035