Publications by authors named "Paola Grammatico"

153 Publications

Protein-protein interaction network analysis applied to DNA copy number profiling suggests new perspectives on the aetiology of Mayer-Rokitansky-Küster-Hauser syndrome.

Sci Rep 2021 Jan 11;11(1):448. Epub 2021 Jan 11.

Department of Experimental Medicine, Sapienza Università Di Roma, Viale del Policlinico, 155, 00161, Rome, Italy.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare disease, characterised by the aplasia of vagina and uterus in women with a 46,XX karyotype. Most cases are sporadic, but familial recurrence has also been described. Herein, we investigated an Italian cohort of 36 unrelated MRKH patients to explore the presence of pathogenic copy number variations (CNVs) by array-CGH and MLPA assays. On the whole, aberrations were found in 9/36 (25%) patients. Interestingly, one patient showed a novel heterozygous microduplication at Xp22.33, not yet described in MRKH patients, containing the PRKX gene. Moreover, a novel duplication of a specific SHOX enhancer was highlighted by MLPA. To predict the potential significance of CNVs in MRKH pathogenesis, we provided a network analysis for protein-coding genes found in the altered genomic regions. Although not all of these genes taken individually showed a clear clinical significance, their combination in a computational network highlighted that the most relevant biological connections are related to the anatomical structure development. In conclusion, the results described in the present study identified novel genetic alterations and interactions that may be likely involved in MRKH phenotype determination, so adding new insights into the complex puzzle of MRKH disease.
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http://dx.doi.org/10.1038/s41598-020-79827-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801512PMC
January 2021

Clinical presentation and molecular characterization of a novel patient with variant POC1A-related syndrome.

Clin Genet 2020 Dec 28. Epub 2020 Dec 28.

Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.

Biallelic pathogenic variants in POC1A result in SOFT (Short-stature, Onychodysplasia, Facial-dysmorphism, and hypoTrichosis) and variant POC1A-related (vPOC1A) syndromes. The latter, nowadays described in only two unrelated subjects, is associated with a restricted spectrum of variants falling in exon 10, which is naturally skipped in a specific POC1A mRNA. The synthesis of an amount of a POC1A isoform from this transcript in individuals with vPOC1A syndrome has been believed as the likely explanation for such a genotype-phenotype correlation. Here, we illustrate the clinical and molecular findings in a woman who resulted to be compound heterozygous for a recurrent frameshift variant in exon 10 and a novel variant in exon 9 of POC1A. Phenotypic characteristics of this woman included severe hyperinsulinemic dyslipidemia, acanthosis nigricans, moderate growth restriction, and dysmorphisms. These manifestations overlap the clinical features of the two previously published individuals with vPOC1A syndrome. RT-PCR analysis on peripheral blood and subsequent sequencing of the obtained amplicons demonstrated a variety of POC1A alternative transcripts that resulted to be expressed in the proband, in the healthy mother, and in controls. We illustrate the possible consequences of the two POC1A identified variants in an attempt to explain pleiotropy in vPOC1A syndrome.
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http://dx.doi.org/10.1111/cge.13911DOI Listing
December 2020

Exon-Trapping Assay Improves Clinical Interpretation of and Intronic Variants in Stickler Syndrome Type 2 and Otospondylomegaepiphyseal Dysplasia.

Genes (Basel) 2020 Dec 17;11(12). Epub 2020 Dec 17.

Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Foggia, Italy.

Stickler syndrome (SS) is a hereditary connective tissue disorder affecting bones, eyes, and hearing. Type 2 SS and the SS variant otospondylomegaepiphyseal dysplasia (OSMED) are caused by deleterious variants in and , respectively. In both genes, available database information indicates a high rate of potentially deleterious intronic variants, but published evidence of their biological effect is usually insufficient for a definite clinical interpretation. We report four previously unpublished intronic variants in (c.2241 + 5G>T, c.2809 - 2A>G, c.3168 + 5G>C) and (c.4392 + 1G>A) identified in type 2 SS/OSMED individuals. The pathogenic effect of these variants was first predicted in silico and then investigated by an exon-trapping assay. We demonstrated that all variants can induce exon in-frame deletions, which lead to the synthesis of shorter collagen XI α1 or 2 chains. Lacking residues are located in the α-triple helical region, which has a crucial role in regulating collagen fibrillogenesis. In conclusion, this study suggests that these alternative and transcripts might result in aberrant triple helix collagen. Our approach may help to improve the diagnostic molecular pathway of -related disorders.
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http://dx.doi.org/10.3390/genes11121513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766184PMC
December 2020

A Single Center Retrospective Review of Patients from Central Italy Tested for Melanoma Predisposition Genes.

Int J Mol Sci 2020 Dec 11;21(24). Epub 2020 Dec 11.

Laboratory of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, 00100 Rome, Italy.

Background: Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. CMM pathogenesis involves genetic and environmental factors. Recent studies have led to the identification of new genes involved in CMM susceptibility: beyond CDKN2A and CDK4, BAP1, POT1, and MITF were recently identified as potential high-risk melanoma susceptibility genes.

Objective: This study is aimed to evaluate the genetic predisposition to CMM in patients from central Italy.

Methods: From 1998 to 2017, genetic testing was performed in 888 cases with multiple primary melanoma and/or familial melanoma. Genetic analyses included the sequencing CDKN2A, CDK4, BAP1, POT1, and MITF in 202 cases, and of only CDKN2A and CDK4 codon 24 in 686 patients. By the evaluation of the personal and familial history, patients were divided in two clinical categories: "low significance" and "high significance" cases.

Results: 128 patients (72% belonging to the "high significance" category, 28% belonging to the "low significance" category) were found to carry a DNA change defined as pathogenic, likely pathogenic, variant of unknown significance (VUS)-favoring pathogenic or VUS.

Conclusions: It is important to verify the genetic predisposition in CMM patients for an early diagnosis of further melanomas and/or other tumors associated with the characterized genotype.
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http://dx.doi.org/10.3390/ijms21249432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763813PMC
December 2020

Koolen-de Vries syndrome in the first adulthood patient of Southern India ancestry.

Am J Med Genet A 2021 03 12;185(3):978-981. Epub 2020 Dec 12.

Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.

Koolen-de Vries syndrome (KdVS, MIM#610443) is a rare malformation condition mainly characterized by cognitive impairment in association with craniofacial and visceral anomalies. The core phenotype is caused by mutations in the chromatin remodeler KANSL1 (MSL1V1, KIAA1267, KAT8 Regulatory NSL Complex Subunit 1, MIM#612452), which maps to 17q21.31 critical genomic region (Koolen et al., Nature Genetics 2012;44:639-641). Considering its molecular basis, KdVS is included in the group of Developmental Disorders of Chromatin Remodeling (DDCRs), also termed chromatinopathies. We describe the first KdVS patient of Southern India ethnicity, harboring the typical de novo 17q21.31 microdeletion, including KANSL1. Observed facial features and congenital anomalies are in line with the already reported KdVS phenotype, suggesting that phenotypic features are consistent across different ethnicities.
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http://dx.doi.org/10.1002/ajmg.a.62006DOI Listing
March 2021

Comprehensive analysis of mitochondrial and nuclear DNA variations in patients affected by hemoglobinopathies: A pilot study.

PLoS One 2020 22;15(10):e0240632. Epub 2020 Oct 22.

Department of Medicine, Hematology, University of Perugia, Perugia, Italy.

The hemoglobin disorders are the most common single gene disorders in the world. Previous studies have suggested that they are deeply geographically structured and a variety of genetic determinants influences different clinical phenotypes between patients inheriting identical β-globin gene mutations. In order to get new insights into the heterogeneity of hemoglobin disorders, we investigated the molecular variations on nuclear genes (i.e. HBB, HBG2, BCL11A, HBS1L and MYB) and mitochondrial DNA control region. This pilot study was carried out on 53 patients belonging to different continents and molecularly classified in 4 subgroup: β-thalassemia (β+/β+, β0/β0 and β+/β0)(15), sickle cell disease (HbS/HbS)(20), sickle cell/β-thalassemia (HbS/β+ or HBS/β0)(10), and non-thalassemic compound heterozygous (HbS/HbC, HbO-Arab/HbC)(8). This comprehensive phylogenetic analysis provided a clear separation between African and European patients either in nuclear or mitochondrial variations. Notably, informing on the phylogeographic structure of affected individuals, this accurate genetic stratification, could help to optimize the diagnostic algorithm for patients with uncertain or unknown origin.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240632PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581000PMC
December 2020

A novel CDKN2A in-frame deletion associated with pancreatic cancer-melanoma syndrome.

Dermatol Online J 2020 Aug 15;26(8). Epub 2020 Aug 15.

Division/Laboratory of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome.

Pancreatic cancer-melanoma syndrome (PCMS) is an inherited condition in which mutation carriers have an increased risk of malignant melanoma and/or pancreatic cancer. About 30% of PCMS cases carry mutations in CDKN2A. This gene encodes several protein isoforms, one of which, known as p16, regulates the cell-cycle by interacting with CDK4/CDK6 kinases and with several non-CDK proteins. Herein, we report on a novel CDKN2A germline in-frame deletion (c.52_57delACGGCC) found in an Italian family with PCMS. By segregation analysis, the c.52_57delACGGCC was proven to segregate in kindred with cutaneous melanoma (CM), in kindred with CM and pancreatic cancer, and in a single case presenting only with pancreatic cancer. In the literature, duplication mapping in the same genic region has been already reported at the germline level in several unrelated CM cases as a variant of unknown clinical significance. A computational approach for studying the effect of mutational changes over p16 protein structure showed that both the deletion and the duplication of the c.52_57 nucleotides result in protein misfolding and loss of interactors' binding. In conclusion, the present results argue that the quantitative alteration of nucleotides c.52_57 has a pathogenic role in p16 function and that the c.52_57delACGGCC is associated with PCMS.
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August 2020

Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype.

Am J Hum Genet 2020 09 5;107(3):555-563. Epub 2020 Aug 5.

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes.
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http://dx.doi.org/10.1016/j.ajhg.2020.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477006PMC
September 2020

Answer to Letter to the Editor regarding the article "Striking phenotypic overlap between Nicolaides-Baraitser and Coffin-Siris syndromes in monozygotic twins with ARID1B intragenic deletion".

Eur J Med Genet 2020 10 20;63(10):103993. Epub 2020 Jun 20.

Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.

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http://dx.doi.org/10.1016/j.ejmg.2020.103993DOI Listing
October 2020

Further delineation of the neurodevelopmental phenotypic spectrum associated to 14q11.2 microduplication.

Neurol Sci 2020 12 11;41(12):3751-3753. Epub 2020 Jun 11.

Medical Genetics Laboratory, Clinical Genetics Division, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense 87, 00152, Rome, Italy.

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http://dx.doi.org/10.1007/s10072-020-04510-6DOI Listing
December 2020

A novel patient with White-Sutton syndrome refines the mutational and clinical repertoire of the POGZ-related phenotype and suggests further observations.

Am J Med Genet A 2020 07 2;182(7):1791-1795. Epub 2020 May 2.

Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.

A rare developmental delay (DD)/intellectual disability (ID) syndrome with craniofacial dysmorphisms and autistic features, termed White-Sutton syndrome (WHSUS, MIM#614787), has been recently described, identifying truncating mutations in the chromatin regulator POGZ (KIAA0461, MIM#614787). We describe a further WHSUS patient harboring a novel nonsense de novo POGZ variant, which afflicts a protein domain with transposase activity less frequently impacted by mutational events (DDE domain). This patient displays additional physical and behavioral features, these latter mimicking Smith-Magenis syndrome (SMS, MIM#182290). Considering sleep-wake cycle anomalies and abnormal behavior manifested by this boy, we reinforced the clinical resemblance between WHSUS and SMS, being both chromatinopathies. In addition, using the DeepGestalt technology, we identified a different facial overlap between WHSUS patients with mutations in the DDE domain (Group 1) and individuals harboring variants in other protein domains/regions (Group 2). This report further delineates the clinical and molecular repertoire of the POGZ-related phenotype, adding a novel patient with uncommon clinical and behavioral features and provides the first computer-aided facial study of WHSUS patients.
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http://dx.doi.org/10.1002/ajmg.a.61605DOI Listing
July 2020

Harmonization of Next-Generation Sequencing Procedure in Italian Laboratories: A Multi-Institutional Evaluation of the SiRe® Panel.

Front Oncol 2020 11;10:236. Epub 2020 Mar 11.

Department of Public Health, University of Naples Federico II, Naples, Italy.

Next-generation sequencing (NGS) needs to be validated and standardized to ensure that cancer patients are reliably selected for target treatments. In Italy, NGS is performed in several institutions and harmonization of wet and dry procedures is needed. To this end, a consortium of five different laboratories, covering the most part of the Italian peninsula, was constituted. A narrow gene panel (SiRe®) covering 568 clinically relevant mutations in six different genes (, and α) with a predictive role for therapy selection in non-small cell lung cancer (NSCLC), gastrointestinal stromal tumor, colorectal carcinoma (CRC), and melanoma was evaluated in each participating laboratory. To assess the NGS inter-laboratory concordance, the SiRe® panel, with a related kit and protocol for library preparation, was used in each center to analyze a common set of 20 NSCLC and CRC routine samples. Concordance rate, in terms of mutation detected and relative allelic frequencies, was assessed. Then, each institution prospectively analyzed an additional set of 40 routine samples (for a total of 160 specimens) to assess the reproducibility of the NGS run parameters in each institution. An inter-laboratory agreement of 100% was reached in analyzing the data obtained from the 20 common sample sets; the concordance rate of allelic frequencies distribution was 0.989. The prospective analysis of the run metric parameters obtained by each center locally showed that the analytical performance of the SiRe® panel in the different institutions was highly reproducible. The SiRe® panel represents a robust diagnostic tool to harmonize the NGS procedure in different Italian laboratories.
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http://dx.doi.org/10.3389/fonc.2020.00236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078327PMC
March 2020

Insights into the molecular pathogenesis of cardiospondylocarpofacial syndrome: MAP3K7 c.737-7A > G variant alters the TGFβ-mediated α-SMA cytoskeleton assembly and autophagy.

Biochim Biophys Acta Mol Basis Dis 2020 06 24;1866(6):165742. Epub 2020 Feb 24.

Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.

Transforming growth factor beta-activated kinase 1 (TAK1) is a highly conserved kinase protein encoded by MAP3K7, and activated by multiple extracellular stimuli, growth factors and cytokines. Heterozygous variants in MAP3K7 cause the cardiospondylocarpofacial syndrome (CSCFS) which is characterized by short stature, dysmorphic facial features, cardiac septal defects with valve dysplasia, and skeletal anomalies. CSCFS has been described in seven patients to date and its molecular pathogenesis is only partially understood. Here, the functional effects of the MAP3K7 c.737-7A > G variant, previously identified in a girl with CSCFS and additional soft connective tissue features, were explored. This splice variant generates an in-frame insertion of 2 amino acid residues in the kinase domain of TAK1. Computational analysis revealed that this in-frame insertion alters protein dynamics in the kinase activation loop responsible for TAK1 autophosphorylation after binding with its interactor TAB1. Co-immunoprecipitation studies demonstrate that the ectopic expression of TAK1-mutated protein impairs its ability to physically bind TAB1. In patient's fibroblasts, MAP3K7 c.737-7A > G variant results in reduced TAK1 autophosphorylation and dysregulation of the downstream TAK1-dependent signaling pathway. TAK1 loss-of-function is associated with an impaired TGFβ-mediated α-SMA cytoskeleton assembly and cell migration, and defective autophagy process. These findings contribute to our understanding of the molecular pathogenesis of CSCFS and might offer the rationale for the design of novel therapeutic targets.
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http://dx.doi.org/10.1016/j.bbadis.2020.165742DOI Listing
June 2020

The p.Arg377Trp variant in ACTL6A underlines a recognizable BAF-opathy phenotype.

Clin Genet 2020 04 29;97(4):672-674. Epub 2020 Jan 29.

Medical Genetics Laboratory, Clinical Genetics Division, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.

We describe the second patient with the de novo p.Arg377Trp variant in ACTL6A (Actin-like 6A) (MIM#604958) and a phenotype reminiscent a disorder of the BRG1-associated factor (BAF) complex, including dysmorphic facies and acral malformations. So far, only three patients with ACTL6A variants and neurodevelopmental delay have been reported but the specific p.Arg377Trp mutation seems to correlate with a distinctive phenotype well-fitting a BAFopathy, which lacks in individuals carrying different mutations. This could suggest an emergent genotype-phenotype correlation among the ACTL6A-related phenotype.
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http://dx.doi.org/10.1111/cge.13682DOI Listing
April 2020

Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish patients with hypertrophic cardiomyopathy.

Pol Arch Intern Med 2020 02 9;130(2):89-99. Epub 2020 Jan 9.

Division of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.

Introduction: Hypertrophic cardiomyopathy (HCM) is a heart disorder caused by autosomal dominant alterations affecting both sarcomeric genes and other nonsarcomeric loci in a minority of cases. However, in some patients, the occurrence of the causal pathogenic variant or variants in homozygosity, compound heterozygosity, or double heterozygosity has also been described. Most of the HCM pathogenic variants are missense and unique, but truncating mutations of the MYBPC3 gene have been reported as founder pathogenic variants in populations from Finland, France, Japan, Iceland, Italy, and the Netherlands.

Objectives: This study aimed to assess the genetic background of HCM in a cohort of Polish patients.

Patients And Methods: Twenty‑nine Polish patients were analyzed by a next generation sequencing panel including 404 cardiovascular genes.

Results: Pathogenic variants were found in 41% of the patients, with ultra‑ rare MYBPC3 c.2541C>G (p.Tyr847Ter) mutation standing for a variant hotspot and correlating with a lower age at HCM diagnosis. Among the nonsarcomeric genes, the CSRP3 mutation was found in a single case carrying the novel c.364C>T (p.Arg122Ter) variant in homozygosity. With this finding, the total number of known HCM cases with human CSRP3 knockout cases has reached 3.

Conclusions: This report expands the mutational spectrum and the inheritance pattern of HCM.
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http://dx.doi.org/10.20452/pamw.15130DOI Listing
February 2020

COL1-related overlap disorder: A novel connective tissue disorder incorporating the osteogenesis imperfecta/Ehlers-Danlos syndrome overlap.

Clin Genet 2020 03 12;97(3):396-406. Epub 2019 Dec 12.

Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo (Foggia), Italy.

The 2017 classification of Ehlers-Danlos syndromes (EDS) identifies three types associated with causative variants in COL1A1/COL1A2 and distinct from osteogenesis imperfecta (OI). Previously, patients have been described with variable features of both disorders, and causative variants in COL1A1/COL1A2; but this phenotype has not been included in the current classification. Here, we expand and re-define this OI/EDS overlap as a missing EDS type. Twenty-one individuals from 13 families were reported, in whom COL1A1/COL1A2 variants were found after a suspicion of EDS. None of them could be classified as affected by OI or by any of the three recognized EDS variants associated with COL1A1/COL1A2. This phenotype is dominated by EDS-related features. OI-related features were limited to mildly reduced bone mass, occasional fractures and short stature. Eight COL1A1/COL1A2 variants were novel and five recurrent with a predominance of glycine substitutions affecting residues within the procollagen N-proteinase cleavage site of α1(I) and α2(I) procollagens. Selected variants were investigated by biochemical, ultrastructural and immunofluorescence studies. The pattern of observed changes in the dermis and in vitro for selected variants was more typical of EDS rather than OI. Our findings indicate the existence of a wider recognizable spectrum associated with COL1A1/COL1A2.
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http://dx.doi.org/10.1111/cge.13683DOI Listing
March 2020

Striking phenotypic overlap between Nicolaides-Baraitser and Coffin-Siris syndromes in monozygotic twins with ARID1B intragenic deletion.

Eur J Med Genet 2020 Mar 14;63(3):103739. Epub 2019 Aug 14.

Medical Genetics Laboratory, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.

The chromatin remodeling AT-Rich interaction domain containing 1B protein (ARID1B) also known as BAF-associated factor, 250-KD, B (BAF250B) codified by the ARID1B gene (MIM#614556), is a small subunit of the mammalian SWI/SNF or BAF complex, an ATP-dependent protein machinery which is able to activate or repress gene transcription, allowing protein access to histones through DNA relaxed conformation. ARID1B gene mutations have been associated with two hereditary syndromic conditions, namely Coffin-Siris (CSS, MIM#135900) and Nicolaides-Baraitser syndromes (NCBRS, MIM#601358), characterized by neurodevelopment delay, craniofacial dysmorphisms and skeletal anomalies. Furthermore, intellectual impairment and central nervous system (CNS) alterations, comprising abnormal corpus callosum, have been associated with mutations in this gene. Moreover, ARID1B anomalies resulted to be involved in neoplastic events and Hirschprung disease. Here we report on two monozygotic male twins, displaying clinical appearance strikingly resembling NCBRS and CSS phenotype, who resulted carriers of a novel 6q25.3 microdeletion, encompassing only part of the ARID1B gene. The deleted segment was not inherited from the only parent tested and afflicted the first exons of the gene, coding for protein disordered region. We also provide, for the first time, a review of previously published ARID1B mutated patients with NCBRS and CSS phenotype and a computer-assisted dysmorphology analysis of NCBRS and ARID1B related CSS individuals, through the Face2Gene suite, confirming the existence of highly overlapping facial gestalt of both conditions. The present findings indicate that ARID1B could be considered a contributing gene not only in CSS but also in NCBRS phenotype, although the main gene related to this latter condition is the SMARCA2 gene (MIM#600014), another component of the BAF complex. So, ARID1B study should be considered in such individuals.
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http://dx.doi.org/10.1016/j.ejmg.2019.103739DOI Listing
March 2020

TAB2 c.1398dup variant leads to haploinsufficiency and impairs extracellular matrix homeostasis.

Hum Mutat 2019 10 27;40(10):1886-1898. Epub 2019 Jun 27.

Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy.

Transforming growth factor β-activated kinase 1 (TAK1) mediates multiple biological processes through the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and the mitogen-activated protein kinase (MAPK) signaling pathways. TAK1 activation is tightly regulated by its binding partners (TABs). In particular, binding with TAB2 is crucial for cardiovascular development and extracellular matrix (ECM) homeostasis. In our previous work, we reported a novel multisystem disorder associated with the heterozygous TAB2 c.1398dup variant. Here, we dissect the functional effects of this variant in order to understand its molecular pathogenesis. We demonstrate that TAB2 c.1398dup considerably undergoes to nonsense-mediated messenger RNA decay and encodes a truncated protein that loses its ability to bind TAK1. We also show an alteration of the TAK1 autophosphorylation status and of selected downstream signaling pathways in patients' fibroblasts. Immunofluorescence analyses and ECM-related polymerase chain reaction-array panels highlight that patient fibroblasts display ECM disorganization and altered expression of selected ECM components and collagen-related pathways. In conclusion, we deeply dissect the molecular pathogenesis of the TAB2 c.1398dup variant and show that the resulting phenotype is well explained by TAB2 loss-of-function. Our data also offer initial insights on the ECM homeostasis impairment as a molecular mechanism probably underlying a multisystem disorder linked to TAB2.
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http://dx.doi.org/10.1002/humu.23834DOI Listing
October 2019

Characterization of Two Novel Intronic Variants Affecting in -Related Disorders.

Genes (Basel) 2019 06 10;10(6). Epub 2019 Jun 10.

Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo FG, Italy.

encodes fibrillin 1, a key structural component of the extracellular matrix, and its variants are associated with a wide range of hereditary connective tissues disorders, such as Marfan syndrome (MFS) and mitral valve-aorta-skeleton-skin (MASS) syndrome. Interpretations of the genomic data and possible genotype-phenotype correlations in are complicated by the high rate of intronic variants of unknown significance. Here, we report two unrelated individuals with the deep intronic variants c.6872-24T>A and c.7571-12T>A, clinically associated with MFS and MASS syndrome, respectively. The individual carrying the c.6872-24T>A variant is positive for aortic disease. Both individuals lacked ectopia lentis. In silico analysis and subsequent mRNA study by RT-PCR demonstrated the effect of the identified variant on the splicing process in both cases. The c.6872-24T>A and c.7571-12T>A variants generate the retention of intronic nucleotides and lead to the introduction of a premature stop codon. This study enlarges the mutation spectrum of and points out the importance of intronic sequence analysis and the need for integrative functional studies in diagnostics.
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http://dx.doi.org/10.3390/genes10060442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627396PMC
June 2019

The facial dysmorphology analysis technology in intellectual disability syndromes related to defects in the histones modifiers.

J Hum Genet 2019 Aug 13;64(8):721-728. Epub 2019 May 13.

Medical Genetics Laboratory, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.

Genetic syndromes are frequently associated with Intellectual Disability (ID), as well as craniofacial dysmorphisms. A group of ID syndromes with typical abnormal face related to chromatin remodeling defects, have been recognized, coining the term chromatinopathies. This is a molecular heterogeneous subset of congenital disorders caused by mutations of the various components of the Chromatin-Marking System (CMS), including modifiers of DNA and chromatin remodelers. We performed a phenotypic study on a sample of 120 individuals harboring variants in genes codifying for the histones enzymes, using the DeepGestalt technology. Three experiments (two multiclass comparison experiments and a frontal face-crop analysis) were conducted, analyzing respectively a total of 181 pediatric images in the first comparison experiment and 180 in the second, all individuals belonging predominantly to Caucasian population. The classification results were expressed in terms of the area under the curve (AUC) of the receiver-operating-characteristic curve (ROC). Significant values of AUC and low p-values were registered for all syndromes in the three experiments, in comparison with each other, with other ID syndromes characterized by recognizable craniofacial dysmorphisms and with unaffected controls. Final findings indicated that this group of diseases is characterized by distinctive dysmorphisms, which result pathognomonic. A correct interrogation and use of adequate informatics aids, could become a valid support for clinicians.
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http://dx.doi.org/10.1038/s10038-019-0598-0DOI Listing
August 2019

Severity classes in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorders: a pilot study of 105 Italian patients.

Rheumatology (Oxford) 2019 10;58(10):1722-1730

Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

Objectives: This study is aimed at identifying discrete severity classes among adults with hypermobile Ehlers-Danlos syndrome (hEDS)/hypermobility spectrum disorders (HSD).

Methods: Subjects were selected according to the old and new nomenclatures and all completed a set of questionnaires exploring pain, fatigue, dysautonomic symptoms, coordination and attention/concentration deficits and quality of life in general. Data were investigated by hierarchical clustering on principal components. Cluster comparisons were then performed by using the two-sample unpaired t test and the standardized mean difference was reported as a measure of effect size. Conditional classification tree analysis and multivariable logistic regression were carried out in order to identify the profiles that were at higher risk to belong to the more severe cluster. Weighted linear combination was used to identify a numerical score measuring this risk.

Results: A total of 105 patients were selected and distributed in two distinct severity groups. These groups were statistically separated on the basis of 47 of 59 items/characteristics. One group featured the worse values of most questionnaire items (complex/severe cluster) and the other was dominated by the better values (simplex/milder cluster). Only three items were able to stratify patients according to their risk to belong to the complex cluster. A severity score was then constructed on these three items.

Conclusion: Adults with hEDS/HSD can be separated in two severity classes, which do not mirror either the old or new criteria for hEDS. The identified severity score could allow a bi-dimensional approach to adults with hEDS/HSD for optimal management planning.
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http://dx.doi.org/10.1093/rheumatology/kez029DOI Listing
October 2019

Autism spectrum disorder in a patient with a genomic rearrangement that only involves the EPHA5 gene.

Psychiatr Genet 2019 06;29(3):86-90

Laboratory of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital.

About one child in 68 is affected by the autism spectrum disorder (ASD), one of the most common neurodevelopmental disorders linked to intellectual disability, especially in males, intellectual disability being diagnosable in about 60-70% of autistic individuals. The biological bases of ASD are not yet fully known, but they are generally considered multifactorial, although many genes and genomic loci have been proposed to be possibly associated with this condition. In this report, we describe the case of a 14-year-old female Italian proband affected by ASD, carrying a novel ~ 270 kb interstitial microduplication, localized at the distal portion of the 4q13.1 region. The rearrangement was inherited from a mild symptomatic father and included a large part of the single EPHA5 gene, a receptor tyrosine kinase involved in the neural development, already indicated to be linked to ASD by previous Genome Wide Association Studies. This imbalance represents, to the best of our knowledge, the smallest duplication identified to date that only impacts the EPHA5 gene. We hypothesize that the duplication of this gene may alter EPHA5 expression and that this may impact the autistic phenotype of the patient.
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http://dx.doi.org/10.1097/YPG.0000000000000217DOI Listing
June 2019

A new HLA-C*04 variant, HLA-C*04:01:106, discovered in an Italian hematopoietic stem cell donor.

HLA 2019 04 3;93(4):232-233. Epub 2019 Feb 3.

S.Camillo-Forlanini Hospital, Medical Genetics Laboratory, Sapienza University, Rome, Italy.

HLA-C*04:01:106 differs from C*04:01:01:01 by a silent nucleotide substitution in exon 4.
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http://dx.doi.org/10.1111/tan.13471DOI Listing
April 2019

LTBP2-related "Marfan-like" phenotype in two Roma/Gypsy subjects with the LTBP2 homozygous p.R299X variant.

Am J Med Genet A 2019 01 18;179(1):104-112. Epub 2018 Dec 18.

Pediatric Cardiology and Arrhythmology Unit, Department of Pediatric Cardiology and Cardiac Surgery, IRCCS-Bambino Gesù Children Hospital and Research Institute, Rome, Italy.

Recessive variants in LTBP2 are associated with eye-restricted phenotypes including (a) primary congenital glaucoma and (b) microspherophakia/megalocornea and ectopia lentis with/without secondary glaucoma. Nosology of LTBP2 pathology in humans is apparently in contrast with the consolidated evidence of a wide expression of this gene in the developing embryo. Accordingly, in previously published patients with LTBP2-related eye disease, additional extraocular findings have been occasionally reported and include, among others, high-arched palate, tall stature, and variable cardiac involvement. Anyway, no emphasis was put on such systemic manifestations. Here, we report two unrelated Roma/Gypsy patients first ascertained for a multisystem disorder mainly characterized by primary congenital glaucoma, complex congenital heart defect, tall stature, long fingers, skin striae and dystrophic scarring, and resembling Marfan syndrome. Heart involvement was severe with polyvalvular heart dysplasia in one, and transposition of great arteries, thoracic arterial tortuosity, polyvalvular heart dysplasia, and neo-aortic root dilatation in the other. Both patients were homozygous for the recurrent c.895C>T[p.(R299X)] variant, typically found in individuals of Roma/Gypsy descent with an eye-restricted phenotype. Our findings point out LTBP2 as responsible of a systemic phenotype coherent with the community of syndromes related to anomalies in genes involved in the TGFβ-pathway. Among these disorders, LTBP2-related systemic disease emerges as a distinct condition with expanding prognostic implications and autosomal recessive inheritance.
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http://dx.doi.org/10.1002/ajmg.a.10DOI Listing
January 2019

Correction: c-MET receptor as potential biomarker and target molecule for malignant testicular germ cell tumors.

Oncotarget 2018 11 13;9(89):36049. Epub 2018 Nov 13.

Department of Anatomy, Histology, Forensic-Medicine and Orthopaedics, "Sapienza" University of Rome, Italy.

[This corrects the article DOI: 10.18632/oncotarget.25867.].
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http://dx.doi.org/10.18632/oncotarget.26374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267602PMC
November 2018

Italian validation of the functional difficulties questionnaire (FDQ-9) and its correlation with major determinants of quality of life in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorder.

Am J Med Genet B Neuropsychiatr Genet 2019 01 23;180(1):25-34. Epub 2018 Nov 23.

Division of Medical Genetics, IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.

The 2017 nosology defines the new criteria for hypermobile Ehlers-Danlos syndrome (hEDS), which is now considered one end of a continuous spectrum encompassing isolated, nonsyndromic joint hypermobility (JH) and hypermobility spectrum disorders (HSDs). Preliminary data indicate a link between JH and neurodevelopmental disorders and, in particular, developmental coordination disorder (DCD) in children. Assessing DCD in adults is difficult and the recently described functional difficulties questionnaire 9 (FDQ-9) is one of the few available tools. The aims of this study are to (a) validate FDQ-9 written in Italian and present normal values in 230 Italian controls; (b) explore the relationship of FDQ-9 with the brief pain inventory, composite autonomic symptom score 31, multidimensional fatigue inventory, attention deficit/hyperactivity disorder self-report version 1.1, and the SF-36 for quality of life in 105 Italian adults with hEDS/HSD. Validation of the FDQ-9 in Italian was carried out by translation, cross-cultural adaptation and test/retest reliability analysis. A case-control study was performed comparing the FDQ-9 outcome between 105 patients and 105 sex- and age-matched controls. Fifty-nine percent of the patients resulted positive compared to the 3.8% of controls (p value < .00001). In patients, FDQ-9 positive result associated with positive attention deficit/hyperactivity disorder self-report version 1.1 (OR = 4.04). Multivariate regression analysis comparing FDQ-9 with the other questionnaires demonstrated a strong association between positive FDQ-9 and the number of painful joints. Our preliminary data open wider management and therapeutic perspectives for coordination difficulties in hypermobile individuals.
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http://dx.doi.org/10.1002/ajmg.b.32698DOI Listing
January 2019

c-MET receptor as potential biomarker and target molecule for malignant testicular germ cell tumors.

Oncotarget 2018 Aug 7;9(61):31842-31860. Epub 2018 Aug 7.

Department of Anatomy, Histology, Forensic-Medicine and Orthopaedics, "Sapienza" University of Rome, Italy.

Type II testicular germ cell tumors (TGCTs) represent the most frequent malignancy in Caucasian males (20-40 years). Even if diagnosed with disseminated disease, >80% of patients are cured; however, a small percentage of cases progress and result in death. It is commonly accepted that these cancers arise from a disturbed testicular embryonic niche that leads to the block of gonocyte differentiation. The subsequent development of the invasive seminomas and non-seminomas is due to a combination of genetic, epigenetic and microenvironment-based alterations (genvironment). Hepatocyte growth factor (HGF) is present in the testicular microenvironment, together with its receptor c-MET, from early embryonic development to an adult stage. In addition, c-MET is a well-known proto-oncogene involved in the onset and progression of various human cancers. Herein, we have investigated the expression and availability of HGF and c-MET in TCam-2, NCCIT and NT2D1 cells, which are type II (T)GCT representative cell lines, and the effect of c-MET activation/repression on the regulation of cancerous biological processes. We found that NT2D1 cells increase their proliferation, polarized migration, and invasion in response to HGF administration. NCCIT cells respond to HGF stimulation only partially, whereas TCam-2 cells do not respond to HGF, at least according to the investigated parameters. Interestingly, the immunohistochemical study of c-MET distribution in TGCTs confirm its presence in both seminoma and non-seminoma lesions with different patterns. Notably, we found the highest c-MET immunoreactivity in the epithelial elements of the various components of TGCTs: teratoma, yolk sac tumor and choriocarcinoma.
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http://dx.doi.org/10.18632/oncotarget.25867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112764PMC
August 2018

Exploring relationships between joint hypermobility and neurodevelopment in children (4-13 years) with hereditary connective tissue disorders and developmental coordination disorder.

Am J Med Genet B Neuropsychiatr Genet 2018 09 2;177(6):546-556. Epub 2018 Aug 2.

Division of Medical Genetics, IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.

Joint hypermobility (JH) is a common, though largely ignored physical trait with increasing clinical reverberations. A few papers suggest a link between JH and selected neurodevelopmental disorders, such as developmental coordination disorder (DCD). JH is also the hallmark of various hereditary connective tissue disorders (HCTDs). Children with HCTDs may present abnormal neurodevelopment but its manifestations remain undetermined. This study examined 23 children (group 1), aged 4-13 years, with different HCTDs (i.e., 19 with hypermobile Ehlers-Danlos syndrome (EDS)/hypermobility spectrum disorder, 3 with molecularly confirmed classical EDS, and 1 with Loeys-Dietz syndrome type 1 due to TGFBR2 mutation) and 23, age- and sex-matched children with DCD (group 2). All underwent 14 different psychometric tests exploring motor, cognitive, executive-attentive, and emotional-behavior features. In group 1, 30%, 22%, and 13% patients presented DCD (with or without dysgraphia), learning disabilities, and attention deficit-hyperactivity disorder, respectively. None had cognitive delay. In group 2, 17% patients presented generalized JH and none had HCTDs. DCD children presented more motor and coordination troubles than HCTDs patients, while quality of life of children with HCTDs resulted more deteriorated due to somatic manifestations and behavioral traits. This study presents the full overview of neurodevelopmental attributes in HCTDs, and compares with standardized tools the neurodevelopmental profile of children with DCD and HCTDs. While the high rate of neurodevelopmental comorbidities in HCTDs deserves attention, the impact of a dysfunctional connective tissue in children with a primary diagnosis of DCD needs more research.
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http://dx.doi.org/10.1002/ajmg.b.32646DOI Listing
September 2018

Correction: Patient experience and utility of genetic information: a cross-sectional study among patients tested for cancer susceptibility and thrombophilia.

Eur J Hum Genet 2018 09;26(9):1398

Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy.

This article was originally published under an incorrect license. This has now been amended and is available under a CC BY-NC-ND 4.0 license. The PDF and HTML versions of the paper have been modified accordingly.
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http://dx.doi.org/10.1038/s41431-018-0186-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117290PMC
September 2018

Two novel RHD alleles encoding truncated, nonfunctional D polypeptides.

Transfusion 2018 08 6;58(8):2082-2083. Epub 2018 May 6.

Transfusion Medicine Unit, San Camillo Forlanini Hospital, Rome, Italy.

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http://dx.doi.org/10.1111/trf.14657DOI Listing
August 2018