Publications by authors named "Dario Cocciadiferro"

16 Publications

  • Page 1 of 1

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

Analysis of ACE2 genetic variants in 131 Italian SARS-CoV-2-positive patients.

Hum Genomics 2020 09 11;14(1):29. Epub 2020 Sep 11.

Medical Genetics Laboratory, Tor Vergata Hospital, Rome, Italy.

Background: Coronaviruses (CoV) are a large family of viruses that are common in humans and many animal species. Animal coronaviruses rarely infect humans with the exceptions of the Middle East respiratory syndrome ( MERS-CoV ), the severe acute respiratory syndrome corona virus (SARS-CoV), and now SARS-CoV-2, which is the cause of the ongoing pandemic of coronavirus disease 2019 (COVID-19). Several studies suggested that genetic variants in the ACE2 gene may influence the host susceptibility or resistance to SARS-CoV-2 infection according to the functional role of ACE2 in human pathophysiology. However, many of these studies have been conducted in silico based on epidemiological and population data. We therefore investigated the occurrence of ACE2 variants in a cohort of 131 Italian unrelated individuals clinically diagnosed with COVID-19 and in an Italian control population, to evaluate a possible allelic association with COVID-19, by direct DNA analysis.

Methods: As a pilot study, we analyzed, by whole-exome sequencing, genetic variants of ACE2 gene in 131 DNA samples of COVID-19 patients hospitalized at Tor Vergata University Hospital and at Bambino Gesù Children's Hospital, Rome. We used a large control group consisting of 1000 individuals (500 males and 500 females).

Results: We identified three different germline variants: one intronic c.439+4G>A and two missense c.1888G>C p.(Asp630His) and c.2158A>G p.(Asn720Asp) in a total of 131 patients with a similar frequency in male and female. Thus far, only the c.1888G>C p.(Asp630His) variant shows a statistically different frequency compared to the ethnically matched populations. Therefore, further studies are needed in larger cohorts, since it was found only in one heterozygous COVID-19 patient.

Conclusions: Our results suggest that there is no strong evidence, in our cohort, of consistent association of ACE2 variants with COVID-19 severity. We might speculate that rare susceptibility/resistant alleles could be located in the non-coding regions of the ACE2 gene, known to play a role in regulation of the gene activity.
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http://dx.doi.org/10.1186/s40246-020-00279-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483483PMC
September 2020

Nonsense variant of gene in heterozygosis and benign recurrent intrahepatic cholestasis: A case report and review of literature.

World J Hepatol 2020 Feb;12(2):64-71

Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy.

Background: Benign recurrent intrahepatic cholestasis is a genetic disorder with recurrent cholestatic jaundice due to and gene mutations encoding for hepato-canalicular transporters. Herein, we firstly provide the evidence that a nonsense variant of gene (c.1558A>T) in heterozygous form is involved in BRIC pathogenesis.

Case Summary: A 29-year-old male showed severe jaundice and laboratory tests consistent with intrahepatic cholestasis despite normal gamma-glutamyltranspeptidase. Acute and chronic liver diseases with viral, metabolic and autoimmune etiology were excluded. Normal intra/extra-hepatic bile ducts were demonstrated by magnetic resonance. Liver biopsy showed: Cholestasis in the centrilobular and intermediate zones with bile plugs and intra-hepatocyte pigment, Kupffer's cell activation/hyperplasia and preserved biliary ducts. Being satisfied benign recurrent intrahepatic cholestasis diagnostic criteria, and gene analysis was performed. Surprisingly, we found a novel nonsense variant of gene (c.1558A>T) in heterozygosis. The variant was confirmed by Sanger sequencing following a standard protocol and tested for familial segregation, showing a maternal inheritance. Immunohistochemistry confirmed a significant reduction of mutated gene related protein (familial intrahepatic cholestasis 1). The patient was treated with ursodeoxycholic acid 15 mg/kg per day and colestyramine 8 g daily with total bilirubin decrease and normalization at the 6 and 12 mo.

Conclusion: A genetic abnormality, different from those already known, could be involved in familial intrahepatic cholestatic disorders and/or pro-cholestatic genetic predisposition, thus encouraging further mutation detection in this field.
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http://dx.doi.org/10.4254/wjh.v12.i2.64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061267PMC
February 2020

The splice c.1815G>A variant in KIAA0586 results in a phenotype bridging short-rib-polydactyly and oral-facial-digital syndrome: A case report and literature review.

Medicine (Baltimore) 2020 Feb;99(8):e19169

Laboratory of Medical Genetics.

Introduction: KIAA0586 variants have been associated to short-rib thoracic dysplasia, an autosomal recessive skeletal ciliopathy characterized by a narrow thorax, short limbs, and radiological skeletal abnormalities.

Patient Concerns: Patients 1 and 2 were two Roma Gypsy siblings presenting thoracic dysplasia and a combination of oral cavity anomalies.

Diagnosis: A custom NGS gene panel, including genes associated to skeletal ciliopathies, identified the homozygous KIAA0586 splicing variant c.1815G>A (p.Gln605Gln) in both siblings, confirming the clinical diagnosis of short-rib-polydactyly.

Intervention: Patients were transferred to neonatal intensive care unit and received life-support treatment.

Outcomes: Patients 1 and 2 died after few hours and 1 month of birth, respectively, because of respiratory failure related with the disease.

Conclusion: We report two patients affected by short-rib polydactyly syndrome and overlapping phenotype with oral-facial-digital syndrome associated with the c.1815G>A variant in KIAA0586, suggesting a quite peculiar genotype-phenotype correlation.
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http://dx.doi.org/10.1097/MD.0000000000019169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034684PMC
February 2020

Expanding the clinical and molecular spectrum of lethal congenital contracture syndrome 8 associated with biallelic variants of ADCY6.

Clin Genet 2020 04 20;97(4):649-654. Epub 2020 Feb 20.

Laboratory of Medical Genetics Unit, Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Arthrogryposis multiplex congenita (AMC) is defined as congenital, non-progressive contractures in more than two joints and in multiple body areas, resulting from reduced fetal mobility. So far, more than 400 causative genes for AMC have been identified. Some isolated AMC phenotypes arise as a result of mutations in genes encoding components required for motor neuron structure, function, and myelination, as in the case of ADCY6 encoding the enzyme adenylyl cyclase type 6. ADCY6 inactivation, due to biallelic variants, have been previously associated with the lethal congenital contracture syndrome 8 (LCCS8). So far, only four LCCS8 patients, from two families, have been reported. Here, we describe a new patient affected by a severe form of AMC, harboring two novel compound heterozygous variants in ADCY6. Our findings expand the clinical and mutational spectrum of LCCS8, showing a possible correlation between the impact of the ADCY6 missense variants reported to date, predicted by molecular modeling, and the severity of the phenotype.
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http://dx.doi.org/10.1111/cge.13691DOI Listing
April 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

Genetic identification and molecular modeling characterization of a novel POU3F4 variant in two Italian deaf brothers.

Int J Pediatr Otorhinolaryngol 2020 Feb 22;129:109790. Epub 2019 Nov 22.

Audiology and Otosurgery Unit, "Bambino Gesù" Pediatric Hospital, Rome, Italy.

In this report, we describe a novel, probably pathogenic hemizygous variant c.870G > T (p.Lys290Asn) in the POU3F4 gene in two deaf brothers from one Italian family with identical inner ear abnormalities specific to X-linked deafness-2 (DFNX2). In addition, we performed homology modeling to predict the effect of the missense variant on the protein structure showing a possible disruption of the normal folding. The identification of pathogenic variants causing X-linked recessive deafness will improve molecular diagnosis, genetic counseling, and knowledge of the molecular epidemiology of hearing loss among Italian individuals. Taken together, we recommend preoperative gene mutation analysis in patients who have DFNX2 diagnosed on the basis of characteristic radiological findings, in order to provide with better prognostic information, the risk of recurrence, and improved rehabilitation options. Finally, the present work strengthens the hypothesis that DFNX-2 could be considered as a syndromic deafness, since mixed hearing loss is associated with other dysfunctions of the neuropsychological profile of the patients.
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http://dx.doi.org/10.1016/j.ijporl.2019.109790DOI Listing
February 2020

Novel exostosin-2 missense variants in a family with autosomal recessive exostosin-2-related syndrome: further evidences on the phenotype.

Clin Genet 2019 01 24;95(1):165-171. Epub 2018 Oct 24.

Laboratory of Medical Genetics, Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Biallelic exostosin-2 (EXT2) pathogenic variants have been described as the cause of the Seizures-Scoliosis-Macrocephaly syndrome (OMIM 616682) characterized by intellectual disability, facial dysmorphisms and seizures. More recently, it has been proposed to rename this disorder with the acronym AREXT2 (autosomal recessive EXT2-related syndrome). Here, we report the third family affected by AREXT2 syndrome, harboring compound missense variants in EXT2, p.Asp227Asn, and p.Tyr608Cys. In addition, our patients developed multiple exostoses, which were not observed in the previously described families. AREXT2 syndrome can be considered as a multiorgan Congenital Disorder of Glycosylation caused by a significant, but non-lethal, decrease in EXT2 expression, thereby affecting the synthesis of the heparan sulfate proteoglycans, which is relevant in many physiological processes. Our finding expands the clinical and molecular spectrum of the AREXT2 syndrome and suggests a possible genotype/phenotype correlation in the development of the exostoses.
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http://dx.doi.org/10.1111/cge.13458DOI Listing
January 2019

Dissecting KMT2D missense mutations in Kabuki syndrome patients.

Hum Mol Genet 2018 11;27(21):3651-3668

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

Kabuki syndrome is a rare autosomal dominant condition characterized by facial features, various organs malformations, postnatal growth deficiency and intellectual disability. The discovery of frequent germline mutations in the histone methyltransferase KMT2D and the demethylase KDM6A revealed a causative role for histone modifiers in this disease. However, the role of missense mutations has remained unexplored. Here, we expanded the mutation spectrum of KMT2D and KDM6A in KS by identifying 37 new KMT2D sequence variants. Moreover, we functionally dissected 14 KMT2D missense variants, by investigating their impact on the protein enzymatic activity and the binding to members of the WRAD complex. We demonstrate impaired H3K4 methyltransferase activity in 9 of the 14 mutant alleles and show that this reduced activity is due in part to disruption of protein complex formation. These findings have relevant implications for diagnostic and counseling purposes in this disease.
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http://dx.doi.org/10.1093/hmg/ddy241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488975PMC
November 2018

TRIM50 regulates Beclin 1 proautophagic activity.

Biochim Biophys Acta Mol Cell Res 2018 Jun 29;1865(6):908-919. Epub 2018 Mar 29.

Division of Medical Genetics, IRCCS Casa Sollievo Della Sofferenza, Viale Cappuccini, 71013 San Giovanni Rotondo, Italy. Electronic address:

Autophagy is a catabolic process needed for maintaining cell viability and homeostasis in response to numerous stress conditions. Emerging evidence indicates that the ubiquitin system has a major role in this process. TRIMs, an E3 ligase protein family, contribute to selective autophagy acting as receptors and regulators of the autophagy proteins recognizing endogenous or exogenous targets through intermediary autophagic tags, such as ubiquitin. Here we report that TRIM50 fosters the initiation phase of starvation-induced autophagy and associates with Beclin1, a central component of autophagy initiation complex. We show that TRIM50, via the RING domain, ubiquitinates Beclin 1 in a K63-dependent manner enhancing its binding with ULK1 and autophagy activity. Finally, we found that the Lys-372 residue of TRIM50, critical for its own acetylation, is necessary for its E3 ligase activity that governs Beclin1 ubiquitination. Our study expands the roles of TRIMs in regulating selective autophagy, revealing an acetylation-ubiquitination dependent control for autophagy modulation.
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http://dx.doi.org/10.1016/j.bbamcr.2018.03.011DOI Listing
June 2018

Clinical and Neurobehavioral Features of Three Novel Kabuki Syndrome Patients with Mosaic KMT2D Mutations and a Review of Literature.

Int J Mol Sci 2017 Dec 28;19(1). Epub 2017 Dec 28.

Division of Medical Genetics, IRCSS Casa Sollievo della Sofferenza Hospital, viale Cappuccini, 71013 San Giovanni Rotondo, Italy.

Kabuki syndrome (KS) is a rare disorder characterized by multiple congenital anomalies and variable intellectual disability caused by mutations in and , two interacting chromatin modifier responsible respectively for 56-75% and 5-8% of the cases. To date, three KS patients with mosaic deletions in blood lymphocytes have been described. We report on three additional subjects displaying gene mosaics including one in which a single nucleotide change results in a new frameshift mutation (p.L1199HfsX7), and two with already-known nonsense mutations (p.R4484X and p.R5021X). Consistent with previously published cases, mosaic mutations may result in mild KS facial dysmorphisms and clinical and neurobehavioral features, suggesting that these characteristics could represent the handles for genetic testing of individuals with slight KS-like traits.
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http://dx.doi.org/10.3390/ijms19010082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796032PMC
December 2017

GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability.

Am J Hum Genet 2016 09 11;99(3):704-710. Epub 2016 Aug 11.

Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy. Electronic address:

GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.
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http://dx.doi.org/10.1016/j.ajhg.2016.06.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010642PMC
September 2016

A novel MED12 mutation: Evidence for a fourth phenotype.

Am J Med Genet A 2016 09 17;170(9):2377-82. Epub 2016 Jun 17.

Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.

Mutations of the MED12 gene have been reported mainly in males with FG (Opitz-Kaveggia), Lujan-Fryns, or X-linked Ohdo syndromes. Recently, a different phenotype characterized by minor anomalies, severe intellectual disability (ID), and absent language was reported in female and male patients belonging to the same family and carrying a frameshift MED12 mutation (c.5898dupC). Here, we report on two brothers and their niece affected by severe and mild ID, respectively, where whole exome sequencing combined with variant analysis within a panel of ID-related genes, disclosed a novel c.2312T>C (p.Ile771Thr) MED12 mutation. This variant, which has not been reported as a polymorphism, was not present in a third unaffected brother, and was predicted to be deleterious by five bioinformatic databases. This finding together with the phenotypic analogies shared with the carriers of c.5898dupC mutation suggests the existence of a fourth MED12-related disorder, characterized by severe ID, absent or deficient language and, milder, clinical manifestation in heterozygotes. We have reviewed the literature on MED12 heterozygotes, their clinical manifestations, and discuss the possible biological causes of this condition. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37805DOI Listing
September 2016

TRIM8 downregulation in glioma affects cell proliferation and it is associated with patients survival.

BMC Cancer 2015 Jun 16;15:470. Epub 2015 Jun 16.

Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, Poliambulatorio Giovanni Paolo II, I-71013, San Giovanni Rotondo (FG), Italy.

Background: Human gliomas are a heterogeneous group of primary malignant brain tumors whose molecular pathogenesis is not yet solved. In this regard, a major research effort has been directed at identifying novel specific glioma-associated genes. Here, we investigated the effect of TRIM8 gene in glioma.

Methods: TRIM8 transcriptional level was profiled in our own glioma cases collection by qPCR and confirmed in the independent TCGA glioma cohort. The association between TRIM8 expression and Overall Survival and Progression-free Survival in TCGA cohort was determined by using uni-multivariable Cox regression analysis. The effect of TRIM8 on patient glioma cell proliferation was evaluated by performing MTT and clonogenic assays. The mechanisms causing the reduction of TRIM8 expression were explored by using qPCR and in vitro assays.

Results: We showed that TRIM8 expression correlates with unfavorable clinical outcome in glioma patients. We found that a restored TRIM8 expression induced a significant reduction of clonogenic potential in U87MG and patient's glioblastoma cells. Finally we provide experimental evidences showing that miR-17 directly targets the 3' UTR of TRIM8 and post-transcriptionally represses the expression of TRIM8.

Conclusions: Our study provides evidences that TRIM8 may participate in the carcinogenesis and progression of glioma and that the transcriptional repression of TRIM8 might have potential value for predicting poor prognosis in glioma patients.
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http://dx.doi.org/10.1186/s12885-015-1449-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468980PMC
June 2015