159 results on '"Agolini E"'
Search Results
2. Phenytoin intoxication associated with omeprazole administration in a child with defective CYP2C9
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Marano, M., Nicoletti, F., Pro, S., Goffredo, B. M., Cecchetti, C., Piervincenzi, E., Agolini, E., and Cocciadiferro, D.
- Published
- 2020
- Full Text
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3. Expanding the clinical and molecular spectrum of PRMT7 mutations: 3 additional patients and review
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Agolini, E., Dentici, M.L., Bellacchio, E., Alesi, V., Radio, F.C., Torella, A., Musacchia, F., Tartaglia, M., Dallapiccola, B., Nigro, V., Digilio, M.C., and Novelli, A.
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- 2018
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4. Epidemiological characterization of SARS-CoV-2 variants in children over the four COVID-19 waves and correlation with clinical presentation (vol 12, 10194, 2022)
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Alteri, C, Scutari, R, Costabile, V, Colagrossi, L, La Rosa, K, Agolini, E, Lanari, V, Chiurchiu, S, Romani, L, Markowich, A, Bernaschi, P, Russo, C, Novelli, A, Bernardi, S, Campana, A, Villani, A, and Perno, C
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Settore MED/38 - Published
- 2022
5. Correction to: Structural modeling of a novel TERC variant in a patient with aplastic anemia and short telomeres
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Rinelli, M., Bellacchio, E., Berardinelli, F., Pascolini, G., Grammatico, P., Sgura, A., Iori, A. P., Quattrocchi, L., Novelli, A., Majore, S., and Agolini, E.
- Published
- 2019
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6. HLA-haploidentical TCRab1/CD191-depleted stem cell transplantation in children and young adults with Fanconi anemia
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Strocchio, L., Pagliara, D., Algeri, M., Pira, G. L., Rossi, F., Bertaina, V., Leone, G., Pinto, R. M., Andreani, M., Agolini, E., Girardi, K., Gaspari, S., Grapulin, L., Bufalo, F. D., Novelli, A., Merli, P., and Locatelli, Franco
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HLA-haploidentical tranpslant ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA - Published
- 2021
7. Novel homozygous mutation in exon 5 of WFS1 gene in an Apulian family with mild phenotypic expression of Wolfram syndrome
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Piccinno, E., Ortolani, F., Vendemiale, M., Tummolo, A., Masciopinto, M., Natale, M. P., De Luca, A., Agolini, E., Aloi, C., Salina, A., DʼAnnunzio, G., Fischetto, R., and Papadia, F.
- Published
- 2014
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8. Structural modeling of a novel TERC variant in a patient with aplastic anemia and short telomeres
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Rinelli M, Bellacchio E, Berardinelli F, Pascolini G, Grammatico P, Sgura A, Iori AP, Quattrocchi L, Novelli A, Majore S, Agolini E., Rinelli, M, Bellacchio, E, Berardinelli, F, Pascolini, G, Grammatico, P, Sgura, A, Iori, Ap, Quattrocchi, L, Novelli, A, Majore, S, and Agolini, E.
- Published
- 2019
9. Loss-of-function variants in CAPRIN1 in patients affected by autism spectrum disorder, language delay and intellectual disability with variable expressivity and incomplete penetrance
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Pavinato, L, Howe, Jl, Carli, D, Agolini, E, Coviello, Da, Van de Laar, Imbh, Pyb, Au, Di Gregorio, E, Giorgio, E, Pozzi, E, Ferrero, M, Cardaropoli, S, Delle Vedove, A, Salpietro, V, Zara, F, Novelli, A, Wirth, B, Ferrero, Gb, Scherer, Sw, and Brusco, A
- Published
- 2020
10. Hermansky-Pudlak Syndrome Subtype 4 (HPS-4): A Novel Mutation in a 44 Years Old Italian Woman with Severe Pulmonary Fibrosis
- Author
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Leone, P.M., primary, Magnini, D., additional, Agolini, E., additional, Sgalla, G., additional, Iovene, B., additional, Varone, F., additional, Novelli, A., additional, and Richeldi, L., additional
- Published
- 2019
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11. P.04.15 THE DISCOVERY OF A NOVEL GENETIC MUTATION IN BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS WIDENS THE INSIGHTS INTO DISORDER RELATED-MOLECULAR ANALYSIS
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Piazzolla, M., primary, Castellaneta, N.M., additional, Novelli, A., additional, Agolini, E., additional, Cocciadiferro, D., additional, Resta, L., additional, Ierardi, E., additional, and Di Leo, A., additional
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- 2019
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12. Correction to: Structural modeling of a novel TERC variant in a patient with aplastic anemia and short telomeres
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Rinelli, M., primary, Bellacchio, E., additional, Berardinelli, F., additional, Pascolini, G., additional, Grammatico, P., additional, Sgura, A., additional, Iori, A. P., additional, Quattrocchi, L., additional, Novelli, A., additional, Majore, S., additional, and Agolini, E., additional
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- 2018
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13. Facial comedonal acne in orofaciodigital syndrome type 1 caused by a novel frameshift variant inOFD 1
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Rotunno, R., primary, Diociaiuti, A., additional, Agolini, E., additional, Latorre, S., additional, Carnevale, C., additional, Novelli, A., additional, El Hachem, M., additional, and Castori, M., additional
- Published
- 2018
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14. Structural modeling of a novel TERC variant in a patient with aplastic anemia and short telomeres
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Rinelli, M., primary, Bellacchio, E., additional, Berardinelli, F., additional, Pascolini, G., additional, Grammatico, P., additional, Sgura, A., additional, Iori, A. P., additional, Quattrocchi, L., additional, Novelli, A., additional, Majore, S., additional, and Agolini, E., additional
- Published
- 2018
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15. Pilot Study of Warfarin Genotype Polymorphisms in Pediatric Patients with Ventricular Assist Devices
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Iodice, F., primary, Baban, A., additional, Di Molfetta, A., additional, Di Chiara, L., additional, Novelli, A., additional, Agolini, E., additional, Amodeo, A., additional, and Testa, G., additional
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- 2017
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16. Expanding the clinical and molecular spectrum of <italic>PRMT7</italic> mutations: 3 additional patients and review.
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Agolini, E., Dentici, M. L., Bellacchio, E., Alesi, V., Radio, F. C., Torella, A., Musacchia, F., Tartaglia, M., Dallapiccola, B., Nigro, V., Digilio, M. C., and Novelli, A.
- Subjects
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PROTEIN arginine methyltransferases regulation , *POST-translational modification , *CELLULAR signal transduction , *DNA repair , *BRACHYDACTYLY - Abstract
Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S‐adenosyl‐l‐methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 7 patients have been described harboring compound heterozygous or homozygous variants in the
PRMT7 gene, causing a novel intellectual disability syndrome, known as SBIDDS syndrome (Short Stature, Brachydactyly, Intellectual Developmental Disability, and Seizures). We report on 3 additional patients from 2 consanguineous families with severe/moderate intellectual disability, short stature, brachydactyly and dysmorphisms. Exome sequencing revealed 2 novel homozygous mutations inPRMT7 . Our findings expand the clinical and molecular spectrum of homozygousPRMT7 mutations, associated to the SBIDDS syndrome, showing a possible correlation between the type of mutation and the severity of the phenotype. [ABSTRACT FROM AUTHOR]- Published
- 2018
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17. (742) - Pilot Study of Warfarin Genotype Polymorphisms in Pediatric Patients with Ventricular Assist Devices
- Author
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Iodice, F., Baban, A., Di Molfetta, A., Di Chiara, L., Novelli, A., Agolini, E., Amodeo, A., and Testa, G.
- Published
- 2017
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18. Facial comedonal acne in orofaciodigital syndrome type 1 caused by a novel frameshift variant in OFD1.
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Rotunno, R., Diociaiuti, A., Agolini, E., Latorre, S., Carnevale, C., Novelli, A., El Hachem, M., and Castori, M.
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AGENESIS of corpus callosum ,ACNE ,SYNDROMES - Abstract
The article presents a case study of a 4-month-old girl with cleft palate and other anomalies. It discusses that the girl presented bifid tongue with nodules, cleft palate and minor digital anomalies. It mentions that physical examination showed thin, wiry and sparse hair of the alae nasi, long philtrum, pseudocleft of the upper lip and depressions of the lower lip. It also mentions the need of essential for early diagnosis and appropriate genetic counselling for oro–facial–digital syndromes.
- Published
- 2019
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19. Novel homozygous mutation in exon 5 ofWFS1gene in an Apulian family with mild phenotypic expression of Wolfram syndrome
- Author
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Piccinno, E., primary, Ortolani, F., additional, Vendemiale, M., additional, Tummolo, A., additional, Masciopinto, M., additional, Natale, M.P., additional, De Luca, A., additional, Agolini, E., additional, Aloi, C., additional, Salina, A., additional, D'Annunzio, G., additional, Fischetto, R., additional, and Papadia, F., additional
- Published
- 2013
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20. Iron overload features in two infants with Zelleweger syndrome with liver disease.
- Author
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Ranucci, G., De Brasi, D., Sibilio, M., Mastrominico, A., Rizzo, C., Agolini, E., Novelli, A., DionisiVici, C., and Mandato, C.
- Published
- 2022
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21. Nectinopathies: An emerging group of ectodermal dysplasia syndromes
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Brancati, F., Agolini, E., and Fortugno Paola
22. Refinement of the clinical and mutational spectrum of UBE2A deficiency syndrome
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Marco Tartaglia, Eric W. Klee, Laura Reed, Daniela Melis, Brendan C. Lanpher, Katherine S. Josephs, Meriel McEntagart, Deciphering Developmental Disorders Study, Bert Callewaert, Jessica M. Tarnowski, Francesca Pantaleoni, Viviana Cordeddu, Isabella Mammi, Stefania Lo Cicero, Katherine C. Nickels, Andrea Haworth, Francesca Clementina Radio, Alessandro Bruselles, Bruno Dallapiccola, Gerarda Cappuccio, Antonio Novelli, Nicola Brunetti-Pierri, Massimo Tatti, Andrea Ciolfi, Emanuele Agolini, Emanuele Bellacchio, Mohnish Suri, Erica L. Macke, Cordeddu, V., Macke, E. L., Radio, F. C., Lo Cicero, S., Pantaleoni, F., Tatti, M., Bellacchio, E., Ciolfi, A., Agolini, E., Bruselles, A., Brunetti-Pierri, Nicola, Suri, M., Josephs, K. S., Mcentagart, M., Lanpher, B., Nickels, K. C., Haworth, A., Reed, L., Cappuccio, G., Mammi, I., Tarnowski, J. M., Novelli, A., Melis, D., Callewaert, B., Dallapiccola, B., Klee, E., and Tartaglia, M.
- Subjects
0301 basic medicine ,Heart Defects, Congenital ,Male ,Deficiency syndrome ,genotype-phenotype correlations ,UBE2A ,clinical variation ,intellectual disability Nascimento type ,mutation spectrum ,030105 genetics & heredity ,Protein degradation ,genotype-phenotype correlation ,Hypogammaglobulinemia ,03 medical and health sciences ,Pineal gland ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Missense mutation ,Humans ,Genetic Predisposition to Disease ,Genetics (clinical) ,Genitourinary system ,business.industry ,Infant ,Genetic Diseases, X-Linked ,medicine.disease ,Pedigree ,030104 developmental biology ,medicine.anatomical_structure ,Child, Preschool ,Urogenital Abnormalities ,Ubiquitin-Conjugating Enzymes ,Skin Abnormalities ,Female ,business ,Binding domain - Abstract
UBE2A deficiency, that is, intellectual disability (ID) Nascimento type (MIM 300860), is an X-linked syndrome characterized by developmental delay, moderate to severe ID, seizures, dysmorphisms, skin anomalies, and urogenital malformations. Forty affected subjects have been reported thus far, with 31 cases having intragenic UBE2A variants. Here, we report on additional eight affected subjects from seven unrelated families who were found to be hemizygous for previously unreported UBE2A missense variants (p.Glu62Lys, p.Arg95Cys, p.Thr99Ala, and p.Arg135Trp) or small in-frame deletions (p.Val81_Ala83del, and p.Asp101del). A wide phenotypic spectrum was documented in these subjects, ranging from moderate ID associated with mild dysmorphisms to severe features including congenital heart defects (CHD), severe cognitive impairment, and pineal gland tumors. Four variants affected residues (Glu62, Arg95, Thr99 and Asp101) that contribute to stabilizing the structure of the E3 binding domain. The three-residue in-frame deletion, p.Val81_Ala83del, resulted from aberrant processing of the transcript. This variant and p.Arg135Trp mapped to regions of the protein located far from the E3 binding region, and caused variably accelerated protein degradation. By reviewing available clinical information, we revise the clinical and molecular profile of the disorder and document genotype-phenotype correlations. Pineal gland cysts/tumors, CHD and hypogammaglobulinemia emerge as recurrent features.
- Published
- 2020
23. Congenital emphysematous lung disease associated with a novel Filamin A mutation. Case report and literature review
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Caterina Cacace, Rossana Bussani, Mirella Collura, Giovanni Corsello, Aurora Puglisi, Valeria Calcaterra, Maria Pia Pappalardo, Gloria Pelizzo, Emanuele Agolini, Antonio Novelli, Maria Piccione, Pelizzo, Gloria, Collura, Mirella, Puglisi, Aurora, Pappalardo, Maria Pia, Agolini, Emanuele, Novelli, Antonio, Piccione, Maria, Cacace, Caterina, Bussani, Rossana, Corsello, Giovanni, Calcaterra, Valeria, Pelizzo, G., Collura, M., Puglisi, A., Pappalardo, M. P., Agolini, E., Novelli, A., Piccione, M., Cacace, C., Bussani, R., Corsello, G., and Calcaterra, V.
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Lung Diseases ,Male ,Pathology ,medicine.medical_specialty ,Filamins ,medicine.medical_treatment ,Children ,Congenital enphysema ,Filamin a ,Lung disease ,Periventricular nodular heterotopia ,Case Report ,Filamin ,Keywords: Filamin a, Congenital enphysema, Lung disease, Children, Periventricular nodular heterotopia ,Lung Disorder ,03 medical and health sciences ,0302 clinical medicine ,Neuroimaging ,Loss of Function Mutation ,030225 pediatrics ,medicine ,Humans ,FLNA ,030212 general & internal medicine ,Lung ,Genetic testing ,Mechanical ventilation ,medicine.diagnostic_test ,business.industry ,lcsh:RJ1-570 ,Brain ,Infant ,lcsh:Pediatrics ,respiratory system ,Respiration, Artificial ,medicine.anatomical_structure ,Pulmonary Emphysema ,Respiratory failure ,Pediatrics, Perinatology and Child Health ,Radiography, Thoracic ,Respiratory Insufficiency ,Tomography, X-Ray Computed ,business - Abstract
Background Progressive lung involvement in Filamin A (FLNA)-related cerebral periventricular nodular heterotopia (PVNH) has been reported in a limited number of cases. Case presentation We report a new pathogenic FLNA gene variant (c.7391_7403del; p.Val2464Alafs*5) in a male infant who developed progressive lung disease with emphysematous lesions and interstitial involvement. Following lobar resection, chronic respiratory failure ensued necessitating continuous mechanical ventilation and tracheostomy. Cerebral periventricular nodular heterotopia was also present. Conclusions We report a novel variant of the FLNA gene, associated with a severe lung disorder and PNVH. The lung disorder led to respiratory failure during infancy and these pulmonary complications may be the first sign of this disorder. Early recognition with thoracic imaging is important to guide genetic testing, neuroimaging and to define optimal timing of potential therapies, such as lung transplant in progressive lung disease.
- Published
- 2019
24. The coexistence of a BRCA2 germline and a DICER1 somatic variant in two first-degree cousins suggests their potential synergic effect.
- Author
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Del Baldo G, Mastronuzzi A, Cipri S, Agolini E, Matraxia M, Novelli A, Cacchione A, Serra A, Carai A, Boccuto L, Colafati GS, Di Paolo PL, Miele E, Barresi S, Alaggio R, Rossi S, and Giovannoni I
- Subjects
- Humans, Female, Male, Pedigree, Child, DEAD-box RNA Helicases genetics, Ribonuclease III genetics, BRCA2 Protein genetics, Germ-Line Mutation, Genetic Predisposition to Disease
- Abstract
Cancer predisposition syndromes are recognized in about 10% of pediatric malignancies with several genes specifically involved in a subset of pediatric tumors such as DICER1, in pleuropulmonary blastoma, cystic nephroma, and brain sarcomas. By contrast, the role of BRCA1/2 in pediatric cancer predisposition is still under investigation. We present two cases of young first-degree cousins, both carrying a germline BRCA2 variant and developing tumors characterized by somatic DICER1 mutations. Patient 1 presented with a cystic nephroma harboring a somatic DICER1 variant (p.Asp1810Tyr), while patient 2 had a primary intracranial DICER1-mutated sarcoma showing a distinct somatic DICER1 variant (p.Asp1709Glu) as well as biallelic inactivation of TP53 (p.Val173Leu, VAF 91%) and APC (p.Ile1307Lys, VAF 95%) and a pathogenic variant in KRAS (p.Gln61His). Both patients carried the same germline BRCA2 variant (p.Arg2842Cys) of unknown significance. The same variant was found in the mother of patient 2 and in the father of patient 1, who are siblings. A homologous recombination deficiency signature was not identified in any of the two tumors, possibly suggesting a reduction of BRCA2 activity. The association of BRCA2 and DICER1 variants in our cases hints at a potential cooperative role in cancer pathogenesis. Further studies are warranted to elucidate the interplay between BRCA1/2 and DICER1 variants and their implications for cancer predisposition and treatment in pediatric patients., (© 2024. The Author(s).)
- Published
- 2024
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25. Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders.
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Cali E, Quirin T, Rocca C, Efthymiou S, Riva A, Marafi D, Zaki MS, Suri M, Dominguez R, Elbendary HM, Alavi S, Abdel-Hamid MS, Morsy H, Mau-Them FT, Nizon M, Tesner P, Ryba L, Zafar F, Rana N, Saadi NW, Firoozfar Z, Gencpinar P, Unay B, Ustun C, Bruel AL, Coubes C, Stefanich J, Sezer O, Agolini E, Novelli A, Vasco G, Lettori D, Milh M, Villard L, Zeidler S, Opperman H, Strehlow V, Issa MY, El Khassab H, Chand P, Ibrahim S, Nejad-Rashidi A, Miryounesi M, Larki P, Morrison J, Cristian I, Thiffault I, Bertsch NL, Noh GJ, Pappas J, Moran E, Marinakis NM, Traeger-Synodinos J, Hosseini S, Abbaszadegan MR, Caumes R, Vissers LELM, Neshatdoust M, Montazer MZ, El Fahime E, Canavati C, Kamal L, Kanaan M, Askander O, Voinova V, Levchenko O, Haider S, Halbach SS, Maia ER, Mansoor S, Vivek J, Tawde S, Santhosh R Challa V, Gowda VK, Srinivasan VM, Victor LA, Pinero-Banos B, Hague J, Ei-Awady HA, Maria de Miranda Henriques-Souza A, Cheema HA, Anjum MN, Idkaidak S, Alqarajeh F, Atawneh O, Mor-Shaked H, Harel T, Zifarelli G, Bauer P, Kok F, Kitajima JP, Monteiro F, Josahkian J, Lesca G, Chatron N, Ville D, Murphy D, Neul JL, Mullegama SV, Begtrup A, Herman I, Mitani T, Posey JE, Tay CG, Javed I, Carr L, Kanani F, Beecroft F, Hane L, Abdelkreem E, Macek M, Bispo L, Elmaksoud MA, Hashemi-Gorji F, Pehlivan D, Amor DJ, Jamra RA, Chung WK, Ghayoor EK, Campeau P, Alkuraya FS, Pagnamenta AT, Gleeson J, Lupski JR, Striano P, Moreno-De-Luca A, Lafontaine DLJ, Houlden H, and Maroofian R
- Abstract
Purpose: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear., Methods: We identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis., Results: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular in pre-rRNA processing., Conclusion: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of 'ribosomopathies'., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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26. Identification of a novel GNAS mutation in a family with pseudohypoparathyroidism type 1A.
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Sippelli F, Briuglia S, Ferraloro C, Capra AP, Agolini E, Abbate T, Pepe G, Aversa T, Wasniewska M, and Corica D
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- Humans, Female, Child, Phenotype, Pedigree, Mutation, Adolescent, Child, Preschool, GTP-Binding Protein alpha Subunits, Gs genetics, Pseudohypoparathyroidism genetics, Pseudohypoparathyroidism diagnosis, Chromogranins genetics
- Abstract
Background: Pseudohypoparathyroidism (PHP) is caused by loss-of-function mutations at the GNAS gene (as in the PHP type 1A; PHP1A), de novo or inherited at heterozygous state, or by epigenetic alterations at the GNAS locus (as in the PHP1B). The condition of PHP refers to a heterogeneous group of disorders that share common clinical and biological features of PTH resistance. Manifestations related to resistance to other hormones are also reported in many patients with PHP, in association with the phenotypic picture of Albright hereditary osteodystrophy characterized by short stature, round facies, subcutaneous ossifications, brachydactyly, mental retardation and, in some subtypes, obesity. The purpose of our study is to report a new mutation in the GNAS gene and to describe the significant phenotypic variability of three sisters with PHP1A bearing the same mutation., Case Presentation: We describe the cases of three sisters with PHP1A bearing the same mutation but characterized by a significantly different phenotypic picture at onset and during follow-up in terms of clinical features, auxological pattern and biochemical changes. Clinical exome sequencing revealed a never before described heterozygote mutation in the GNAS gene (NM_000516.5 c.118_139 + 51del) of autosomal dominant maternal transmission in the three siblings, confirming the diagnosis of PHP1A., Conclusions: This study reported on a novel mutation of GNAS gene and highlighted the clinical heterogeneity of PHP1A characterized by wide genotype-phenotype variability. The appropriate diagnosis has crucial implications for patient care and long-term multidisciplinary follow-up., (© 2024. The Author(s).)
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- 2024
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27. A second case report of medulloblastoma in a patient carrying biallelic pathogenic MUTYH germline variants.
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Cipri S, Del Baldo G, Carai A, Cacchione A, Agolini E, Novelli A, Rossi S, Colafati GS, Boccuto L, and Mastronuzzi A
- Subjects
- Humans, Germ-Line Mutation, Mutation, Genetic Predisposition to Disease, Medulloblastoma, Cerebellar Neoplasms, Colorectal Neoplasms pathology
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- 2024
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28. First Case of a Dominant De Novo SEC23A Mutation with Neurological and Psychiatric Features: New Insights into Cranio-Lenticulo-Sutural Dysplasia with Literature Review.
- Author
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Minale EMP, De Falco A, Agolini E, Novelli A, Russo R, Andolfo I, Iolascon A, and Piscopo C
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- Male, Humans, Child, Mutation, Missense, Endoplasmic Reticulum metabolism, Golgi Apparatus metabolism, Vesicular Transport Proteins genetics, Vesicular Transport Proteins metabolism, Intellectual Disability genetics, Intellectual Disability metabolism
- Abstract
Cranio-lenticulo-sutural dysplasia (CLSD, OMIM #607812) is a rare genetic condition characterized by late-closing fontanels, skeletal defects, dysmorphisms, and congenital cataracts that are caused by bi-allelic or monoallelic variants in the SEC23A gene. Autosomal recessive inheritance (AR-CLSD) has been extensively documented in several cases with homozygous or compound heterozygous variants in SEC23A , whereas autosomal dominant inheritance (AD-CLSD) involving heterozygous inherited variants has been reported just in three patients. The SEC23A gene encodes for one of the main components of a protein coat complex known as coat-protein-complex II (COPII), responsible for the generation of the envelope of the vesicles exported from the endoplasmic reticulum (ER) toward the Golgi complex (GC). AR-CLSD and AD-CLSD exhibit common features, although each form also presents distinctive and peculiar characteristics. Herein, we describe a rare case of a 10-year-old boy with a history of an anterior fontanel that closed only at the age of 9. The patient presents with short proportionate stature, low weight, and neurological impairment, including intellectual disability, global developmental delay, abnormal coordination, dystonia, and motor tics, along with dysmorphisms such as a wide anterior fontanel, hypertelorism, frontal bossing, broad nose, high-arched palate, and micrognathia. Trio clinical exome was performed, and a de novo heterozygous missense variant in SEC23A (p.Arg716Cys) was identified. This is the first reported case of CLSD caused by a de novo heterozygous missense variant in SEC23A presenting specific neurological manifestations never described before. For the first time, we have conducted a comprehensive phenotype-genotype correlation using data from our patient and the eight most well-documented cases in the literature. Our work has allowed us to identify the main specific and characteristic signs of both forms of CLSD (AR-CLSD, AD CLSD), offering valuable insights that can guide physicians in the diagnostic process. Notably, detailed descriptions of neurological features such as intellectual disability, global developmental delay, and motor impairment have not been documented before. Furthermore, our literature overview is crucial in the current landscape of CLSD due to the absence of guidelines for the clinical diagnosis and proper follow-up of these patients, especially during childhood.
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- 2024
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29. Case Report: A rare form of congenital erythrocytosis due to SLC30A10 biallelic variants-differential diagnosis and recommendation for biochemical and genetic screening.
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Giannini R, Agolini E, Palumbo G, Novelli A, Garone G, Grasso M, Colafati GS, Matraxia M, Piccirilli E, Deodati A, and Ceglie G
- Abstract
Congenital erythrocytosis recognizes heterogeneous genetic basis and despite the use of NGS technologies, more than 50% of cases are still classified as idiopathic. Herein, we describe the case of a 3-year-old boy with a rare metabolic disorder due to SLC30A10 bi-allelic mutations and characterized by hypermanganesemia, congenital erythrocytosis and neurodegeneration, also known as hypermanganesemia with dystonia 1 (HMNDYT1). The patient was treated with iron supplementation and chelation therapy with CaNa2EDTA, resulting in a significative reduction of blood manganese levels and erythrocytosis indexes. Although it couldn't be excluded that the patient's developmental impairment was part of the phenotypic spectrum of the disease, after three months from starting treatment no characteristic extrapyramidal sign was detectable. Our findings suggest the importance of assessing serum manganese levels in patients with unexplained polycythemia and increased liver enzymes. Moreover, we highlight the importance of extended genetic testing as a powerful diagnostic tool to uncover rare genetic forms of congenital erythrocytosis. In the described patient, identifying the molecular cause of erythrocytosis has proven essential for proper clinical management and access to therapeutic options., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Giannini, Agolini, Palumbo, Novelli, Garone, Grasso, Colafati, Matraxia, Piccirilli, Deodati and Ceglie.)
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- 2024
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30. Case report: A safeguard in the sea of variants of uncertain significance: a case study on child with high risk neuroblastoma and acute myeloid leukemia.
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Fabozzi F, Carrozzo R, Lodi M, Di Giannatale A, Cipri S, Rosignoli C, Giovannoni I, Stracuzzi A, Rizza T, Montante C, Agolini E, Di Nottia M, Galaverna F, Del Baldo G, Del Bufalo F, Mastronuzzi A, and De Ioris MA
- Abstract
The increased availability of genetic technologies has significantly improved the detection of novel germline variants conferring a predisposition to tumor development in patients with malignant disease. The identification of variants of uncertain significance (VUS) represents a challenge for the clinician, leading to difficulties in decision-making regarding medical management, the surveillance program, and genetic counseling. Moreover, it can generate confusion and anxiety for patients and their family members. Herein, we report a 5-year-old girl carrying a VUS in the Succinate Dehydrogenase Complex Subunit C ( SHDC) gene who had been previously treated for high-risk neuroblastoma and subsequently followed by the development of secondary acute myeloid leukemia. In this context, we describe how functional studies can provide additional insight on gene function determining whether the variant interferes with normal protein function or stability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Fabozzi, Carrozzo, Lodi, Di Giannatale, Cipri, Rosignoli, Giovannoni, Stracuzzi, Rizza, Montante, Agolini, Di Nottia, Galaverna, Del Baldo, Del Bufalo, Mastronuzzi and De Ioris.)
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- 2024
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31. Exploiting in silico structural analysis to introduce emerging genotype-phenotype correlations in DHCR24-related sterol biosynthesis disorder: a case study.
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Cocciadiferro D, Mazza T, Vecchio D, Biagini T, Petrizzelli F, Agolini E, Villani A, Minervino D, Martinelli D, Rizzo C, Boenzi S, Panfili FM, Buonuomo PS, Macchiaiolo M, Bartuli A, and Novelli A
- Abstract
Desmosterolosis is a rare sterol biosynthesis disorder characterized by multiple congenital anomalies, failure to thrive, severe developmental delay, progressive epileptic encephalopathy, and elevated levels of desmosterol caused by biallelic mutations of DHCR24 encoding 3-β-hydroxysterol Δ-24-reductase. DHCR24 is regarded as the key enzyme of cholesterol synthesis in the metabolism of brain cholesterol as it catalyzes the reduction of the Δ-24 double bond of sterol intermediates during cholesterol biosynthesis. To date, 15 DHCR24 variants, detected in 2 related and 14 unrelated patients, have been associated with the desmosterolosis disorder. Here, we describe a proband harboring the never-described DHCR24 homozygous missense variant NM_014762.4:c.506T>C, NP_055577.1:p.M169T, whose functional validation was confirmed through biochemical assay. By using molecular dynamics simulation techniques, we investigated the impact of this variant on the protein stability and interaction network with the flavin adenine dinucleotide cofactor, thereby providing a preliminary assessment of its mechanistic role in comparison to all known pathogenic variants, the wild-type protein, and a known benign DHCR24 variant. This report expands the clinical and molecular spectra of the DHCR24-related disorder, reports on a novel DHCR24 deleterious variant associated with desmosterolosis, and gives new insights into genotype-phenotype correlations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Cocciadiferro, Mazza, Vecchio, Biagini, Petrizzelli, Agolini, Villani, Minervino, Martinelli, Rizzo, Boenzi, Panfili, Buonuomo, Macchiaiolo, Bartuli and Novelli.)
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- 2024
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32. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.
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Li D, Wang Q, Bayat A, Battig MR, Zhou Y, Bosch DG, van Haaften G, Granger L, Petersen AK, Pérez-Jurado LA, Aznar-Laín G, Aneja A, Hancarova M, Bendova S, Schwarz M, Kremlikova Pourova R, Sedlacek Z, Keena BA, March ME, Hou C, O'Connor N, Bhoj EJ, Harr MH, Lemire G, Boycott KM, Towne M, Li M, Tarnopolsky M, Brady L, Parker MJ, Faghfoury H, Parsley LK, Agolini E, Dentici ML, Novelli A, Wright M, Palmquist R, Lai K, Scala M, Striano P, Iacomino M, Zara F, Cooper A, Maarup TJ, Byler M, Lebel RR, Balci TB, Louie R, Lyons M, Douglas J, Nowak C, Afenjar A, Hoyer J, Keren B, Maas SM, Motazacker MM, Martinez-Agosto JA, Rabani AM, McCormick EM, Falk MJ, Ruggiero SM, Helbig I, Møller RS, Tessarollo L, Tomassoni Ardori F, Palko ME, Hsieh TC, Krawitz PM, Ganapathi M, Gelb BD, Jobanputra V, Wilson A, Greally J, Jacquemont S, Jizi K, Bruel AL, Quelin C, Misra VK, Chick E, Romano C, Greco D, Arena A, Morleo M, Nigro V, Seyama R, Uchiyama Y, Matsumoto N, Taira R, Tashiro K, Sakai Y, Yigit G, Wollnik B, Wagner M, Kutsche B, Hurst AC, Thompson ML, Schmidt R, Randolph L, Spillmann RC, Shashi V, Higginbotham EJ, Cordeiro D, Carnevale A, Costain G, Khan T, Funalot B, Tran Mau-Them F, Fernandez Garcia Moya L, García-Miñaúr S, Osmond M, Chad L, Quercia N, Carrasco D, Li C, Sanchez-Valle A, Kelley M, Nizon M, Jensson BO, Sulem P, Stefansson K, Gorokhova S, Busa T, Rio M, Hadj Habdallah H, Lesieur-Sebellin M, Amiel J, Pingault V, Mercier S, Vincent M, Philippe C, Fatus-Fauconnier C, Friend K, Halligan RK, Biswas S, Rosser J, Shoubridge C, Corbett M, Barnett C, Gecz J, Leppig K, Slavotinek A, Marcelis C, Pfundt R, de Vries BB, van Slegtenhorst MA, Brooks AS, Cogne B, Rambaud T, Tümer Z, Zackai EH, Akizu N, Song Y, and Hakonarson H
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- Humans, Gene Regulatory Networks, Mutation, Missense, RNA Splicing, RNA Splicing Factors genetics, Nuclear Proteins genetics, DNA Repair Enzymes genetics, Spliceosomes genetics, Neurodevelopmental Disorders genetics
- Abstract
Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
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- 2024
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33. Nucleotide substitutions at the p.Gly117 and p.Thr180 mutational hot-spots of SKI alter molecular dynamics and may affect cell cycle.
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Fusco C, Nardella G, Morlino S, Micale L, Tragni V, Agolini E, Novelli A, Massuras S, Giambra V, Pierri CL, and Castori M
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- Humans, DNA-Binding Proteins metabolism, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Cell Cycle genetics, Transforming Growth Factor beta, Molecular Dynamics Simulation, Marfan Syndrome
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Heterozygous deleterious variants in SKI cause Shprintzen-Goldberg Syndrome, which is mainly characterized by craniofacial features, neurodevelopmental disorder and thoracic aorta dilatations/aneurysms. The encoded protein is a member of the transforming growth factor beta signaling. Paucity of reported studies exploring the SGS molecular pathogenesis hampers disease recognition and clinical interpretation of private variants. Here, the unpublished c.349G>A, p.[Gly117Ser] and the recurrent c.539C>T, p.[Thr180Met] SKI variants were studied combining in silico and in vitro approach. 3D comparative modeling and calculation of the interaction energy predicted that both variants alter the SKI tertiary protein structure and its interactions. Computational data were functionally corroborated by the demonstration of an increase of MAPK phosphorylation levels and alteration of cell cycle in cells expressing the mutant SKI. Our findings confirmed the effects of SKI variants on MAPK and opened the path to study the role of perturbations of the cell cycle in SGS., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)
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- 2024
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34. Early prenatal diagnosis of a recurrent case of short-rib thoracic dysplasia 3 due to compound heterozygosity for variations in the DYNC2H1 gene: an "ultrasound first" approach.
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Fontana P, Agolini E, Cocciadiferro D, Mazzarelli LL, Di Meglio A, Novelli A, Scarano G, Lombardi C, Ciavarella M, and Lonardo F
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- Pregnancy, Female, Humans, Prenatal Diagnosis, Ultrasonography, Ribs, Ultrasonography, Prenatal, Cytoplasmic Dyneins genetics, Short Rib-Polydactyly Syndrome diagnosis, Short Rib-Polydactyly Syndrome genetics, Osteochondrodysplasias diagnostic imaging, Osteochondrodysplasias genetics
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Short-rib thoracic dysplasia 3 with or without polydactyly (OMIM # 613091) represents a clinical spectrum encompassing a heterogeneous group of skeletal dysplasias associated with homozygous or compound heterozygous mutations of DYNC2H1. We describe the case of a couple with two consecutive therapeutic abortions due to a diagnosis of short-rib thoracic dysplasia mutations. In the first pregnancy, the diagnosis has been made at 21 weeks. In the second one, an accurate and early ultrasound examination allowed a diagnosis at 12 weeks. DYNC2H1 mutations were confirmed in both cases. In this report, we underline the importance of an ultrasound evaluation at the end of the first trimester of pregnancy in the detection of early signs of skeletal dysplasias. An early prenatal diagnosis of a short-rib skeletal dysplasia, such as for other severe skeletal dysplasias, is critical to offer a couple the chance of a weighted, informed, and less traumatic decision about the continuation of the pregnancy.
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- 2023
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35. Genetic newborn screening and digital technologies: A project protocol based on a dual approach to shorten the rare diseases diagnostic path in Europe.
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Garnier N, Berghout J, Zygmunt A, Singh D, Huang KA, Kantz W, Blankart CR, Gillner S, Zhao J, Roettger R, Saier C, Kirschner J, Schenk J, Atkins L, Ryan N, Zarakowska K, Zschüntzsch J, Zuccolo M, Müllenborn M, Man YS, Goodman L, Trad M, Chalandon AS, Sansen S, Martinez-Fresno M, Badger S, Walther van Olden R, Rothmann R, Lehner P, Tschohl C, Baillon L, Gumus G, Gross E, Stefanov R, Iskrov G, Raycheva R, Kostadinov K, Mitova E, Einhorn M, Einhorn Y, Schepers J, Hübner M, Alves F, Iskandar R, Mayer R, Renieri A, Piperkova A, Gut I, Beltran S, Matthiesen ME, Poetz M, Hansson M, Trollmann R, Agolini E, Ottombrino S, Novelli A, Bertini E, Selvatici R, Farnè M, Fortunato F, and Ferlini A
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- Infant, Newborn, Humans, Child, Artificial Intelligence, Digital Technology, Europe, Neonatal Screening methods, Rare Diseases diagnosis, Rare Diseases epidemiology, Rare Diseases genetics
- Abstract
Since 72% of rare diseases are genetic in origin and mostly paediatrics, genetic newborn screening represents a diagnostic "window of opportunity". Therefore, many gNBS initiatives started in different European countries. Screen4Care is a research project, which resulted of a joint effort between the European Union Commission and the European Federation of Pharmaceutical Industries and Associations. It focuses on genetic newborn screening and artificial intelligence-based tools which will be applied to a large European population of about 25.000 infants. The neonatal screening strategy will be based on targeted sequencing, while whole genome sequencing will be offered to all enrolled infants who may show early symptoms but have resulted negative at the targeted sequencing-based newborn screening. We will leverage artificial intelligence-based algorithms to identify patients using Electronic Health Records (EHR) and to build a repository "symptom checkers" for patients and healthcare providers. S4C will design an equitable, ethical, and sustainable framework for genetic newborn screening and new digital tools, corroborated by a large workout where legal, ethical, and social complexities will be addressed with the intent of making the framework highly and flexibly translatable into the diverse European health systems., Competing Interests: none., (Copyright: © 2023 Garnier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2023
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36. Identification of a robust DNA methylation signature for Fanconi anemia.
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Pagliara D, Ciolfi A, Pedace L, Haghshenas S, Ferilli M, Levy MA, Miele E, Nardini C, Cappelletti C, Relator R, Pitisci A, De Vito R, Pizzi S, Kerkhof J, McConkey H, Nazio F, Kant SG, Di Donato M, Agolini E, Matraxia M, Pasini B, Pelle A, Galluccio T, Novelli A, Barakat TS, Andreani M, Rossi F, Mecucci C, Savoia A, Sadikovic B, Locatelli F, and Tartaglia M
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- Humans, Fanconi Anemia Complementation Group Proteins genetics, Fanconi Anemia Complementation Group Proteins metabolism, DNA Methylation genetics, Proteins genetics, DNA metabolism, Fanconi Anemia diagnosis, Fanconi Anemia genetics, Fanconi Anemia metabolism
- Abstract
Fanconi anemia (FA) is a clinically variable and genetically heterogeneous cancer-predisposing disorder representing the most common bone marrow failure syndrome. It is caused by inactivating predominantly biallelic mutations involving >20 genes encoding proteins with roles in the FA/BRCA DNA repair pathway. Molecular diagnosis of FA is challenging due to the wide spectrum of the contributing gene mutations and structural rearrangements. The assessment of chromosomal fragility after exposure to DNA cross-linking agents is generally required to definitively confirm diagnosis. We assessed peripheral blood genome-wide DNA methylation (DNAm) profiles in 25 subjects with molecularly confirmed clinical diagnosis of FA (FANCA complementation group) using Illumina's Infinium EPIC array. We identified 82 differentially methylated CpG sites that allow to distinguish subjects with FA from healthy individuals and subjects with other genetic disorders, defining an FA-specific DNAm signature. The episignature was validated using a second cohort of subjects with FA involving different complementation groups, documenting broader genetic sensitivity and demonstrating its specificity using the EpiSign Knowledge Database. The episignature properly classified DNA samples obtained from bone marrow aspirates, demonstrating robustness. Using the selected probes, we trained a machine-learning model able to classify EPIC DNAm profiles in molecularly unsolved cases. Finally, we show that the generated episignature includes CpG sites that do not undergo functional selective pressure, allowing diagnosis of FA in individuals with reverted phenotype due to gene conversion. These findings provide a tool to accelerate diagnostic testing in FA and broaden the clinical utility of DNAm profiling in the diagnostic setting., Competing Interests: Declaration of interests Dr. Sadikovic is a shareholder in EpiSign Inc, a software company involved in commercialization of EpiSign Technology., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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- 2023
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37. De novo PHF5A variants are associated with craniofacial abnormalities, developmental delay, and hypospadias.
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Harms FL, Dingemans AJM, Hempel M, Pfundt R, Bierhals T, Casar C, Müller C, Niermeijer JF, Fischer J, Jahn A, Hübner C, Majore S, Agolini E, Novelli A, van der Smagt J, Ernst R, van Binsbergen E, Mancini GMS, van Slegtenhorst M, Barakat TS, Wakeling EL, Kamath A, Downie L, Pais L, White SM, de Vries BBA, and Kutsche K
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- 2023
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38. Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness.
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Sinibaldi L, Garone G, Mandarino A, Iarossi G, Chioma L, Dentici ML, Merla G, Agolini E, Micalizzi A, Mancini C, Niceta M, Macchiaiolo M, Diodato D, Onesimo R, Blandino R, Delogu AB, De Rosa G, Trevisan V, Iademarco M, Zampino G, Tartaglia M, Novelli A, Bartuli A, Digilio MC, and Calcagni G
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- Humans, Child, beta Catenin genetics, Syndrome, Heart Defects, Congenital diagnosis, Intellectual Disability genetics, Neurodevelopmental Disorders
- Abstract
CTNNB1 [OMIM *116806] encodes β-catenin, an integral part of the cadherin/catenin complex, which functions as effector of Wnt signaling. CTNNB1 is highly expressed in brain as well as in other tissues, including heart. Heterozygous CTNNB1 pathogenic variations are associated with a neurodevelopmental disorder characterized by spastic diplegia and visual defects (NEDSDV) [OMIM #615075], featuring psychomotor delay, intellectual disability, behavioral disturbances, movement disorders, visual defects and subtle facial and somatic features. We report on a new series of 19 NEDSDV patients (mean age 10.3 years), nine of whom bearing novel CTNNB1 variants. Notably, five patients showed congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, and mitral valve prolapse. We focused on the cardiac phenotype characterizing such cases and reviewed the congenital heart defects in previously reported NEDSDV patients. While congenital heart defects had occasionally been reported so far, the present findings configure a higher rate of cardiac anomalies, suggesting dedicated heart examination to NEDSDV clinical management., (© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)
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- 2023
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39. Recurrent, founder and hypomorphic variants contribute to the genetic landscape of Joubert syndrome.
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Serpieri V, Mortarini G, Loucks H, Biagini T, Micalizzi A, Palmieri I, Dempsey JC, D'Abrusco F, Mazzotta C, Battini R, Bertini ES, Boltshauser E, Borgatti R, Brockmann K, D'Arrigo S, Nardocci N, Fischetto R, Agolini E, Novelli A, Romano A, Romaniello R, Stanzial F, Signorini S, Strisciuglio P, Gana S, Mazza T, Doherty D, and Valente EM
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- Humans, Cerebellum abnormalities, Retina abnormalities, Abnormalities, Multiple genetics, Eye Abnormalities genetics, Kidney Diseases, Cystic genetics
- Abstract
Background: Joubert syndrome (JS) is a neurodevelopmental ciliopathy characterised by a distinctive mid-hindbrain malformation, the 'molar tooth sign'. Over 40 JS-associated genes are known, accounting for two-thirds of cases., Methods: While most variants are novel or extremely rare, we report on 11 recurring variants in seven genes, including three known 'founder variants' in the Ashkenazi Jewish, Hutterite and Finnish populations. We evaluated variant frequencies in ~550 European patients with JS and compared them with controls (>15 000 Italian plus gnomAD), and with an independent cohort of ~600 JS probands from the USA., Results: All variants were markedly enriched in the European JS cohort compared with controls. When comparing allele frequencies in the two JS cohorts, the Ashkenazim founder variant ( TMEM216 c.218G>T) was significantly enriched in American compared with European patients with JS, while MKS1 c.1476T>G was about 10 times more frequent among European JS. Frequencies of other variants were comparable in the two cohorts. Genotyping of several markers identified four novel European founder haplotypes.Two recurrent variants ( MKS1 c.1476T>G and KIAA0586 c.428delG), have been detected in homozygosity in unaffected individuals, suggesting they could act as hypomorphic variants. However, while fibroblasts from a MKS1 c.1476T>G healthy homozygote showed impaired ability to form primary cilia and mildly reduced ciliary length, ciliary parameters were normal in cells from a KIAA0586 c.428delG healthy homozygote., Conclusion: This study contributes to understand the complex genetic landscape of JS, explain its variable prevalence in distinct geographical areas and characterise two recurrent hypomorphic variants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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40. BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients.
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Engel C, Valence S, Delplancq G, Maroofian R, Accogli A, Agolini E, Alkuraya FS, Baglioni V, Bagnasco I, Becmeur-Lefebvre M, Bertini E, Borggraefe I, Brischoux-Boucher E, Bruel AL, Brusco A, Bubshait DK, Cabrol C, Cilio MR, Cornet MC, Coubes C, Danhaive O, Delague V, Denommé-Pichon AS, Di Giacomo MC, Doco-Fenzy M, Engels H, Cremer K, Gérard M, Gleeson JG, Heron D, Goffeney J, Guimier A, Harms FL, Houlden H, Iacomino M, Kaiyrzhanov R, Kamien B, Karimiani EG, Kraus D, Kuentz P, Kutsche K, Lederer D, Massingham L, Mignot C, Morris-Rosendahl D, Nagarajan L, Odent S, Ormières C, Partlow JN, Pasquier L, Penney L, Philippe C, Piccolo G, Poulton C, Putoux A, Rio M, Rougeot C, Salpietro V, Scheffer I, Schneider A, Srivastava S, Straussberg R, Striano P, Valente EM, Venot P, Villard L, Vitobello A, Wagner J, Wagner M, Zaki MS, Zara F, Lesca G, Yassaee VR, Miryounesi M, Hashemi-Gorji F, Beiraghi M, Ashrafzadeh F, Galehdari H, Walsh C, Novelli A, Tacke M, Sadykova D, Maidyrov Y, Koneev K, Shashkin C, Capra V, Zamani M, Van Maldergem L, Burglen L, and Piard J
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- Humans, Nuclear Proteins genetics, Phenotype, Genotype, Genetic Association Studies, Atrophy, Epilepsy genetics, Neurodegenerative Diseases genetics
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BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17)., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)
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- 2023
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41. SHH medulloblastoma and very early onset of bowel polyps in a child with PTEN hamartoma tumor syndrome.
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Caroleo AM, Rotulo S, Agolini E, Macchiaiolo M, Boccuto L, Antonelli M, Colafati GS, Cacchione A, Megaro G, Carai A, De Ioris MA, Lodi M, Tornesello A, Simone V, Torroni F, Cinalli G, and Mastronuzzi A
- Abstract
Phosphatase and tensin homolog ( PTEN ) hamartoma tumor syndrome (PHTS) is a cancer predisposition syndrome characterized by an increased risk of developing benign and malignant tumors, caused by germline pathogenic variants of the PTEN tumour suppressor gene. PTEN gene variants often present in childhood with macrocephaly, developmental delay, and/or autism spectrum disorder while tumors and intestinal polyps are commonly detected in adults. PHTS is rarely associated with childhood brain tumors with only two reported cases of medulloblastoma (MB). We report the exceptional case of an infant carrying a germline and somatic pathogenic variant of PTEN and a germline and somatic pathogenic variant of CHEK2 who developed a MB SHH in addition to intestinal polyposis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Caroleo, Rotulo, Agolini, Macchiaiolo, Boccuto, Antonelli, Colafati, Cacchione, Megaro, Carai, De Ioris, Lodi, Tornesello, Simone, Torroni, Cinalli and Mastronuzzi.)
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- 2023
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42. Long-term follow-up in a pediatric patient with Ligneous Conjunctivitis due to PLG gene mutation in topical plasminogen treatment after successful use of ocular prosthesis for aesthetic rehabilitation: a case report.
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Panfili FM, Valente P, Ficari A, Cortellessa F, Vecchio D, Gonfiantini MV, Buonuomo PS, Colafati GS, Agolini E, Bartuli M, Modugno AC, and Macchiaiolo M
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- Adolescent, Female, Humans, Esthetics, Follow-Up Studies, Mutation, Eye, Artificial, Plasminogen
- Abstract
Background: Ligneous Conjunctivitis (LC) is the most common clinical manifestation of Type I Plasminogen deficiency (T1PD; OMIM# 217090), and it is characterized by the formation of pseudomembranes (due to deposition of fibrin) on the conjunctivae leading to progressive vision loss. In past times, patients with LC were treated with surgery, topical anti-inflammatory, cytostatic agents, and systemic immunosuppressive drugs with limited results (Blood 108:3021-3026, 2006, Ophthalmology 129:955-957, 2022, Surv Ophthalmol 48:369-388, 2003, Blood 131:1301-1310, 2018). The surgery can also trigger the development of membranes, as observed in patients needing ocular prosthesis (Surv Ophthalmol 48:369-388, 2003). Treatment with topical purified plasminogen is used to prevent pseudomembranes formation (Blood 108:3021-3026, 2006, Ophthalmology 129:955-957, 2022)., Case Presentation: We present the case of a sixteen-year-old girl with LC with severe left eye involvement. We reported the clinical conditions of the patient before and after the use of topical plasminogen eye drops and described the treatment schedule allowing the surgical procedure for the pseudomembranes debulking and the subsequent use of ocular prosthesis for aesthetic rehabilitation., Conclusions: The patient showed a progressive response to the topical plasminogen, with a complete absence of pseudomembrane formation at a twelve-year follow-up, despite using an ocular prosthesis., (© 2023. Società Italiana di Pediatria.)
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- 2023
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43. Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis.
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Frost FG, Morimoto M, Sharma P, Ruaud L, Belnap N, Calame DG, Uchiyama Y, Matsumoto N, Oud MM, Ferreira EA, Narayanan V, Rangasamy S, Huentelman M, Emrick LT, Sato-Shirai I, Kumada S, Wolf NI, Steinbach PJ, Huang Y, Pusey BN, Passemard S, Levy J, Drunat S, Vincent M, Guet A, Agolini E, Novelli A, Digilio MC, Rosenfeld JA, Murphy JL, Lupski JR, Vezina G, Macnamara EF, Adams DR, Acosta MT, Tifft CJ, Gahl WA, and Malicdan MCV
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- Humans, HeLa Cells, Protein Isoforms genetics, RNA-Seq, Male, Female, Pedigree, Alleles, Infant, Child, Preschool, Child, Adolescent, Protein Structure, Secondary, RNA, Small Nuclear genetics, Paraparesis, Spastic genetics, Alternative Splicing, DNA-Binding Proteins genetics, Transcription Factors genetics
- Abstract
The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development and developmental regression after the first year of life, followed by progressive spasticity that led to gait alterations, paraparesis, and oromotor dysfunction. Most individuals had cerebral, cerebellar, or basal ganglia volume loss by brain MRI. In the available cells from affected individuals, SNAPC4 abundance was decreased compared to unaffected controls, suggesting that the bi-allelic variants affect SNAPC4 accumulation. The depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing. Analysis of available fibroblasts from affected individuals showed decreased snRNA expression and global dysregulation of alternative splicing compared to unaffected cells. Altogether, these data suggest that these bi-allelic SNAPC4 variants result in loss of function and underlie the neuroregression and progressive spasticity in these affected individuals., Competing Interests: Declaration of interests J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Genetics Center, and is a co-inventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic and genomic testing conducted at Baylor Genetics (BG); J.R.L. serves on the Scientific Advisory Board (SAB) of BG., (Published by Elsevier Inc.)
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- 2023
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44. Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy.
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Paul MS, Duncan AR, Genetti CA, Pan H, Jackson A, Grant PE, Shi J, Pinelli M, Brunetti-Pierri N, Garza-Flores A, Shahani D, Saneto RP, Zampino G, Leoni C, Agolini E, Novelli A, Blümlein Tobias B Haack U, Heinritz W, Matzker E, Alhaddad B, Jamra RA, Bartolomaeus T, AlHamdan S, Carapito R, Isidor B, Bahram S, Ritter A, Izumi K, Shakked BP, Barel O, Ben Zeev B, Begtrup A, Carere DA, Mullegama SV, Palculict TB, Calame DG, Schwan K, Aycinena ARP, Traberg R, Douzgou S, Pirt H, Ismayilova N, Banka S, Chao HT, and Agrawal PB
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- 2023
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45. Heterozygous and homozygous variants in STX1A cause a neurodevelopmental disorder with or without epilepsy.
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Luppe J, Sticht H, Lecoquierre F, Goldenberg A, Gorman KM, Molloy B, Agolini E, Novelli A, Briuglia S, Kuismin O, Marcelis C, Vitobello A, Denommé-Pichon AS, Julia S, Lemke JR, Abou Jamra R, and Platzer K
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- Humans, Phenotype, Syntaxin 1 genetics, Heterozygote, Autistic Disorder genetics, Epilepsy genetics, Intellectual Disability pathology, Neurodevelopmental Disorders genetics
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The neuronal SNARE complex drives synaptic vesicle exocytosis. Therefore, one of its core proteins syntaxin 1A (STX1A) has long been suspected to play a role in neurodevelopmental disorders. We assembled eight individuals harboring ultra rare variants in STX1A who present with a spectrum of intellectual disability, autism and epilepsy. Causative variants comprise a homozygous splice variant, three de novo missense variants and two inframe deletions of a single amino acid. We observed a phenotype mainly driven by epilepsy in the individuals with missense variants in contrast to intellectual disability and autistic behavior in individuals with single amino acid deletions and the splicing variant. In silico modeling of missense variants and single amino acid deletions show different impaired protein-protein interactions. We hypothesize the two phenotypic courses of affected individuals to be dependent on two different pathogenic mechanisms: (1) a weakened inhibitory STX1A-STXBP1 interaction due to missense variants results in an STX1A-related developmental epileptic encephalopathy and (2) a hampered SNARE complex formation due to inframe deletions causes an STX1A-related intellectual disability and autism phenotype. Our description of a STX1A-related neurodevelopmental disorder with or without epilepsy thus expands the group of rare diseases called SNAREopathies., (© 2022. The Author(s).)
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- 2023
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46. Coexistence of Genetic Diseases Is a New Clinical Challenge: Three Unrelated Cases of Dual Diagnosis.
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Capra AP, La Rosa MA, Briguori S, Civa R, Passarelli C, Agolini E, Novelli A, and Briuglia S
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- Humans, Diagnosis, Dual (Psychiatry), Stargardt Disease, Homozygote, ATP-Binding Cassette Transporters genetics, Muscular Dystrophies genetics, Substance-Related Disorders
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Technological advancements in molecular genetics and cytogenetics have led to the diagnostic definition of complex or atypical clinical pictures. In this paper, a genetic analysis identifies multimorbidities, one due to either a copy number variant or a chromosome aneuploidy, and a second due to biallelic sequence variants in a gene associated with an autosomal recessive disorder. We diagnosed the simultaneous presence of these conditions, which co-occurred by chance, in three unrelated patients: a 10q11.22q11.23 microduplication and a homozygous variant, c.3470A>G (p.Tyr1157Cys), in the WDR19 gene associated with autosomal recessive ciliopathy; down syndrome and two variants, c.850G>A; p.(Gly284Arg) and c.5374G>T; p.(Glu1792*), in the LAMA2 gene associated with merosin-deficient congenital muscular dystrophy type 1A (MDC1A); and a de novo 16p11.2 microdeletion syndrome and homozygous variant, c.2828G>A (p.Arg943Gln), in the ABCA4 gene associated with Stargardt disease 1 (STGD1). The possibility of being affected by two relatively common or rare inherited genetic conditions would be suspected when signs and symptoms are incoherent with the primary diagnosis. All this could have important implications for improving genetic counseling, determining the correct prognosis, and, consequently, organizing the best long-term follow-up.
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- 2023
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47. CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD.
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Pavinato L, Delle Vedove A, Carli D, Ferrero M, Carestiato S, Howe JL, Agolini E, Coviello DA, van de Laar I, Au PYB, Di Gregorio E, Fabbiani A, Croci S, Mencarelli MA, Bruno LP, Renieri A, Veltra D, Sofocleous C, Faivre L, Mazel B, Safraou H, Denommé-Pichon AS, van Slegtenhorst MA, Giesbertz N, van Jaarsveld RH, Childers A, Rogers RC, Novelli A, De Rubeis S, Buxbaum JD, Scherer SW, Ferrero GB, Wirth B, and Brusco A
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- Animals, Mice, Humans, Haploinsufficiency genetics, Proteins genetics, Cell Cycle Proteins genetics, Autism Spectrum Disorder genetics, Attention Deficit Disorder with Hyperactivity, Induced Pluripotent Stem Cells, Neurodevelopmental Disorders complications, Neurodevelopmental Disorders genetics, Language Development Disorders
- Abstract
We describe an autosomal dominant disorder associated with loss-of-function variants in the Cell cycle associated protein 1 (CAPRIN1; MIM*601178). CAPRIN1 encodes a ubiquitous protein that regulates the transport and translation of neuronal mRNAs critical for synaptic plasticity, as well as mRNAs encoding proteins important for cell proliferation and migration in multiple cell types. We identified 12 cases with loss-of-function CAPRIN1 variants, and a neurodevelopmental phenotype characterized by language impairment/speech delay (100%), intellectual disability (83%), attention deficit hyperactivity disorder (82%) and autism spectrum disorder (67%). Affected individuals also had respiratory problems (50%), limb/skeletal anomalies (50%), developmental delay (42%) feeding difficulties (33%), seizures (33%) and ophthalmologic problems (33%). In patient-derived lymphoblasts and fibroblasts, we showed a monoallelic expression of the wild-type allele, and a reduction of the transcript and protein compatible with a half dose. To further study pathogenic mechanisms, we generated sCAPRIN1+/- human induced pluripotent stem cells via CRISPR-Cas9 mutagenesis and differentiated them into neuronal progenitor cells and cortical neurons. CAPRIN1 loss caused reduced neuronal processes, overall disruption of the neuronal organization and an increased neuronal degeneration. We also observed an alteration of mRNA translation in CAPRIN1+/- neurons, compatible with its suggested function as translational inhibitor. CAPRIN1+/- neurons also showed an impaired calcium signalling and increased oxidative stress, two mechanisms that may directly affect neuronal networks development, maintenance and function. According to what was previously observed in the mouse model, measurements of activity in CAPRIN1+/- neurons via micro-electrode arrays indicated lower spike rates and bursts, with an overall reduced activity. In conclusion, we demonstrate that CAPRIN1 haploinsufficiency causes a novel autosomal dominant neurodevelopmental disorder and identify morphological and functional alterations associated with this disorder in human neuronal models., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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48. Delineation of the clinical profile of CNOT2 haploinsufficiency and overview of the IDNADFS phenotype.
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Niceta M, Pizzi S, Inzana F, Peron A, Bakhtiari S, Nizon M, Levy J, Mancini C, Cogné B, Radio FC, Agolini E, Cocciadiferro D, Novelli A, Salih MA, Recalcati MP, Arancio R, Besnard M, Tabet AC, Kruer MC, Priolo M, Dallapiccola B, and Tartaglia M
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- Humans, Chromosome Deletion, Haploinsufficiency genetics, Phenotype, Repressor Proteins genetics, Neurodevelopmental Disorders genetics, Intellectual Disability diagnosis, Intellectual Disability genetics, Intellectual Disability pathology
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CNOT2 haploinsufficiency underlies a rare neurodevelopmental disorder named Intellectual Developmental disorder with NAsal speech, Dysmorphic Facies, and variable Skeletal anomalies (IDNADFS, OMIM 618608). The condition clinically overlaps with chromosome 12q15 deletion syndrome, suggesting a major contribution of CNOT2 haploinsufficiency to the latter. CNOT2 is a member of the CCR4-NOT complex, which is a master regulator of multiple cellular processes, including gene expression, RNA deadenylation, and protein ubiquitination. To date, less than 20 pathogenic 12q15 microdeletions encompassing CNOT2, together with a single truncating variant of the gene, and two large intragenic deletions have been reported. Due to the small number of affected subjects described so far, the clinical profile of IDNADFS has not been fully delineated. Here we report five unrelated individuals, three of which carrying de novo intragenic CNOT2 variants, one presenting with a multiexon intragenic deletion, and an additional case of 12q15 microdeletion syndrome. Finally, we assess the features of IDNADFS by reviewing published and present affected individuals and reevaluate the clinical phenotype of this neurodevelopmental disorder., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)
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- 2023
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49. Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature.
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van Jaarsveld RH, Reilly J, Cornips MC, Hadders MA, Agolini E, Ahimaz P, Anyane-Yeboa K, Bellanger SA, van Binsbergen E, van den Boogaard MJ, Brischoux-Boucher E, Caylor RC, Ciolfi A, van Essen TAJ, Fontana P, Hopman S, Iascone M, Javier MM, Kamsteeg EJ, Kerkhof J, Kido J, Kim HG, Kleefstra T, Lonardo F, Lai A, Lev D, Levy MA, Lewis MES, Lichty A, Mannens MMAM, Matsumoto N, Maya I, McConkey H, Megarbane A, Michaud V, Miele E, Niceta M, Novelli A, Onesimo R, Pfundt R, Popp B, Prijoles E, Relator R, Redon S, Rots D, Rouault K, Saida K, Schieving J, Tartaglia M, Tenconi R, Uguen K, Verbeek N, Walsh CA, Yosovich K, Yuskaitis CJ, Zampino G, Sadikovic B, Alders M, and Oegema R
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- Mice, Animals, Humans, DNA Methylation genetics, DNA, Mutation, Neurodevelopmental Disorders genetics, Intellectual Disability genetics
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Purpose: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD., Methods: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature., Results: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism., Conclusion: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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50. Safety and Efficacy of Mek Inhibitors in the Treatment of Plexiform Neurofibromas: A Retrospective Study.
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Cacchione A, Fabozzi F, Carai A, Colafati GS, Baldo GD, Rossi S, Diana M, Megaro G, Milano GM, Macchiaiolo M, Crocoli A, De Ioris MA, Boccuto L, Secco DE, Zama M, Agolini E, Tomà P, and Mastronuzzi A
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- Humans, Retrospective Studies, Quality of Life, Protein Kinase Inhibitors adverse effects, Mitogen-Activated Protein Kinase Kinases therapeutic use, Neurofibroma, Plexiform drug therapy, Neurofibroma, Plexiform pathology, Neurofibroma, Plexiform surgery, Neurofibromatosis 1 drug therapy, Neurofibromatosis 1 chemically induced, Neurofibromatosis 1 pathology
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Introduction: Plexiform neurofibromas (PN) represent the main cause of morbidity in patients affected by Neurofibromatosis Type 1 (NF1). Until recently, surgery has been the main treatment option in these patients, but it is burdened with a low efficacy rate and a high incidence of side effects as well as recurrence. In recent years, MEK inhibitors (MEKi) such as selumetinib and trametinib have shown great promise., Methods: We retrospectively describe a single center cohort of NF1 patients affected by PN1 and treated with MEKi since 2019 to 2021. Patients recruited in the study were affected by PN that were not eligible to complete surgical excision, symptomatic or with major cosmetic deformation or functional neurological deficits., Results: Most patients experienced improvement in clinical symptoms and quality of life, with reduction or stabilization of lesions. However, no complete response was achieved. The most common adverse effects involved the skin, affecting every patient. Importantly, no life-threatening adverse effects occurred., Conclusions: In our experience, MEKi treatment has been shown to be both safe and effective in improving symptomatology and quality of life.
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- 2023
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