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1. Cell-free DNA next-generation sequencing liquid biopsy as a new revolutionary approach for arteriovenous malformation

Author

Maria Palmieri, MS, Aurora Currò, MD, Andrea Tommasi, MD, Laura Di Sarno, MS, Gabriella Doddato, MS, Margheria Baldassarri, MD, Elisa Frullanti, MS, Ann Rita Giliberti, MS, Chiara Fallerini, MS, Angelo Spinazzola, MD, Anna Maria Pinto, MD, PhD, Alessandra Renieri, MD, PhD, and Massimo Vaghi, MD

Subjects
Arteriovenous malformation, Liquid biopsy, cf-DNA, KRAS mutation, Noninvasive technique, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Objective: Somatic mosaicism of KRAS gene is currently recognized as the only established molecular basis of arteriovenous malformations (AVM). However, given the limitations of the current technologies, KRAS somatic mutations are detected only in a limited proportion of AVMs and tissue biopsy remains an invasive high risky, sometimes life-threatening, diagnostic procedure. Next-generation sequencing liquid biopsy using cell-free DNA (cfDNA) has emerged as an innovative noninvasive approach for early detection and monitoring of cancer. This approach overcomes the space-time profile constraint of tissue biopsies opens a new scenario for vascular malformations owing to somatic mosaicism. Here, we propose a new approach as a fast noninvasive reliable tool in order to investigate the cfDNA coming from the AVMs. Methods: A group of five patients suffering from AVM were selected. Blood samples from peripheral vein and efferent vein from vascular malformation were collected and cfDNA was extracted. The cfDNA libraries were performed using Oncomine Pan-Cancer Cell-Free Assay. We used Ion Proton for sequencing and Ion Reporter Software for analysis (Life Technologies, Carlsbad, Calif). Results: In all cases, either G12D or G12V mutations in KRAS were identified. The mutational load was higher in the efferent vein than in peripheral blood, confirming the causative role of the identified mutation at a somatic level. Conclusions: We demonstrate that cfDNA next-generation sequencing liquid biopsy is able to identify the KRAS mutation detected in affected tissues. Moreover, we have shown that blood sample withdrawal at the lesion site increases variant allele frequency with an order of magnitude above the limit of detection (usually 0.05%), decreasing the risk of a false negative. Finally, the noninvasiveness of the method avoids any risk of bleeding, being easily performed also in children. We propose this technique as the method of choice to better investigate AVMs and consequently to identify the therapy tailored to the genetic defect. Clinical Relevance: This article highlights the importance of using liquid biopsy as a new method to investigate the molecular profile of AVMs. In view of the frequent inaccessibility of vascular tissues owing to the invasiveness of solid biopsy and the relative high incidence of biopsies with low diagnostic power, here we evaluated the efficacy of detecting cfDNA fragments released into the bloodstream from the affected tissue cells. Through a simple blood draw from the efferent vein at the vascular malformation site, the liquid biopsy allowed us to identify KRAS pathogenic mutations piloting a personalized therapeutic approach and opening a new scenario for new therapeutic strategies.

Published
2020
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2. Corrigendum: Exome Sequencing in BRCA1-2 Candidate Familias: The Contribution of Other Cancer Susceptibility Genes

Author

Gabriella Doddato, Floriana Valentino, Annarita Giliberti, Filomena Tiziana Papa, Rossella Tita, Lucia Pia Bruno, Sara Resciniti, Chiara Fallerini, Elisa Benetti, Maria Palmieri, Maria Antonietta Mencarelli, Alessandra Fabbiani, Mirella Bruttini, Alfredo Orrico, Margherita Baldassarri, Francesca Fava, Diego Lopergolo, Caterina Lo Rizzo, Vittoria Lamacchia, Sara Mannucci, Anna Maria Pinto, Aurora Currò, Virginia Mancini, Oncologic Multidisciplinary Team, Azienda Ospedaliera Universitaria Senese, Azienda Usl Toscana Sud Est, Francesca Mari, Alessandra Renieri, and Francesca Ariani

Subjects
BRCA1, BRCA2, cancer susceptibility genes, HBOC, ES (Exome Sequencing), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2021
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3. Exome Sequencing in BRCA1-2 Candidate Familias: The Contribution of Other Cancer Susceptibility Genes

Author

Gabriella Doddato, Floriana Valentino, Annarita Giliberti, Filomena Tiziana Papa, Rossella Tita, Lucia Pia Bruno, Sara Resciniti, Chiara Fallerini, Elisa Benetti, Maria Palmieri, Maria Antonietta Mencarelli, Alessandra Fabbiani, Mirella Bruttini, Alfredo Orrico, Margherita Baldassarri, Francesca Fava, Diego Lopergolo, Caterina Lo Rizzo, Vittoria Lamacchia, Sara Mannucci, Anna Maria Pinto, Aurora Currò, Virginia Mancini, Oncologic Multidisciplinary Team, Azienda Ospedaliera Universitaria Senese, Oncologic Multidisciplinary Team, Azienda Usl Toscana Sud Est, Francesca Mari, Alessandra Renieri, Francesca Ariani, Alessandro Neri, Donato Casella, Andrea Bernini, Stefania Marsili, Roberto Petrioli, Salvatora Tindara Miano, Alessandra Pascucci, Ignazio Martellucci, Monica Crociani, Marta Vannini, Federica Fantozzi, Andrea Stella, Alessia Carmela Tripodi, Angelamaria Giusti, Alfonso Fausto, Lucia Mantovani, and Francesca Belardi

Subjects
BRCA1, BRCA2, cancer susceptibility genes, HBOC, ES (Exome Sequencing), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is a condition in which the risk of breast and ovarian cancer is higher than in the general population. The prevalent pathogenesis is attributable to inactivating variants of the BRCA1-2 highly penetrant genes, however, other cancer susceptibility genes may also be involved. By Exome Sequencing (ES) we analyzed a series of 200 individuals selected for genetic testing in BRCA1-2 genes according to the updated National Comprehensive Cancer Network (NCCN) guidelines. Analysis by MLPA was performed to detect large BRCA1-2 deletions/duplications. Focusing on BRCA1-2 genes, data analysis identified 11 cases with pathogenic variants (4 in BRCA1 and 7 in BRCA1-2) and 12 with uncertain variants (7 in BRCA1 and 5 in BRCA2). Only one case was found with a large BRCA1 deletion. Exome analysis allowed to characterize pathogenic variants in 21 additional genes: 10 genes more traditionally associated to breast and ovarian cancer (ATM, BRIP1, CDH1, PALB2, PTEN, RAD51C, and TP53) (5% diagnostic yield) and 11 in candidate cancer susceptibility genes (DPYD, ERBB3, ERCC2, MUTYH, NQO2, NTHL1, PARK2, RAD54L, and RNASEL). In conclusion, this study allowed a personalized risk assessment and clinical surveillance in an increased number of HBOC families and to broaden the spectrum of causative variants also to candidate “non-canonical” genes.

Published
2021
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4. Natural history of KBG syndrome in a large European cohort

Author

Lorenzo Loberti, Lucia Pia Bruno, Stefania Granata, Gabriella Doddato, Sara Resciniti, Francesca Fava, Michele Carullo, Elisa Rahikkala, Guillaume Jouret, Leonie A Menke, Damien Lederer, Pascal Vrielynck, Lukáš Ryba, Nicola Brunetti-Pierri, Amaia Lasa-Aranzasti, Anna Maria Cueto-González, Laura Trujillano, Irene Valenzuela, Eduardo F Tizzano, Alessandro Mauro Spinelli, Irene Bruno, Aurora Currò, Franco Stanzial, Francesco Benedicenti, Diego Lopergolo, Filippo Maria Santorelli, Constantia Aristidou, George A Tanteles, Isabelle Maystadt, Tinatin Tkemaladze, Tiia Reimand, Helen Lokke, Katrin Õunap, Maria K Haanpää, Andrea Holubová, Veronika Zoubková, Martin Schwarz, Riina Žordania, Kai Muru, Laura Roht, Annika Tihveräinen, Rita Teek, Ulvi Thomson, Isis Atallah, Andrea Superti-Furga, Sabrina Buoni, Roberto Canitano, Valeria Scandurra, Annalisa Rossetti, Salvatore Grosso, Roberta Battini, Margherita Baldassarri, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Mirella Bruttini, Francesca Mari, Francesca Ariani, Alessandra Renieri, Anna Maria Pinto, Loberti, Lorenzo, Bruno, Lucia Pia, Granata, Stefania, Doddato, Gabriella, Resciniti, Sara, Fava, Francesca, Carullo, Michele, Rahikkala, Elisa, Jouret, Guillaume, Menke, Leonie A, Lederer, Damien, Vrielynck, Pascal, Ryba, Lukáš, Brunetti-Pierri, Nicola, Lasa-Aranzasti, Amaia, Cueto-González, Anna Maria, Trujillano, Laura, Valenzuela, Irene, Tizzano, Eduardo F, Spinelli, Alessandro Mauro, Bruno, Irene, Currò, Aurora, Stanzial, Franco, Benedicenti, Francesco, Lopergolo, Diego, Santorelli, Filippo Maria, Aristidou, Constantia, Tanteles, George A, Maystadt, Isabelle, Tkemaladze, Tinatin, Reimand, Tiia, Lokke, Helen, Õunap, Katrin, Haanpää, Maria K, Holubová, Andrea, Zoubková, Veronika, Schwarz, Martin, Žordania, Riina, Muru, Kai, Roht, Laura, Tihveräinen, Annika, Teek, Rita, Thomson, Ulvi, Isis, Atallah, Superti-Furga, Andrea, Buoni, Sabrina, Canitano, Roberto, Scandurra, Valeria, Rossetti, Annalisa, Grosso, Salvatore, Battini, Roberta, Baldassarri, Margherita, Mencarelli, Maria Antonietta, Rizzo, Caterina Lo, Bruttini, Mirella, Mari, Francesca, Ariani, Francesca, Renieri, Alessandra, Pinto, Anna Maria, General Paediatrics, ANS - Cellular & Molecular Mechanisms, ANS - Complex Trait Genetics, ARD - Amsterdam Reproduction and Development, and Pediatrics

Subjects
Genetics, General Medicine, Molecular Biology, Genetics (clinical)
Abstract

KBG syndrome (KBGS) is characterized by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterize natural history of KBGS. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array- based Comparative Genomic Hybridization and next generation sequencing (NGS) approach investigated both genomic Copy Number Variants and SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while occipitofrontal circumference (median value: −0.88 SD at birth) normalized over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ear-nose-throat (ENT) evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.

Published
2022

5. MET somatic activating mutations are responsible for lymphovenous malformation and can be identified using cell-free DNA next generation sequencing liquid biopsy

Author

Alessandra Renieri, Margherita Baldassarri, Annarita Giliberti, Laura Di Sarno, Elisa Frullanti, Chiara Fallerini, Gabriella Doddato, Andrea Tommasi, Aldo Arzini, Aurora Currò, Anna Maria Pinto, Massimo Vaghi, and Maria Palmieri

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Vascular Malformations, Somatic cell, DNA Mutational Analysis, 030204 cardiovascular system & hematology, medicine.disease_cause, Risk Assessment, Vascular anomaly, Noninvasive technique, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Predictive Value of Tests, Risk Factors, medicine, Activating MET Mutation, Humans, Genetic Predisposition to Disease, Prospective Studies, 030212 general & internal medicine, cfDNA, Liquid biopsy, Genetic Association Studies, Mutation, Lymphatic Abnormalities, business.industry, Vascular malformation, Lymphovenous malformation, MET mutation, Liquid Biopsy, High-Throughput Nucleotide Sequencing, Middle Aged, Proto-Oncogene Proteins c-met, medicine.disease, Phenotype, Lymphatic system, Italy, Female, Surgery, Cardiology and Cardiovascular Medicine, business, Cell-Free Nucleic Acids
Abstract

Objective Germline mutations of either the endothelial cell-specific tyrosine kinase receptor TIE2 or the glomulin (GLMN) gene are responsible for rare inherited venous malformations. Both genes affect the hepatocyte growth factor receptor c-Met, inducing vascular smooth muscle cell migration. Germline mutations of hepatocyte growth factor are responsible for lymphatic malformations, leading to lymphedema. The molecular alteration leading to the abnormal mixed vascular anomaly defined as lymphovenous malformation has remained unknown. Methods A group of 4 patients with lymphovenous malformations were selected. Plasma was obtained from both peripheral and efferent vein samples at the vascular malformation site for cell-free DNA extraction. When possible, we analyzed tissue biopsy samples from the vascular lesion. Results We have demonstrated that in all four patients, an activating MET mutation was present. In three of the four patients, the same pathogenic activating mutation, T1010I, was identified. The mutation was found at the tissue level for the patient with tissue samples available, confirming its causative role in the lymphovenous malformations. Conclusions In the present study, we have demonstrated that cell-free DNA next generation sequencing liquid biopsy is able to identify the MET mutations in affected tissues. Although a wider cohort of patients is necessary to confirm its causative role in lymphovenous malformations, these data suggest that lymphovenous malformations could result from postzygotic somatic mutations in genes that are key regulators of lymphatic development. The noninvasiveness of the method avoids any risk of bleeding and can be easily performed in children. We are confident that the present pioneering results have provided a viable alternative in the future for lymphovenous malformation diagnosis, allowing for subsequent therapy tailored to the genetic defect.

Published
2021

6. Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts

Author

Giuliana, Giannuzzi, Nicolas, Chatron, Katrin, Mannik, Chiara, Auwerx, Sylvain, Pradervand, Gilles, Willemin, Kendra, Hoekzema, Xander, Nuttle, Jacqueline, Chrast, Sadler, Marie C., Eleonora, Porcu, Katrin, Männik, Damien, Sanlaville, Caroline, Schluth-Bolard, Cédric Le Caignec, Mathilde, Nizon, Sandra, Martin, Sébastien, Jacquemont, Armand, Bottani, Marion, Gérard, Sacha, Weber, Aurélia, Jacquette, Catherine, Vincent-Delorme, Aurora, Currò, Francesca, Mari, Alessandra, Renieri, Brusco, Alfredo, Ferrero, Giovanni Battista, Yann, Herault, Bertrand, Isidor, Brigitte, Gilbert-Dussardier, Eichler, Evan E., Zoltan, Kutalik, Alexandre, Reymond, 16p11.2 Consortium, Männik, K., Sanlaville, D., Schluth-Bolard, C., Le Caignec, C., Nizon, M., Martin, S., Jacquemont, S., Bottani, A., Gérard, M., Weber, S., Jacquette, A., Vincent-Delorme, C., Currò, A., Mari, F., Renieri, A., Brusco, A., and Ferrero, G.B.

Subjects
BOLA2, neurodevelopmental disease, Recurrent copy-number variations, CNV, 16p11.2, BOLA2, neurodevelopmental disease, neutropenia, lymphopenia, CNV, Genetics, neutropenia, lymphopenia, 16p11.2, Recurrent copy-number variations, Molecular Biology, Genetics (clinical)
Abstract

Recurrent copy-number variations (CNVs) at chromosome 16p11.2 are associated with neurodevelopmental diseases, skeletal system abnormalities, anemia, and genitourinary defects. Among the 40 protein-coding genes encompassed within the rearrangement, some have roles in leukocyte biology and immunodeficiency, like SPN and CORO1A. We therefore investigated leukocyte differential counts and disease in 16p11.2 CNV carriers. In our clinically-recruited cohort, we identified three deletion carriers from two families (out of 32 families assessed) with neutropenia and lymphopenia. They had no deleterious single-nucleotide or indel variant in known cytopenia genes, suggesting a possible causative role of the deletion. Noticeably, all three individuals had the lowest copy number of the human-specific BOLA2 duplicon (copy-number range: 3–8). Consistent with the lymphopenia and in contrast with the neutropenia associations, adult deletion carriers from UK biobank (n = 74) showed lower lymphocyte (Padj = 0.04) and increased neutrophil (Padj = 8.31e-05) counts. Mendelian randomization studies pinpointed to reduced CORO1A, KIF22, and BOLA2-SMG1P6 expressions being causative for the lower lymphocyte counts. In conclusion, our data suggest that 16p11.2 deletion, and possibly also the lowest dosage of the BOLA2 duplicon, are associated with low lymphocyte counts. There is a trend between 16p11.2 deletion with lower copy-number of the BOLA2 duplicon and higher susceptibility to moderate neutropenia. Higher numbers of cases are warranted to confirm the association with neutropenia and to resolve the involvement of the deletion coupled with deleterious variants in other genes and/or with the structure and copy number of segments in the CNV breakpoint regions.

Published
2022

7. Cell-free DNA next-generation sequencing liquid biopsy as a new revolutionary approach for arteriovenous malformation

Author

Alessandra Renieri, Laura Di Sarno, Gabriella Doddato, Massimo Vaghi, Aurora Currò, Anna Maria Pinto, Chiara Fallerini, Margheria Baldassarri, Elisa Frullanti, Ann Rita Giliberti, Angelo Spinazzola, Maria Palmieri, and Andrea Tommasi

Subjects
Pathology, medicine.medical_specialty, medicine.disease_cause, Arteriovenous malformation, Noninvasive technique, Biopsy, medicine, Diseases of the circulatory (Cardiovascular) system, Clinical significance, Liquid biopsy, cf-DNA, KRAS mutation, medicine.diagnostic_test, business.industry, Vascular malformation, Basic Reserch Study, Cancer, medicine.disease, Cell-free fetal DNA, RC666-701, Malformations, KRAS, business
Abstract

Objective Somatic mosaicism of KRAS gene is currently recognized as the only established molecular basis of arteriovenous malformations (AVM). However, given the limitations of the current technologies, KRAS somatic mutations are detected only in a limited proportion of AVMs and tissue biopsy remains an invasive high risky, sometimes life-threatening, diagnostic procedure. Next-generation sequencing liquid biopsy using cell-free DNA (cfDNA) has emerged as an innovative noninvasive approach for early detection and monitoring of cancer. This approach overcomes the space-time profile constraint of tissue biopsies opens a new scenario for vascular malformations owing to somatic mosaicism. Here, we propose a new approach as a fast noninvasive reliable tool in order to investigate the cfDNA coming from the AVMs. Methods A group of five patients suffering from AVM were selected. Blood samples from peripheral vein and efferent vein from vascular malformation were collected and cfDNA was extracted. The cfDNA libraries were performed using Oncomine Pan-Cancer Cell-Free Assay. We used Ion Proton for sequencing and Ion Reporter Software for analysis (Life Technologies, Carlsbad, Calif). Results In all cases, either G12D or G12V mutations in KRAS were identified. The mutational load was higher in the efferent vein than in peripheral blood, confirming the causative role of the identified mutation at a somatic level. Conclusions We demonstrate that cfDNA next-generation sequencing liquid biopsy is able to identify the KRAS mutation detected in affected tissues. Moreover, we have shown that blood sample withdrawal at the lesion site increases variant allele frequency with an order of magnitude above the limit of detection (usually 0.05%), decreasing the risk of a false negative. Finally, the noninvasiveness of the method avoids any risk of bleeding, being easily performed also in children. We propose this technique as the method of choice to better investigate AVMs and consequently to identify the therapy tailored to the genetic defect. Clinical Relevance This article highlights the importance of using liquid biopsy as a new method to investigate the molecular profile of AVMs. In view of the frequent inaccessibility of vascular tissues owing to the invasiveness of solid biopsy and the relative high incidence of biopsies with low diagnostic power, here we evaluated the efficacy of detecting cfDNA fragments released into the bloodstream from the affected tissue cells. Through a simple blood draw from the efferent vein at the vascular malformation site, the liquid biopsy allowed us to identify KRAS pathogenic mutations piloting a personalized therapeutic approach and opening a new scenario for new therapeutic strategies.

Published
2020

8. Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants

Author

Ji-eun Yoon, Arjun Krishnan, Marie Vincent, Marco Fichera, Claire Beneteau, Erik A. Sistermans, Nathalie Marle, Luana Mandarà, Sau Wai Cheung, R. Frank Kooy, Teresa Mattina, Rachel L. Kember, Mathilde Nizon, Jill A. Rosenfeld, Alexandre Reymond, Bertrand Isidor, Sophie Blesson, Jean-Hubert Caberg, Cindy Skinner, Emanuela Avola, Charles Perrine, Paolo Prontera, Susan Zeesman, Małgorzata J.M. Nowaczyk, Kate Pope, Lucilla Pizzo, David J. Amor, Boris Keren, Matthew Jensen, Katrin Männik, Patrick Callier, Pawel Stankiewicz, Damian Pazuchanics, Els Voorhoeve, Ornella Galesi, Joris Andrieux, Lucia Castiglia, Anne Laure Mosca-Boidron, Mathilde Lefebvre, Charles E. Schwartz, Santhosh Girirajan, Elizabeth McCready, Anke Van Dijck, Sandra Mercier, Maja Bucan, Corrado Romano, Laurence Faivre, Francesca Mari, Dominique Martin-Coignard, Vijay Kumar, Alessandra Renieri, Andrew Polyak, Emily Huber, Cédric Le Caignec, Aurora Currò, Olivier Pichon, Pennsylvania State University (Penn State), Penn State System, Baylor College of Medicine (BCM), Baylor University, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Michigan State University [East Lansing], Michigan State University System, McMaster University [Hamilton, Ontario], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Antwerp University Hospital [Edegem] (UZA), Murdoch Children's Research Institute (MCRI), Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Perelman School of Medicine, University of Pennsylvania [Philadelphia], Medical Genetics, Service de Génétique Médicale, Hôpital Bretonneau, Tours, Laboratoire de génétique médicale et cytogénétique [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Liège (CHU-Liège), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Greenwood Genetic Center, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Greenwood Genetic Center [Greenwood, South Carolina, USA], Institut de Génétique Médicale [CHRU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)

Subjects
Male, Parents, 0301 basic medicine, Proband, Neuronal, Genetic Carrier Screening, 16p11.2 deletion, 030105 genetics & heredity, Cognition, Family history, Neural Cell Adhesion Molecules, Genetics (clinical), Exome sequencing, Sequence Deletion, Genetics, Phenotype, Penetrance, Pedigree, Autistic Disorder/genetics, Autistic Disorder/physiopathology, Cell Adhesion Molecules, Neuronal/genetics, Chromosomes, Human, Pair 16/genetics, Cognition/physiology, DNA Copy Number Variations/genetics, Female, Gene Expression Regulation/genetics, Genetic Background, Humans, Methyltransferases/genetics, Nerve Tissue Proteins/genetics, Proteins/genetics, Sequence Deletion/genetics, Siblings, CNV, autism, modifier, phenotypic variability, Human, DNA Copy Number Variations, Cell Adhesion Molecules, Neuronal, Nerve Tissue Proteins, Biology, Chromosomes, Article, 03 medical and health sciences, mental disorders, medicine, Autistic Disorder, Gene, Pair 16, Calcium-Binding Proteins, Proteins, Methyltransferases, medicine.disease, Cytoskeletal Proteins, 030104 developmental biology, Gene Expression Regulation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, Human medicine, Chromosomes, Human, Pair 16, Cell Adhesion Molecules, Transcription Factors
Abstract

Purpose: To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. Methods: We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. Results: The number of rare likely deleterious variants in functionally intolerant genes (“other hits”) correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. Conclusion: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.

Published
2019

9. A pilot study of next generation sequencing–liquid biopsy on cell-free DNA as a novel non-invasive diagnostic tool for Klippel–Trenaunay syndrome

Author

Luca Primo, Aurora Currò, Margherita Baldassarri, Gabriella Doddato, Francesco Molinaro, Benedetta Mussolin, Elisa Frullanti, Maria Palmieri, Massimo Vaghi, Alessandra Renieri, Annarita Giliberti, Chiara Fallerini, Laura di Blasio, Valentina Monica, Laura Di Sarno, and Anna Maria Pinto

Subjects
Male, Klippel-Trenaunay-Weber Syndrome, Pathology, Klippel-Trenaunay syndrome, cell-free DNA-next generation sequencing–liquid biopsy, Klippel–Trenaunay syndrome, non-invasive technique, PIK3CA mutation, Slow-flow vascular malformations, vascular system injuries, Somatic cell, Pilot Projects, 030204 cardiovascular system & hematology, 0302 clinical medicine, Medicine, 0303 health sciences, Mosaicism, High-Throughput Nucleotide Sequencing, General Medicine, Middle Aged, Prognosis, Phenotype, Cell-free fetal DNA, Female, Cardiology and Cardiovascular Medicine, Cell-Free Nucleic Acids, Adult, Genetic Markers, medicine.medical_specialty, Class I Phosphatidylinositol 3-Kinases, Clinical Decision-Making, DNA sequencing, 03 medical and health sciences, PIK3CA gene, Predictive Value of Tests, Humans, Radiology, Nuclear Medicine and imaging, Liquid biopsy, 030304 developmental biology, business.industry, Pik3ca mutation, Non invasive, Liquid Biopsy, DNA, Sequence Analysis, DNA, medicine.disease, Mutation, Surgery, business
Abstract

Objectives Somatic mosaicism of PIK3CA gene is currently recognized as the molecular driver of Klippel–Trenaunay syndrome. However, given the limitation of the current technologies, PIK3CA somatic mutations are detected only in a limited proportion of Klippel–Trenaunay syndrome cases and tissue biopsy remains an invasive high risky, sometimes life-threatening, diagnostic procedure. Next generation sequencing liquid biopsy using cell-free DNA has emerged as an innovative non-invasive approach for early detection and monitoring of cancer. This approach, overcoming the space-time profile constraint of tissue biopsies, opens a new scenario also for others diseases caused by somatic mutations. Methods In the present study, we performed a comprehensive analysis of seven patients (four females and three males) with Klippel–Trenaunay syndrome. Blood samples from both peripheral and efferent vein from malformation were collected and cell-free DNA was extracted from plasma. Tissue biopsies from vascular lesions were also collected when available. Cell-free DNA libraries were performed using Oncomine™ Pan-Cancer Cell-Free Assay. Ion Proton for sequencing and Ion Reporter Software for analysis were used (Life Technologies, Carlsbad, CA, USA). Results Cell-free circulating DNA analysis revealed pathogenic mutations in PIK3CA gene in all patients. The mutational load was higher in plasma obtained from the efferent vein at lesional site (0.81%) than in the peripheral vein (0.64%) leading to conclude for a causative role of the identified variants. Tissue analysis, available for one amputated patient, confirmed the presence of the mutation at the malformation site at a high molecular frequency (14–25%), confirming its causative role. Conclusions Our data prove for the first time that the cell-free DNA-next generation sequencing–liquid biopsy, which is currently used exclusively in an oncologic setting, is indeed the most effective tool for Klippel–Trenaunay syndrome diagnosis and tailored personalized treatment.

Published
2021

10. Author response for '<scp>IQSEC2</scp> disorder: a new disease entity or a Rett spectrum continuum?'

Author

Anna Maria Pinto, Diego Lopergolo, Roberto Canitano, Flavia Privitera, Judith Armstrong, Gian Paolo Ramelli, Caterina Lo Rizzo, Hilde Van Esch, Gerardo Mejia Baltodano, Alessandra Renieri, Sabrina Mueller, Vittoria Lamacchia, Maria Antonietta Mencarelli, Maria Del Carmen Fons-Estupina, Aurora Currò, Mercè Pineda, Lionel Van Maldergem, Damien Lederer, Candy Kumps, Francesca Ariani, Elisabetta Vaghi, Bert Callewaert, Mercedes Serrano, Giuseppe Castello, Alessandra Ferrarini, Jeroen Breckpot, and Francesca Mari

Subjects
Physics, Theoretical physics, Continuum (measurement), New disease, Spectrum (topology)
Published
2020

11. IQSEC2 disorder: A new disease entity or a Rett spectrum continuum?

Author

Anna Maria Pinto, Giuseppe Castello, Lionel Van Maldergem, Caterina Lo Rizzo, Alessandra Ferrarini, Vittoria Lamacchia, Jeroen Breckpot, Candy Kumps, Damien Lederer, Francesca Mari, Alessandra Renieri, Mercè Pineda, Elisabetta Vaghi, Diego Lopergolo, Judith Armstrong, Francesca Ariani, Maria Del Carmen Fons-Estupina, Flavia Privitera, Mercedes Serrano, Sabrina Mueller, Gian Paolo Ramelli, Roberto Canitano, Bert Callewaert, Gerardo Mejia Baltodano, Hilde Van Esch, Maria Antonietta Mencarelli, and Aurora Currò

Subjects
0301 basic medicine, Male, INTELLECTUAL DISABILITY, 030105 genetics & heredity, Bioinformatics, phenotype-genotype, IQSEC2, Rett syndrome, Intellectual disability, Medicine and Health Sciences, Guanine Nucleotide Exchange Factors, Genetics(clinical), intellectual disability, Child, Genetics (clinical), Clinical course, Middle Aged, Phenotype, New disease, Child, Preschool, Phenotype genotype, INACTIVATION, Female, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, PHENOTYPIC VARIABILITY, Diagnosis, Differential, 03 medical and health sciences, Young Adult, Intellectual Disability, Exome Sequencing, Genetics, medicine, Rett Syndrome, Humans, Point Mutation, Genetic Association Studies, LANDSCAPE, MUTATIONS, business.industry, Point mutation, medicine.disease, GENE, 030104 developmental biology, Differential diagnosis, business
Abstract

IQSEC2 mutations are associated with IQSEC2-related intellectual disability (ID). Phenotypic spectrum has been better defined in the last few years by the increasing number of reported cases although the genotype-phenotype relationship for IQSEC2 remains overall complex. As for IQSEC2-related ID a wide phenotypic diversity has been described in Rett syndrome (RTT). Several patients harboring IQSEC2 mutations present with clinical symptoms similar to RTT and some cases meet most of the criteria for classic RTT. With the aim of establishing a genotype-phenotype correlation, we collected data of 16 patients harboring IQSEC2 point mutations (15 of them previously unreported) and of five novel patients carrying CNVs encompassing IQSEC2. Most of our patients surprisingly shared a moderate-to-mild phenotype. The similarities in the clinical course between our mild cases and patients with milder forms of atypical RTT reinforce the hypothesis that also IQSEC2 mutated patients may lay under the wide clinical spectrum of RTT and thus IQSEC2 should be considered in the differential diagnosis. Our data confirm that position, type of variant and gender are crucial for IQSEC2-associated phenotype delineation.

Published
2020

12. CDKL5 mutations may mimic Pitt-Hopkins syndrome phenotype

Author

Aurora Currò, Giuseppe Marangi, Anna Maria Pinto, Mirella Bruttini, Michele Zappella, Alessandra Renieri, Marcella Zollino, and Gabriella Doddato

Subjects
0301 basic medicine, Adult, Encephalopathy, CDKL5, Pitt–Hopkins syndrome, 030105 genetics & heredity, Protein Serine-Threonine Kinases, Bioinformatics, Settore MED/03 - GENETICA MEDICA, Diagnosis, Differential, 03 medical and health sciences, Epilepsy, Pitt-hopkins, Intellectual Disability, Differential diagnosis, Overlapping phenotypes, Rett, Genetics, Medicine, Humans, Hyperventilation, Atypical Rett syndrome, Genetics (clinical), Adult patients, business.industry, Facies, General Medicine, medicine.disease, Phenotype, 030104 developmental biology, Mutation, Female, business
Abstract

Genetic conditions comprise a wide spectrum of different phenotypes, rapidly expanding due to new diagnostic methodologies. Patients’ facial features and clinical history represent the key elements leading clinicians to the right diagnosis. CDKL5-early onset epilepsy and Pitt-Hopkins syndrome are two well-known genetic conditions, with a defined phenotype sharing some common characteristics like early-onset epilepsy and hyperventilation episodes. Whilst facial features represent a diagnostic handle in patients with Pitt-Hopkins syndrome, clinical history is crucial in patients carrying a mutation in CDKL5. Here we present the clinical case of a girl evaluated for the first time when she was 24-years old, with a clinical phenotype mimicking Pitt-Hopkins syndrome. Her facial features have become coarser while she was growing up, leading geneticists to raise different clinical hypotheses and to perform several molecular tests before getting the diagnosis of CDKL5-early-epileptic encephalopathy. This finding highlights that although typical facial gestalt has not so far extensively been described in CDKL5 mutated adult patients, peculiar facial features could be present later in life and may let CDKL5-related disorder mimic Pitt Hopkins. Thus, considering atypical Rett syndrome in the differential diagnosis of Pitt Hopkins syndrome could be important to solve complex clinical cases.

Published
2020

13. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Author

Gail E. Herman, Jennifer Reichert, Camilla Stoltenberg, Stephen Sanders, Menachem Fromer, Branko Aleksic, Julian Maller, Rachel Nguyen, Utku Norman, J. Jay Gargus, Donna M. Werling, David J. Cutler, Silvia De Rubeis, Kathryn Roeder, Ryan N. Doan, Sherif Gerges, Joseph D. Buxbaum, Per Magnus, Patrick Turley, Moyra Smith, Isaac N. Pessah, Rebecca J. Schmidt, Chiara Fallerini, Michael E. Talkowski, Carla Lintas, Pål Surén, Paige M. Siper, Duncan S. Palmer, Timothy W. Yu, Michael S. Breen, Sven Sandin, Esben Agerbo, Rich Belliveau, Antonio M. Persico, Elaine Cristina Zachi, Matthew W. State, Karoline Teufel, Margaret A. Pericak-Vance, Caitlin E. Carey, Ryan Collins, Lambertus Klei, Lara Tang, Mads V. Hollegaard, Ole Mors, Iuliana Ionita-Laza, Elisa Giorgio, Astanand Jugessur, Gerry Schellenberg, Christopher A. Walsh, A. Ercument Cicek, Caroline Dias, Gun Peggy Knudsen, Louise Gallagher, Elise B. Robinson, Abraham Reichenberg, Judith Miller, Ashley Dumont, Flora Tassone, Grace Schwartz, Peter Szatmari, Jacqueline I. Goldstein, Evelise Riberi, Brian H.Y. Chung, Stephen W. Scherer, Fátima Lopes, Jesslyn Jamison, Thomas Werge, Mara Parellada, Gabriela Soares, Hilary Coon, Shan Dong, Terho Lehtimäki, Norio Ozaki, Lauren A. Weiss, Susan L. Santangelo, F. Kyle Satterstrom, Daniel P. Howrigan, Emily Hansen-Kiss, Anders D. Børglum, Vivek Appadurai, Maria Rita Passos-Bueno, Hailiang Huang, Marcus C.Y. Chan, Eric M. Morrow, Stephen J. Guter, Catalina Betancur, Ditte Demontis, Matthew W. Mosconi, Pierandrea Muglia, Joanna Martin, Jack A. Kosmicki, Christine M. Freitag, Suma Jacob, W. Ian Lipkin, Angel Carracedo, Mark J. Daly, Andreas G. Chiocchetti, Eduarda Montenegro M. de Souza, Carsten Bøcker Pedersen, Isabela Maya Wahys Silva, Elizabeth E. Guerrero, Mafalda Barbosa, A. Jeremy Willsey, Maureen Mulhern, Claire Churchhouse, Raymond K. Walters, Timothy Poterba, Alessandra Renieri, Emilie M. Wigdor, Lauren M. Schmitt, Jennifer L. Moran, Mullin H.C. Yu, Edwin H. Cook, Jiebiao Wang, Behrang Mahjani, Kaitlin E. Samocha, Kaija Puura, Xin He, Ezra Susser, Aarno Palotie, Bernardo Dalla Bernardina, Montserrat Fernández-Prieto, Thomas Damm Als, Mykyta Artomov, Emma Wilkinson, Mads E. Hauberg, Enrico Domenici, Joon Yong An, Christine Søholm Hansen, Somer L. Bishop, Idan Menashe, So Lun Lee, Marianne Giørtz Pedersen, Alfredo Brusco, Nancy J. Minshew, Michael E. Zwick, Jesper Buchhave Poulsen, Elaine T. Lim, Benjamin M. Neale, Harrison Brand, Danielle Halpern, Elisabetta Trabetti, Alexander Kolevzon, Christine Stevens, Aurora Currò, Miia Kaartinen, Gal Meiri, Richard Anney, Søren Dalsgaard, Minshi Peng, Kimberly Chambert, Brooke Sheppard, Yunin Ludena, James S. Sutcliffe, Marie Bækvad-Hansen, Xinyi Xu, Audrey Thurm, Itaru Kushima, Michael Gill, Irva Hertz-Picciotto, Jonatan Pallesen, Stephan Ripke, Dara S. Manoach, Giovanni Battista Ferrero, Nell Maltman, Michael L. Cuccaro, David M. Hougaard, Javier González-Peñas, Wesley K. Thompson, Felecia Cerrato, Danielle de Paula Moreira, Jonas Bybjerg-Grauholm, Alicia R. Martin, Merete Nordentoft, John A. Sweeney, Alfonso Buil, Tarjinder Singh, Bernie Devlin, Jakob Grove, Daniel H. Geschwind, Manuel Mattheisen, Patrícia Maciel, Preben Bo Mortensen, Andrew J. Schork, Ryan Yuen, Christina M. Hultman, Maria del Pilar Trelles, Aparna Bhaduri, Sabine Schlitt, Diego Lopergolo, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Carnegie Mellon University [Pittsburgh] (CMU), Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of California [San Francisco] (UCSF), University of California, Korea University [Seoul], The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University [Aarhus], Center for Genomics and Personalized Medicine [Aarhus, Denmark] (CGPM), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research [San Francisco, CA, USA], Bilkent University [Ankara], University of California [Irvine] (UCI), Medical Investigation of Neurodevelopmental Disorders Institute [Davis, CA, USA] (MIND), University of California [Davis] (UC Davis), University of California-University of California, Boston Children's Hospital, Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Illinois [Chicago] (UIC), University of Illinois System, Trinity College Dublin, Vanderbilt University School of Medicine [Nashville], National Institute of Mental Health (NIMH), Emory University School of Medicine, Emory University [Atlanta, GA], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Autism Sequencing Consortium : Branko Aleksic, Richard Anney, Mafalda Barbosa, Somer Bishop, Alfredo Brusco, Jonas Bybjerg-Grauholm, Angel Carracedo, Marcus C.Y. Chan, Andreas G. Chiocchetti, Brian H.Y. Chung, Hilary Coon, Michael L. Cuccaro, Aurora Curro´ , Bernardo Dalla Bernardina, Ryan Doan, Enrico Domenici, Shan Dong, Chiara Fallerini, Montserrat Ferna´ ndez-Prieto, Giovanni Battista Ferrero, Christine M. Freitag, Menachem Fromer, J. Jay Gargus, Daniel Geschwind, Elisa Giorgio, Javier Gonza´ lez-Pen˜ as, Stephen Guter, Danielle Halpern, Emily HansenKiss, Xin He, Gail E. Herman, Irva Hertz-Picciotto, David M. Hougaard, Christina M. Hultman, Iuliana Ionita-Laza, Suma Jacob, Jesslyn Jamison, Astanand Jugessur, Miia Kaartinen, Gun Peggy Knudsen, Alexander Kolevzon, Itaru Kushima, So Lun Lee, Terho Lehtima¨ ki, Elaine T. Lim, Carla Lintas, W. Ian Lipkin, Diego Lopergolo, Fa´ tima Lopes, Yunin Ludena, Patricia Maciel, Per Magnus, Behrang Mahjani, Nell Maltman, Dara S. Manoach, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Eduarda M.S. Montenegro, Danielle Moreira, Eric M. Morrow, Ole Mors, Preben Bo Mortensen, Matthew Mosconi, Pierandrea Muglia, Benjamin M. Neale, Merete Nordentoft, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Margaret Pericak-Vance, Antonio M. Persico, Isaac Pessah, Kaija Puura, Abraham Reichenberg, Alessandra Renieri, Evelise Riberi, Elise B. Robinson, Kaitlin E. Samocha, Sven Sandin, Susan L. Santangelo, Gerry Schellenberg, Stephen W. Scherer, Sabine Schlitt, Rebecca Schmidt, Lauren Schmitt, Isabela M.W. Silva, Tarjinder Singh, Paige M. Siper, Moyra Smith, Gabriela Soares, Camilla Stoltenberg, Pa˚ l Suren, Ezra Susser, John Sweeney, Peter Szatmari, Lara Tang, Flora Tassone, Karoline Teufel, Elisabetta Trabetti, Maria del Pilar Trelles, Christopher A. Walsh, Lauren A. Weiss, Thomas Werge, Donna M. Werling, Emilie M. Wigdor, Emma Wilkinson, A. Jeremy Willsey, Timothy W. Yu, Mullin H.C. Yu, Ryan Yuen, and Elaine Zachi. and iPSYCH-Broad Consortium : e Esben Agerbo, Thomas Damm Als, Vivek Appadurai, Marie Bækvad-Hansen, Rich Belliveau, Alfonso Buil, Caitlin E. Carey, Felecia Cerrato, Kimberly Chambert, Claire Churchhouse, Søren Dalsgaard, Ditte Demontis, Ashley Dumont, Jacqueline Goldstein, Christine S. Hansen, Mads Engel Hauberg, Mads V. Hollegaard, Daniel P. Howrigan, Hailiang Huang, Julian Maller, Alicia R. Martin, Joanna Martin, Manuel Mattheisen, Jennifer Moran, Jonatan Pallesen, Duncan S. Palmer, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Timothy Poterba, Jesper Buchhave Poulsen, Stephan Ripke, Andrew J. Schork, Wesley K. Thompson, Patrick Turley, and Raymond K. Walters., Norman, Utku, Çicek, A. Ercüment, Betancur, Catalina, University of California [San Francisco] (UC San Francisco), University of California (UC), University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki

Subjects
Male, INTELLECTUAL DISABILITY, genetic structures, MESH: Neurons, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Whole Exome Sequencing, Cohort Studies, 0302 clinical medicine, Gene Frequency, Neurobiology, MESH: Gene Expression Regulation, Developmental, Spectrum disorder, Exome, Developmental, genetics, Copy-number variation, excitatory-inhibitory balance, MESH: Cohort Studies, Exome sequencing, Genetics, Cerebral Cortex, Neurons, 0303 health sciences, MESH: Exome, autism spectrum disorder, cell type, cytoskeleton, excitatory neurons, exome sequencing, inhibitory neurons, liability, neurodevelopment, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, Phenotype, Autism spectrum disorder, Female, Single-Cell Analysis, AGED 8 YEARS, MESH: Autistic Disorder, UNITED-STATES, GENETIC RISK, Biology, MESH: Phenotype, behavioral disciplines and activities, SAND DOMAIN, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Sex Factors, MESH: Sex Factors, MESH: Whole Exome Sequencing, MESH: Neurobiology, mental disorders, medicine, MESH: Gene Frequency, Humans, Cell Lineage, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Autistic Disorder, Allele frequency, Case-Control Studies, Mutation, Missense, Gene Expression Regulation, Developmental, SPECTRUM DISORDER, COPY NUMBER VARIATION, 030304 developmental biology, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Cell Lineage, medicine.disease, MESH: Male, MESH: Cerebral Cortex, DISABILITIES MONITORING NETWORK, Gene Expression Regulation, DE-NOVO MUTATIONS, Mutation, Autism, Missense, MESH: Female, 030217 neurology & neurosurgery, MESH: Single-Cell Analysis
Abstract

International audience; We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

Published
2020

14. MEIS2 gene is responsible for intellectual disability, cardiac defects and a distinct facial phenotype

Author

Gianni Coriolani, Salvatore Grosso, Filomena Tiziana Papa, Francesca Mari, Annarita Giliberti, Francesca Ariani, Elisa Frullanti, Alessandra Renieri, and Aurora Currò

Subjects
0301 basic medicine, Heart Septal Defects, Ventricular, Male, Heart Diseases, Developmental Disabilities, Nonsense mutation, Intellectual disability, 030105 genetics & heredity, Ventricular septal defect, Bioinformatics, MEIS2, 03 medical and health sciences, Exome analysis, MEIS2 Gene, Exome Sequencing, Genetics, medicine, Humans, Exome, Child, Genetics (clinical), Exome sequencing, Low anterior hairline, Homeodomain Proteins, business.industry, Point mutation, General Medicine, medicine.disease, Phenotype, Mutagenesis, Insertional, 030104 developmental biology, Face, Mutation, Gastrointestinal function, business, Transcription Factors
Abstract

Myeloid ecotropic insertion site 2 (MEIS2) gene, encoding a homeodomain-containing transcription factor, has been recently related to syndromic intellectual disability with cleft palate and cardiac defects. Here, we present a male patient, aged 10, with cardiac defects, intellectual disability, facial dysmorphisms and gastroesophageal reflux. Whole exome sequencing revealed a novel de novo nonsense mutation in the MEIS2 gene. This patient represents another reported case with a de novo MEIS2 point mutation and helps to characterize a distinct facial phenotype consisting in low anterior hairline, thin eyebrows, anteverted nares, hypoplastic alae nasi, and M-shape upper lip. Furthermore, these data confirm the role of this gene in cardiac, nervous system development and gastrointestinal function.

Published
2020

15. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author

Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St George’s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)

Subjects
0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Published
2019

16. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Author

Evelise Riber, Suma Jacob, Isabela Maya Wahys Silva, Edwin H. Cook, Jennifer Reichert, Merete Nordentoft, Jiebiao Wang, Kaitlin E. Samocha, John A. Sweeney, Elaine Cristina Zachi, Brooke Sheppard, Yunin Ludena, Maureen Mulhern, Lambertus Klei, Christina M. Hultman, Branko Aleksic, Paige M. Siper, Nell Maltman, Fátima Lopes, Jesslyn Jamison, Astanand Jugessur, Timothy W. Yu, F. Kyle Satterstrom, Tarjinder Singh, Bernie Devlin, Per Magnus, Mara Parellada, Louise Gallagher, Christine Stevens, Susan L. Santangelo, David J. Cutler, Shan Dong, Margaret A. Pericak-Vance, Norio Ozaki, Camilla Stoltenberg, Matthew W. State, Emma Wilkinson, Lauren A. Weiss, Michael L. Cuccaro, Stephen Sanders, Aparna Bhaduri, Brian H.Y. Chung, Maria del Pilar Trelles, Ezra Susser, Somer L. Bishop, Catalina Betancur, Donna M. Werling, Sabine Schlitt, Diego Lopergolo, Abraham Reichenberg, Judith Miller, Gabriela Soares, Karoline Teufel, David M. Hougaard, Enrico Domenici, Thomas Werge, Terho Lehtimäki, Sherif Gerges, Audrey Thurm, Emily Hansen-Kiss, Christopher T. Walsh, Michael Gill, Maria Rita Passos-Bueno, Aurora Currò, Utku Norman, Nancy J. Minshew, Harrison Brand, Elisa Giorgio, A. Ercument Cicek, Elaine T. Lim, Joseph D. Buxbaum, Chiara Fallerini, Caroline Dias, Miia Kaartinen, Gal Meiri, Rachel Nguyen, Isaac N. Pessah, J. Jay Gargus, Ryan N. Doan, Minshi Peng, Matthew W. Mosconi, Elizabeth E. Guerrero, Michael E. Talkowski, Iuliana Ionita-Laza, Carla Lintas, Gerry Schellenberg, Alessandra Renieri, Marcus C.Y. Chan, Stephen J. Guter, Danielle Halpern, Javier González-Peñas, Flora Tassone, So Lun Lee, Elise B. Robinson, Alfredo Brusco, Danielle de Paula Moreira, Bernardo Dalla Bernardina, Benjamin M. Neale, Gun Peggy Knudsen, Behrang Mahjani, Peter Szatmari, Elisabetta Trabetti, Lauren M. Schmitt, Kaija Puura, Mykyta Artomov, Rebecca J. Schmidt, Michael S. Breen, Mark J. Daly, Joon Yong An, Dara S. Manoach, Grace Schwartz, Hilary Coon, Christine M. Freitag, Andreas G. Chiocchetti, Eduarda Montenegro M. de Souza, Ryan L. Collins, Mafalda Barbosa, Emilie M. Wigdor, Montserrat Fernández-Prieto, Stephen W. Scherer, Anders D. Børglum, Jack A. Kosmicki, W. Ian Lipkin, Mullin H.C. Yu, Michael E. Zwick, Irva Hertz-Picciotto, Kathryn Roeder, Moyra Smith, Gail E. Herman, James S. Sutcliffe, Xinyi Xu, A. Jeremy Willsey, Alexander Kolevzon, Itaru Kushima, Menachem Fromer, Jakob Grove, Patrícia Maciel, Preben Bo Mortensen, Xin He, Aarno Palotie, Silvia De Rubeis, Idan Menashe, Jonas Bybjerg-Grauholm, Pål Surén, Antonio M. Persico, Ole Mors, Sven Sandin, Lara Tang, Eric M. Morrow, Pierandrea Muglia, Angel Carracedo, Ryan Yuen, and Giovanni Battista Ferrero

Subjects
False discovery rate, Regulation of gene expression, Genetics, 0303 health sciences, Biology, medicine.disease, Phenotype, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, mental disorders, medicine, Autism, Copy-number variation, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

Published
2019

17. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism

Author

Shan Dong, Norio Ozaki, Ryan K. C. Yuen, David J. Cutler, Lauren A. Weiss, Catalina Betancur, Abraham Reichenberg, Hassen-Kiss E, Judith Miller, Brooke Sheppard, Yunin Ludena, Astanand Jugessur, Irva Hertz-Picciotto, Donna M. Werling, Aurora Currò, Isaac N. Pessah, Giovanni Battista Ferrero, Somer L. Bishop, Utku Norman, Nancy J. Minshew, Tarjinder Singh, Bernie Devlin, Michael E. Talkowski, Carla Lintas, Susan L. Santangelo, Miia Kaartinen, Gal Meiri, Camilla Stoltenberg, Stephen Sanders, Sherif Gerges, Michael L. Cuccaro, Ryan N. Doan, Suma Jacob, Matthew W. Mosconi, Lambertus Klei, Michael E. Zwick, Kathryn Roeder, Merete Nordentoft, Lauren M. Schmitt, John A. Sweeney, Elizabeth E. Guerrero, Kaija Puura, Alessandra Renieri, Elaine T. Lim, Maureen Mulhern, Danielle de Paula Moreira, Cicek Ae, Nell Maltman, Aparna Bhaduri, Mara Parellada, Sabine Schlitt, Diego Lopergolo, Gun Peggy Knudsen, Christina M. Hultman, Jesslyn Jamison, Rebecca J. Schmidt, So Lun Lee, Iuliana Ionita-Laza, Peter Szatmari, Gerry Schellenberg, Alfredo Brusco, Christine M. Freitag, Andreas G. Chiocchetti, Javier González-Peñas, Michael S. Breen, Jakob Grove, Ryan L. Collins, Mafalda Barbosa, Emilie M. Wigdor, Elise B. Robinson, Cathy A. Stevens, Gabriela Soares, Benjamin M. Neale, Edwin H. Cook, Jiebiao Wang, David M. Hougaard, Enrico Domenici, Gail E. Herman, Patrícia Maciel, Kaitlin E. Samocha, Preben Bo Mortensen, Stephen W. Scherer, Yu Mhc, Elaine Cristina Zachi, Menachem Fromer, Antonio M. Persico, Anders D. Børglum, Minshi Peng, Megan Smith, Elisabetta Trabetti, Rachel Nguyen, Fátima Lopes, James S. Sutcliffe, Trelles Mdp, Xinyi Xu, Emma Wilkinson, Joseph D. Buxbaum, Audrey Thurm, Chiara Fallerini, Jack A. Kosmicki, Michael Gill, Paige M. Siper, Timothy W. Yu, Grace Schwartz, Thomas Werge, Terho Lehtimäki, Itaru Kushima, Jay Gargus, Dalla Bernardina B, Hilary Coon, Maria Rita Passos-Bueno, Stephen J. Guter, Margaret A. Pericak-Vance, Matthew W. State, Per Magnus, Christopher A. Walsh, Evelise Riberi, Ezra Susser, Xin He, Aarno Palotie, Idan Menashe, Eric M. Morrow, Jonas Bybjerg-Grauholm, Pierandrea Muglia, Pål Surén, De Rubeis S, Angel Carracedo, Sven Sandin, Montse Fernández-Prieto, Lara Tang, Lipkin Wi, Ole Mors, Louise Gallagher, Montenegro M. de Souza E, Brian H.Y. Chung, Anney Rjl, Alexander Kolevzon, Dara S. Manoach, Daniel H. Geschwind, Silva Imw, Caroline Dias, Jeremy Willsey, Jennifer Reichert, Elisa Giorgio, Branko Aleksic, Flora Tassone, Satterstrom Fk, Senthil G, Karoline Teufel, Chan Mcy, Harrison Brand, Danielle Halpern, Behrang Mahjani, Mykyta Artomov, Mark J. Daly, Joon Yong An, and Lehner T

Subjects
Genetics, Regulation of gene expression, 0303 health sciences, medicine.medical_specialty, Neurogenetics, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, mental disorders, medicine, Autism, Medical genetics, Copy-number variation, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract

SummaryWe present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

Published
2018
Full Text
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18. Evidence of predisposing epimutation in retinoblastoma

Author

Anna Maria Pinto, Valentina Imperatore, Aurora Currò, Francesca Ariani, Sonia De Francesco, Serena Somma, Mirella Bruttini, Theodora Hadjistilianou, Alessandra Renieri, Elisa Gelli, Francesca Mari, Marta Giulia Cannone, and Daniela Galimberti

Subjects
Male, Ubiquitin-Protein Ligases, promoter methylation, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Germline, Epigenesis, Genetic, 03 medical and health sciences, medicine, Genetics, Humans, epimutation, gene silencing, mosaicism, retinoblastoma, Genetics (clinical), Genetic Predisposition to Disease, Multiplex ligation-dependent probe amplification, Gene Silencing, Allele, Promoter Regions, Genetic, Gene, Alleles, 030304 developmental biology, 0303 health sciences, Mutation, Retinoblastoma, 030305 genetics & heredity, Infant, Methylation, DNA Methylation, medicine.disease, Retinoblastoma Binding Proteins, DNA methylation, Cancer research, Female
Abstract

Retinoblastoma (RB), which represents the most common childhood eye cancer, is caused by biallelic inactivation of RB1 gene. Promoter hypermethylation is quite frequent in RB tissues but conclusive evidence of soma-wide predisposing epimutations is currently scant. Here, 50 patients who tested negative for RB1 germline sequence alterations were screened for aberrant promoter methylation using methylation-specific MLPA. The assay, performed on blood, identified a sporadic patient with methylation of CpG106, absent in parents' DNA. Bisulfite pyrosequencing accurately quantified CpG methylation in blood DNA (mean ∼49%) and also confirmed the aberration in DNA isolated from oral mucosa although at lower levels (mean ∼34%). Using a tag-SNP, methylation was demonstrated to affect the maternal allele. Real-time qPCR demonstrated RB1 transcriptional silencing. In conclusion, we documented that promoter methylation can act as the first "hit" in Knudson's model. This mosaic epimutation mimics the effect of an inactivating mutation and phenocopies RB onset.

Published
2018

19. Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

Author

Jill A. Rosenfeld, Vijay Kumar, Alessandra Renieri, Alexandre Reymond, Charles E. Schwartz, Claire Beneteau, Emily Huber, Katrin Männik, Cédric Le Caignec, Anne Laure Mosca-Boidron, Aurora Currò, Teresa Mattina, Paolo Prontera, Corrado Romano, Damian Pazuchanics, Erik A. Sistermans, Dominique Martin-Coignard, Lucia Castiglia, Luana Mandarà, Kate Pope, Pawel Stankiewicz, Matthew Jensen, Mathilde Lefebvre, Anke Van Dijck, Laurence Faivre, Sau Wai Cheung, R. Frank Kooy, Sophie Blesson, Nathalie Marle, Marie Vincent, Bertrand Isidor, Marco Fichera, Emanuela Avola, Ornella Galesi, Joris Andrieux, Jean-Hubert Caberg, Cindy Skinner, Sandra Mercier, Małgorzata J.M. Nowaczyk, Mathilde Nizon, Susan Zeesman, David J. Amor, Els Voorhoeve, Santhosh Girirajan, Andrew Polyak, Maja Bucan, Boris Keren, Elizabeth McCready, Olivier Pichon, Francesca Mari, Ji-eun Yoon, Arjun Krishnan, Rachel L. Kember, Lucilla Pizzo, Charles Perrine, and Patrick Callier

Subjects
Genetics, Proband, 0303 health sciences, Candidate gene, Mutation, Genetic heterogeneity, Disease, Biology, medicine.disease, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, medicine, Autism, Expressivity (genetics), Family history, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

PurposeTo assess the contribution of rare variants in the genetic background towards variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive mutations.MethodsWe analyzed quantitative clinical information, exome-sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated mutations.ResultsThe number of rare secondary mutations in functionally intolerant genes (second-hits) correlated with the expressivity of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in probands with autism carrying gene-disruptive mutations (n=184, p=0.03) compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of second-hits compared to those with mild/no family history (p=0.001). The number of secondary variants also correlated with the severity of cognitive impairment in probands carrying pathogenic rare CNVs (n=53) or de novo mutations in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These second-hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for genes affecting cellular and developmental processes.ConclusionAccurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

Published
2018
Full Text
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