Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

I. Ivanovski, O. Djuric, S.G. Caraffi, D. Santodirocco, M. Pollazzon, S. Rosato, D.M. Cordelli, E. Abdalla, P. Accorsi, M.P. Adam, P.F. Ajmone, M. Badura-Stronka, C. Baldo, M. Baldi, A. Bayat, S. Bigoni, F. Bonvicini, J. Breckpot, B. Callewaert, G. CocchiG. Cuturilo, D. De Brasi, K. Devriendt, M.B. Dinulos, T.D. Hjortshøj, R. Epifanio, F. Faravelli, A. Fiumara, D. Formisano, L. Giordano, M. Grasso, S. Grønborg, A. Iodice, L. Iughetti, V. Kuburovic, A. Kutkowska-Kazmierczak, D. Lacombe, C. Lo Rizzo, A. Luchetti, B. Malbora, I. Mammi, F. Mari, G. Montorsi, S. Moutton, R.S. Møller, P. Muschke, J.E.K. Nielsen, E. Obersztyn, C. Pantaleoni, A. Pellicciari, M.A. Pisanti, I. Prpic, M.L. Poch-Olive, F. Raviglione, A. Renieri, E. Ricci, F. Rivieri, G.W. Santen, S. Savasta, G. Scarano, I. Schanze, A. Selicorni, M. Silengo, R. Smigiel, L. Spaccini, G. Sorge, K. Szczaluba, L. Tarani, L.G. Tone, A. Toutain, A. Trimouille, E.T. Valera, S.S. Vergano, N. Zanotta, M. Zenker, A. Conidi, M. Zollino, A. Rauch, C. Zweier, L. Garavelli

Research output: Contribution to journalArticle

Abstract

Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. Conclusion: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care. © 2018, American College of Medical Genetics and Genomics.
Original languageEnglish
Pages (from-to)965-975
Number of pages11
JournalGenetics in Medicine
Volume20
Issue number9
DOIs
Publication statusPublished - 2018

Fingerprint

Genotype
Phenotype
Mutation
Genomics
Natural History
Intellectual Disability
Patient Care
Genes
Proteins

Keywords

  • Hirschsprung
  • intellectual disability
  • management
  • Mowat–Wilson syndrome
  • ZEB2
  • zinc finger E box binding homeobox 2
  • adolescent
  • adult
  • age
  • Article
  • brain malformation
  • cardiovascular malformation
  • child
  • clinical feature
  • correlational study
  • disease severity
  • epilepsy
  • family history
  • female
  • gene
  • gene deletion
  • gene locus
  • genetic association
  • genetic variation
  • genotype
  • genotype phenotype correlation
  • growth curve
  • head circumference
  • human
  • infant
  • intellectual impairment
  • major clinical study
  • male
  • mental disease
  • missense mutation
  • Mowat Wilson syndrome
  • musculoskeletal system malformation
  • patient care
  • phenotype
  • prediction
  • prevalence
  • protein function
  • ZEB2 gene

Cite this

Ivanovski, I., Djuric, O., Caraffi, S. G., Santodirocco, D., Pollazzon, M., Rosato, S., ... Garavelli, L. (2018). Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care. Genetics in Medicine, 20(9), 965-975. https://doi.org/10.1038/gim.2017.221

Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care. / Ivanovski, I.; Djuric, O.; Caraffi, S.G.; Santodirocco, D.; Pollazzon, M.; Rosato, S.; Cordelli, D.M.; Abdalla, E.; Accorsi, P.; Adam, M.P.; Ajmone, P.F.; Badura-Stronka, M.; Baldo, C.; Baldi, M.; Bayat, A.; Bigoni, S.; Bonvicini, F.; Breckpot, J.; Callewaert, B.; Cocchi, G.; Cuturilo, G.; De Brasi, D.; Devriendt, K.; Dinulos, M.B.; Hjortshøj, T.D.; Epifanio, R.; Faravelli, F.; Fiumara, A.; Formisano, D.; Giordano, L.; Grasso, M.; Grønborg, S.; Iodice, A.; Iughetti, L.; Kuburovic, V.; Kutkowska-Kazmierczak, A.; Lacombe, D.; Lo Rizzo, C.; Luchetti, A.; Malbora, B.; Mammi, I.; Mari, F.; Montorsi, G.; Moutton, S.; Møller, R.S.; Muschke, P.; Nielsen, J.E.K.; Obersztyn, E.; Pantaleoni, C.; Pellicciari, A.; Pisanti, M.A.; Prpic, I.; Poch-Olive, M.L.; Raviglione, F.; Renieri, A.; Ricci, E.; Rivieri, F.; Santen, G.W.; Savasta, S.; Scarano, G.; Schanze, I.; Selicorni, A.; Silengo, M.; Smigiel, R.; Spaccini, L.; Sorge, G.; Szczaluba, K.; Tarani, L.; Tone, L.G.; Toutain, A.; Trimouille, A.; Valera, E.T.; Vergano, S.S.; Zanotta, N.; Zenker, M.; Conidi, A.; Zollino, M.; Rauch, A.; Zweier, C.; Garavelli, L.

In: Genetics in Medicine, Vol. 20, No. 9, 2018, p. 965-975.

Research output: Contribution to journalArticle

Ivanovski, I, Djuric, O, Caraffi, SG, Santodirocco, D, Pollazzon, M, Rosato, S, Cordelli, DM, Abdalla, E, Accorsi, P, Adam, MP, Ajmone, PF, Badura-Stronka, M, Baldo, C, Baldi, M, Bayat, A, Bigoni, S, Bonvicini, F, Breckpot, J, Callewaert, B, Cocchi, G, Cuturilo, G, De Brasi, D, Devriendt, K, Dinulos, MB, Hjortshøj, TD, Epifanio, R, Faravelli, F, Fiumara, A, Formisano, D, Giordano, L, Grasso, M, Grønborg, S, Iodice, A, Iughetti, L, Kuburovic, V, Kutkowska-Kazmierczak, A, Lacombe, D, Lo Rizzo, C, Luchetti, A, Malbora, B, Mammi, I, Mari, F, Montorsi, G, Moutton, S, Møller, RS, Muschke, P, Nielsen, JEK, Obersztyn, E, Pantaleoni, C, Pellicciari, A, Pisanti, MA, Prpic, I, Poch-Olive, ML, Raviglione, F, Renieri, A, Ricci, E, Rivieri, F, Santen, GW, Savasta, S, Scarano, G, Schanze, I, Selicorni, A, Silengo, M, Smigiel, R, Spaccini, L, Sorge, G, Szczaluba, K, Tarani, L, Tone, LG, Toutain, A, Trimouille, A, Valera, ET, Vergano, SS, Zanotta, N, Zenker, M, Conidi, A, Zollino, M, Rauch, A, Zweier, C & Garavelli, L 2018, 'Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care', Genetics in Medicine, vol. 20, no. 9, pp. 965-975. https://doi.org/10.1038/gim.2017.221
Ivanovski I, Djuric O, Caraffi SG, Santodirocco D, Pollazzon M, Rosato S et al. Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care. Genetics in Medicine. 2018;20(9):965-975. https://doi.org/10.1038/gim.2017.221
Ivanovski, I. ; Djuric, O. ; Caraffi, S.G. ; Santodirocco, D. ; Pollazzon, M. ; Rosato, S. ; Cordelli, D.M. ; Abdalla, E. ; Accorsi, P. ; Adam, M.P. ; Ajmone, P.F. ; Badura-Stronka, M. ; Baldo, C. ; Baldi, M. ; Bayat, A. ; Bigoni, S. ; Bonvicini, F. ; Breckpot, J. ; Callewaert, B. ; Cocchi, G. ; Cuturilo, G. ; De Brasi, D. ; Devriendt, K. ; Dinulos, M.B. ; Hjortshøj, T.D. ; Epifanio, R. ; Faravelli, F. ; Fiumara, A. ; Formisano, D. ; Giordano, L. ; Grasso, M. ; Grønborg, S. ; Iodice, A. ; Iughetti, L. ; Kuburovic, V. ; Kutkowska-Kazmierczak, A. ; Lacombe, D. ; Lo Rizzo, C. ; Luchetti, A. ; Malbora, B. ; Mammi, I. ; Mari, F. ; Montorsi, G. ; Moutton, S. ; Møller, R.S. ; Muschke, P. ; Nielsen, J.E.K. ; Obersztyn, E. ; Pantaleoni, C. ; Pellicciari, A. ; Pisanti, M.A. ; Prpic, I. ; Poch-Olive, M.L. ; Raviglione, F. ; Renieri, A. ; Ricci, E. ; Rivieri, F. ; Santen, G.W. ; Savasta, S. ; Scarano, G. ; Schanze, I. ; Selicorni, A. ; Silengo, M. ; Smigiel, R. ; Spaccini, L. ; Sorge, G. ; Szczaluba, K. ; Tarani, L. ; Tone, L.G. ; Toutain, A. ; Trimouille, A. ; Valera, E.T. ; Vergano, S.S. ; Zanotta, N. ; Zenker, M. ; Conidi, A. ; Zollino, M. ; Rauch, A. ; Zweier, C. ; Garavelli, L. / Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care. In: Genetics in Medicine. 2018 ; Vol. 20, No. 9. pp. 965-975.
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title = "Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care",
abstract = "Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. Conclusion: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care. {\circledC} 2018, American College of Medical Genetics and Genomics.",
keywords = "Hirschsprung, intellectual disability, management, Mowat–Wilson syndrome, ZEB2, zinc finger E box binding homeobox 2, adolescent, adult, age, Article, brain malformation, cardiovascular malformation, child, clinical feature, correlational study, disease severity, epilepsy, family history, female, gene, gene deletion, gene locus, genetic association, genetic variation, genotype, genotype phenotype correlation, growth curve, head circumference, human, infant, intellectual impairment, major clinical study, male, mental disease, missense mutation, Mowat Wilson syndrome, musculoskeletal system malformation, patient care, phenotype, prediction, prevalence, protein function, ZEB2 gene",
author = "I. Ivanovski and O. Djuric and S.G. Caraffi and D. Santodirocco and M. Pollazzon and S. Rosato and D.M. Cordelli and E. Abdalla and P. Accorsi and M.P. Adam and P.F. Ajmone and M. Badura-Stronka and C. Baldo and M. Baldi and A. Bayat and S. Bigoni and F. Bonvicini and J. Breckpot and B. Callewaert and G. Cocchi and G. Cuturilo and {De Brasi}, D. and K. Devriendt and M.B. Dinulos and T.D. Hjortsh{\o}j and R. Epifanio and F. Faravelli and A. Fiumara and D. Formisano and L. Giordano and M. Grasso and S. Gr{\o}nborg and A. Iodice and L. Iughetti and V. Kuburovic and A. Kutkowska-Kazmierczak and D. Lacombe and {Lo Rizzo}, C. and A. Luchetti and B. Malbora and I. Mammi and F. Mari and G. Montorsi and S. Moutton and R.S. M{\o}ller and P. Muschke and J.E.K. Nielsen and E. Obersztyn and C. Pantaleoni and A. Pellicciari and M.A. Pisanti and I. Prpic and M.L. Poch-Olive and F. Raviglione and A. Renieri and E. Ricci and F. Rivieri and G.W. Santen and S. Savasta and G. Scarano and I. Schanze and A. Selicorni and M. Silengo and R. Smigiel and L. Spaccini and G. Sorge and K. Szczaluba and L. Tarani and L.G. Tone and A. Toutain and A. Trimouille and E.T. Valera and S.S. Vergano and N. Zanotta and M. Zenker and A. Conidi and M. Zollino and A. Rauch and C. Zweier and L. Garavelli",
note = "Cited By :3 Export Date: 25 January 2019 CODEN: GEMEF Correspondence Address: Garavelli, L.; Clinical Genetics Unit, Department of Obstetrics and Pediatrics, AUSL-IRCCS of Reggio EmiliaItaly; email: livia.garavelli@ausl.re.it Funding details: Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu, PUMS Funding details: 7Division Funding details: Universitaire Ziekenhuizen Leuven, KU Leuven, UZ Leuven Funding details: Universit{\`a} di Bologna, UNIBO Funding details: Alexandria University, AU Funding details: Universit{\`a} di Catania Funding details: Children’s Medical Research Institute, CMRI Funding details: Universit{\`a} Degli Studi di Modena e Reggio Emila, UNIMORE, 3Institute Funding details: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 9Chair Funding details: Washington University School of Medicine in St. Louis Funding details: Universitair Ziekenhuis Gent, UZ Gent Funding details: U1211 Funding details: School of Medicine Funding details: Dartmouth-Hitchcock Medical Center, DHMC Funding details: Great Ormond Street Hospital for Children, GOSH Funding details: GEP 14131 Funding details: GTB12001 Funding details: Alzheimer Society of B.C. Funding text 1: 1Clinical Genetics Unit, Department of Obstetrics and Pediatrics, AUSL-IRCCS of Reggio Emilia, Reggio Emilia, Italy; 2Department of Surgical, Medical, Dental, and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy; 3Institute of Epidemiology, School of Medicine, University of Belgrade, Belgrade, Serbia; 4Child Neurology and Psychiatry Unit, S Orsola Malpighi Hospital, University of Bologna, Bologna, Italy; 5Department of Human Genetics, Medical Research Institute, University of Alexandria, Alexandria, Egypt; 6Neuropsychiatric Department, Spedali Civili Brescia, Brescia, Italy; 7Division of Genetic Medicine, University of Washington School of Medicine, Seattle, Washington, USA; 8Child and Adolescent Neuropsychiatric Service (UONPIA) Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 9Chair and Department of Medical Genetics, Poznan University of Medical Sciences, Poznań, Poland; 10Laboratory of Human Genetics; Galliera Hospital, Genoa, Italy; 11Department of Pediatrics, University Hospital of Copenhagen/Hvidovre, Copenhagen, Denmark; 12Department of Clinical Genetics, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark; 13UOL of Medical Genetics, University Hospital of Ferrara, Ferrara, Italy; 14Pediatric Unit, Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy; 15Center for Human Genetics, Catholic University of Leuven, Leuven, Belgium; 16Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; 17Neonatology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; 18Faculty of Medicine, University of Belgrade, Belgrade, Serbia; 19Department of Medical Genetics, University Children’s Hospital, Belgrade, Serbia; 20Department of Pediatrics, AORN Santobono Pausilipon, Naples, Italy; 21Department of Pediatrics, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA; 22Department of Clinical Genetics, Kennedy Center, Glostrup, Denmark; 23Clinical Neurophysiology Unit, IRCCS, E Medea Scientific Institute, Bosisio Parini, Lecco, Italy; 24Clinical Genetics, NE Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; 25Department of Clinical and Experimental Medicine, Regional Referral Center for Inborn Errors Metabolism, Pediatric Clinic, University of Catania, Catania, Italy; 26Scientific Directorate, Arcispedale Santa Maria Nuova–IRCCS, Reggio Emilia, Italy; 27Center for Rare Diseases, Department of Clinical Genetics, University Hospital Copenhagen, Copenhagen, Denmark; 28Neuropsychiatric Department, Arcispedale Santa Maria Nuova– IRCCS, Reggio Emilia, Italy; 29Department of Cardiology, Mother and Child Health Care Institute, Belgrade, Serbia; 30Department of Medical Genetics, Institute of the Mother and Child, Warsaw, Poland; 31CHU de Bordeaux, Service de G{\'e}n{\'e}tique M{\'e}dicale, Bordeaux, France; 32INSERM U1211, Univ. Bordeaux, Bordeaux, France; 33Medical Genetics, University of Siena, Siena, Italy; 34Child Neuropsychiatry Unit, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy; 35Department of Pediatric Hematology & Oncology, Tepecik Training and Research Hospital, Izmir, Turkey; 36Medical Genetics Unit, Dolo Hospital, Venice, Italy; 37Faculty of Medicine, University of Modena and Reggio Funding text 2: The financial support of Telethon Italy (grant GEP 14131) is gratefully acknowledged. The authors thank the Galliera Genetic Bank, member of the Telethon Genetic Biobank Network (project GTB12001), funded by Telethon Italy, and the Associazione Italiana Mowat Wilson ONLUS (AIMW), for their assistance and kind collaboration. We also thank all cooperating family members for contributing the medical data necessary for this study. In addition, we are grateful to Luca Valcavi for helping with the design and adaptation of the figures and tables. We also thank the photographer Marco Bonazzi, the genetic nurse Maria Claudia Menozzi, and the nurse Margherita Raucci for their excellent work. B.C. is a senior clinical investigator of the Scientific Research Fund—Flanders. Written consent for publication of the clinical pictures was obtained from the patients’ parents. References: Mowat, D.R., Croaker, G.D., Cass, D.T., Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23 (1998) J Med Genet, 35, pp. 617-623. , COI: 1:STN:280:DyaK1czotlyluw{\%}3D{\%}3D; Lurie, I.W., Supovitz, K.R., Rosenblum-Vos, L.S., Wulfsberg, E.A., Phenotypic variability of del(2) (q22-q23): report of a case with a review of the literature (1994) Genet Couns., 5, pp. 11-14. , COI: 1:STN:280:DyaK2czgsVGktg{\%}3D{\%}3D, PID: 8031530; Wakamatsu, N., Yamada, Y., Yamada, K., Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease (2001) Nat Genet., 27, pp. 369-370. , COI: 1:CAS:528:DC{\%}2BD3MXjtFShs70{\%}3D; Cacheux, V., Dastot-Le Moal, F., Kaariainen, H., Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease (2001) Hum Mol Genet, 10, pp. 1503-1510. , COI: 1:CAS:528:DC{\%}2BD3MXlsFOgu78{\%}3D; Zweier, C., Albrecht, B., Mitulla, B., Mowat-Wilson” syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene (2002) Am J Med Genet, 108, pp. 177-181; Yamada, K., Yamada, Y., Nomura, N., Nonsense and frameshift mutations in ZFHX1B, encoding Smad-interacting protein 1, cause a complex developmental disorder with a great variety of clinical features (2001) Am J Hum Genet, 69, pp. 1178-1185. , COI: 1:CAS:528:DC{\%}2BD38XhslShsg{\%}3D{\%}3D; Wilson, M., Mowat, D., Dastot-Le Moal, F., Further delineation of the phenotype associated with heterozygous mutations in ZFHX1B (2003) Am J Med Genet A, 119A, pp. 257-265; Zweier, C., Temple, I.K., Beemer, F., Characterisation of deletions of the ZFHX1B region and genotype-phenotype analysis in Mowat-Wilson syndrome (2003) J Med Genet, 40, pp. 601-605. , COI: 1:CAS:528:DC{\%}2BD3sXnslGmt78{\%}3D; Cerruti Mainardi, P., Pastore, G., Zweier, C., Rauch, A., Mowat-Wilson syndrome and mutation in the zinc finger homeo box 1B gene: a well defined clinical entity (2004) J Med Genet, 41. , COI: 1:STN:280:DC{\%}2BD2c{\%}2Fls1KlsQ{\%}3D{\%}3D; Ishihara, N., Yamada, K., Yamada, Y., Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFHX1B mutations and deletions at 2q22-q24.1 (2004) J Med Genet, 41, pp. 387-393. , COI: 1:CAS:528:DC{\%}2BD2cXkvFChtL4{\%}3D; Garavelli, L., Cerruti-Mainardi, P., Virdis, R., Genitourinary anomalies in Mowat-Wilson syndrome with deletion/mutation in the zinc finger homeo box 1B gene (ZFHX1B). Report of three Italian cases with hypospadias and review (2005) Horm Res., 63, pp. 187-192. , COI: 1:CAS:528:DC{\%}2BD2MXlt1Snu7w{\%}3D, PID: 15908750; Zweier, C., Thiel, C.T., Dufke, A., Clinical and mutational spectrum of Mowat-Wilson syndrome (2005) Eur J Med Genet, 48, pp. 97-111; Adam, M.P., Schelley, S., Gallagher, R., Clinical features and management issues in Mowat-Wilson syndrome (2006) Am J Med Genet A, 140, pp. 2730-2741; Dastot-Le Moal, F., Wilson, M., Mowat, D., Collot, N., Niel, F., Goossens, M., ZFHX1B mutations in patients with Mowat-Wilson syndrome (2007) Hum Mutat., 28, pp. 313-321. , COI: 1:CAS:528:DC{\%}2BD2sXltVWls7g{\%}3D; Garavelli, L., Zollino, M., Mainardi, P.C., Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature (2009) Am J Med Genet A, 149A, pp. 417-426. , COI: 1:CAS:528:DC{\%}2BD1MXjvVyks7w{\%}3D; Yamada, Y., Nomura, N., Yamada, K., The spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations (2014) Am J Med Genet A, 164A, pp. 1899-1908; Coyle, D., Puri, P., Hirschsprung’s disease in children with Mowat-Wilson syndrome (2015) Pediatr Surg Int, 31, pp. 711-717; Cecconi, M., Forzano, F., Garavelli, L., Recurrence of Mowat-Wilson syndrome in siblings with a novel mutation in the ZEB2 gene (2008) Am J Med Genet A, 146A, pp. 3095-3099. , COI: 1:CAS:528:DC{\%}2BD1MXnsV2mtQ{\%}3D{\%}3D; McGaughran, J., Sinnott, S., Dastot-Le Moal, F., Recurrence of Mowat-Wilson syndrome in siblings with the same proven mutation (2005) Am J Med Genet A, 137A, pp. 302-304; Ohtsuka, M., Oguni, H., Ito, Y., Mowat-Wilson syndrome affecting 3 siblings (2008) J Child Neurol, 23, pp. 274-278; Garavelli, L., Ivanovski, I., Caraffi, S.G., Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients (2017) Genet Med., 19, pp. 691-700; Zweier, C., Horn, D., Kraus, C., Rauch, A., Atypical ZFHX1B mutation associated with a mild Mowat-Wilson syndrome phenotype (2006) Am J Med Genet A, 140, pp. 869-872; Yu, J.M., Liao, C.P., Ge, S., The prevalence and clinical impact of pulmonary artery sling on school-aged children: a large-scale screening study (2008) Pediatr Pulmonol., 43, pp. 656-661; Bourchany, A., Giurgea, I., Thevenon, J., Clinical spectrum of eye malformations in four patients with Mowat-Wilson syndrome (2015) Am J Med Genet A, 167, pp. 1587-1592. , COI: 1:CAS:528:DC{\%}2BC2MXhtVegsrzK; Evans, E., Einfeld, S., Mowat, D., Taffe, J., Tonge, B., Wilson, M., The behavioral phenotype of Mowat-Wilson syndrome (2012) Am J Med Genet A, 158A, pp. 358-366; Pradier, B., Jeub, M., Markert, A., Smad-interacting protein 1 affects acute and tonic, but not chronic pain (2014) Eur J Pain, 18, pp. 249-257. , COI: 1:CAS:528:DC{\%}2BC2cXlvFWmsw{\%}3D{\%}3D; Garavelli, L., Mainardi, P.C., Mowat-Wilson syndrome (2007) Orphanet J Rare Dis, 2, p. 42; Cordelli, D.M., Garavelli, L., Savasta, S., Epilepsy in Mowat-Wilson syndrome: delineation of the electroclinical phenotype (2013) Am J Med Genet A, 161A, pp. 273-284; Cordelli, D.M., Pellicciari, A., Kiriazopulos, D., Franzoni, E., Garavelli, L., Epilepsy in Mowat-Wilson syndrome: is it a matter of GABA? (2013) Epilepsia., 54, pp. 1331-1332. , COI: 1:CAS:528:DC{\%}2BC3sXht1amu7rO; Beltran, M., Puig, I., Pena, C., A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition (2008) Genes Dev., 22, pp. 756-769. , COI: 1:CAS:528:DC{\%}2BD1cXjvFeqs74{\%}3D; Ghoumid, J., Drevillon, L., Alavi-Naini, S.M., ZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat-Wilson syndrome (2013) Hum Mol Genet, 22, pp. 2652-2661. , COI: 1:CAS:528:DC{\%}2BC3sXptVOitrw{\%}3D; Heinritz, W., Zweier, C., Froster, U.G., A missense mutation in the ZFHX1B gene associated with an atypical Mowat-Wilson syndrome phenotype (2006) Am J Med Genet A, 140, pp. 1223-1227",
year = "2018",
doi = "10.1038/gim.2017.221",
language = "English",
volume = "20",
pages = "965--975",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

AU - Ivanovski, I.

AU - Djuric, O.

AU - Caraffi, S.G.

AU - Santodirocco, D.

AU - Pollazzon, M.

AU - Rosato, S.

AU - Cordelli, D.M.

AU - Abdalla, E.

AU - Accorsi, P.

AU - Adam, M.P.

AU - Ajmone, P.F.

AU - Badura-Stronka, M.

AU - Baldo, C.

AU - Baldi, M.

AU - Bayat, A.

AU - Bigoni, S.

AU - Bonvicini, F.

AU - Breckpot, J.

AU - Callewaert, B.

AU - Cocchi, G.

AU - Cuturilo, G.

AU - De Brasi, D.

AU - Devriendt, K.

AU - Dinulos, M.B.

AU - Hjortshøj, T.D.

AU - Epifanio, R.

AU - Faravelli, F.

AU - Fiumara, A.

AU - Formisano, D.

AU - Giordano, L.

AU - Grasso, M.

AU - Grønborg, S.

AU - Iodice, A.

AU - Iughetti, L.

AU - Kuburovic, V.

AU - Kutkowska-Kazmierczak, A.

AU - Lacombe, D.

AU - Lo Rizzo, C.

AU - Luchetti, A.

AU - Malbora, B.

AU - Mammi, I.

AU - Mari, F.

AU - Montorsi, G.

AU - Moutton, S.

AU - Møller, R.S.

AU - Muschke, P.

AU - Nielsen, J.E.K.

AU - Obersztyn, E.

AU - Pantaleoni, C.

AU - Pellicciari, A.

AU - Pisanti, M.A.

AU - Prpic, I.

AU - Poch-Olive, M.L.

AU - Raviglione, F.

AU - Renieri, A.

AU - Ricci, E.

AU - Rivieri, F.

AU - Santen, G.W.

AU - Savasta, S.

AU - Scarano, G.

AU - Schanze, I.

AU - Selicorni, A.

AU - Silengo, M.

AU - Smigiel, R.

AU - Spaccini, L.

AU - Sorge, G.

AU - Szczaluba, K.

AU - Tarani, L.

AU - Tone, L.G.

AU - Toutain, A.

AU - Trimouille, A.

AU - Valera, E.T.

AU - Vergano, S.S.

AU - Zanotta, N.

AU - Zenker, M.

AU - Conidi, A.

AU - Zollino, M.

AU - Rauch, A.

AU - Zweier, C.

AU - Garavelli, L.

N1 - Cited By :3 Export Date: 25 January 2019 CODEN: GEMEF Correspondence Address: Garavelli, L.; Clinical Genetics Unit, Department of Obstetrics and Pediatrics, AUSL-IRCCS of Reggio EmiliaItaly; email: livia.garavelli@ausl.re.it Funding details: Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu, PUMS Funding details: 7Division Funding details: Universitaire Ziekenhuizen Leuven, KU Leuven, UZ Leuven Funding details: Università di Bologna, UNIBO Funding details: Alexandria University, AU Funding details: Università di Catania Funding details: Children’s Medical Research Institute, CMRI Funding details: Università Degli Studi di Modena e Reggio Emila, UNIMORE, 3Institute Funding details: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 9Chair Funding details: Washington University School of Medicine in St. Louis Funding details: Universitair Ziekenhuis Gent, UZ Gent Funding details: U1211 Funding details: School of Medicine Funding details: Dartmouth-Hitchcock Medical Center, DHMC Funding details: Great Ormond Street Hospital for Children, GOSH Funding details: GEP 14131 Funding details: GTB12001 Funding details: Alzheimer Society of B.C. Funding text 1: 1Clinical Genetics Unit, Department of Obstetrics and Pediatrics, AUSL-IRCCS of Reggio Emilia, Reggio Emilia, Italy; 2Department of Surgical, Medical, Dental, and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy; 3Institute of Epidemiology, School of Medicine, University of Belgrade, Belgrade, Serbia; 4Child Neurology and Psychiatry Unit, S Orsola Malpighi Hospital, University of Bologna, Bologna, Italy; 5Department of Human Genetics, Medical Research Institute, University of Alexandria, Alexandria, Egypt; 6Neuropsychiatric Department, Spedali Civili Brescia, Brescia, Italy; 7Division of Genetic Medicine, University of Washington School of Medicine, Seattle, Washington, USA; 8Child and Adolescent Neuropsychiatric Service (UONPIA) Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 9Chair and Department of Medical Genetics, Poznan University of Medical Sciences, Poznań, Poland; 10Laboratory of Human Genetics; Galliera Hospital, Genoa, Italy; 11Department of Pediatrics, University Hospital of Copenhagen/Hvidovre, Copenhagen, Denmark; 12Department of Clinical Genetics, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark; 13UOL of Medical Genetics, University Hospital of Ferrara, Ferrara, Italy; 14Pediatric Unit, Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy; 15Center for Human Genetics, Catholic University of Leuven, Leuven, Belgium; 16Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; 17Neonatology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; 18Faculty of Medicine, University of Belgrade, Belgrade, Serbia; 19Department of Medical Genetics, University Children’s Hospital, Belgrade, Serbia; 20Department of Pediatrics, AORN Santobono Pausilipon, Naples, Italy; 21Department of Pediatrics, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA; 22Department of Clinical Genetics, Kennedy Center, Glostrup, Denmark; 23Clinical Neurophysiology Unit, IRCCS, E Medea Scientific Institute, Bosisio Parini, Lecco, Italy; 24Clinical Genetics, NE Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; 25Department of Clinical and Experimental Medicine, Regional Referral Center for Inborn Errors Metabolism, Pediatric Clinic, University of Catania, Catania, Italy; 26Scientific Directorate, Arcispedale Santa Maria Nuova–IRCCS, Reggio Emilia, Italy; 27Center for Rare Diseases, Department of Clinical Genetics, University Hospital Copenhagen, Copenhagen, Denmark; 28Neuropsychiatric Department, Arcispedale Santa Maria Nuova– IRCCS, Reggio Emilia, Italy; 29Department of Cardiology, Mother and Child Health Care Institute, Belgrade, Serbia; 30Department of Medical Genetics, Institute of the Mother and Child, Warsaw, Poland; 31CHU de Bordeaux, Service de Génétique Médicale, Bordeaux, France; 32INSERM U1211, Univ. Bordeaux, Bordeaux, France; 33Medical Genetics, University of Siena, Siena, Italy; 34Child Neuropsychiatry Unit, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy; 35Department of Pediatric Hematology & Oncology, Tepecik Training and Research Hospital, Izmir, Turkey; 36Medical Genetics Unit, Dolo Hospital, Venice, Italy; 37Faculty of Medicine, University of Modena and Reggio Funding text 2: The financial support of Telethon Italy (grant GEP 14131) is gratefully acknowledged. The authors thank the Galliera Genetic Bank, member of the Telethon Genetic Biobank Network (project GTB12001), funded by Telethon Italy, and the Associazione Italiana Mowat Wilson ONLUS (AIMW), for their assistance and kind collaboration. We also thank all cooperating family members for contributing the medical data necessary for this study. In addition, we are grateful to Luca Valcavi for helping with the design and adaptation of the figures and tables. We also thank the photographer Marco Bonazzi, the genetic nurse Maria Claudia Menozzi, and the nurse Margherita Raucci for their excellent work. B.C. is a senior clinical investigator of the Scientific Research Fund—Flanders. Written consent for publication of the clinical pictures was obtained from the patients’ parents. References: Mowat, D.R., Croaker, G.D., Cass, D.T., Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23 (1998) J Med Genet, 35, pp. 617-623. , COI: 1:STN:280:DyaK1czotlyluw%3D%3D; Lurie, I.W., Supovitz, K.R., Rosenblum-Vos, L.S., Wulfsberg, E.A., Phenotypic variability of del(2) (q22-q23): report of a case with a review of the literature (1994) Genet Couns., 5, pp. 11-14. , COI: 1:STN:280:DyaK2czgsVGktg%3D%3D, PID: 8031530; Wakamatsu, N., Yamada, Y., Yamada, K., Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease (2001) Nat Genet., 27, pp. 369-370. , COI: 1:CAS:528:DC%2BD3MXjtFShs70%3D; Cacheux, V., Dastot-Le Moal, F., Kaariainen, H., Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease (2001) Hum Mol Genet, 10, pp. 1503-1510. , COI: 1:CAS:528:DC%2BD3MXlsFOgu78%3D; Zweier, C., Albrecht, B., Mitulla, B., Mowat-Wilson” syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene (2002) Am J Med Genet, 108, pp. 177-181; Yamada, K., Yamada, Y., Nomura, N., Nonsense and frameshift mutations in ZFHX1B, encoding Smad-interacting protein 1, cause a complex developmental disorder with a great variety of clinical features (2001) Am J Hum Genet, 69, pp. 1178-1185. , COI: 1:CAS:528:DC%2BD38XhslShsg%3D%3D; Wilson, M., Mowat, D., Dastot-Le Moal, F., Further delineation of the phenotype associated with heterozygous mutations in ZFHX1B (2003) Am J Med Genet A, 119A, pp. 257-265; Zweier, C., Temple, I.K., Beemer, F., Characterisation of deletions of the ZFHX1B region and genotype-phenotype analysis in Mowat-Wilson syndrome (2003) J Med Genet, 40, pp. 601-605. , COI: 1:CAS:528:DC%2BD3sXnslGmt78%3D; Cerruti Mainardi, P., Pastore, G., Zweier, C., Rauch, A., Mowat-Wilson syndrome and mutation in the zinc finger homeo box 1B gene: a well defined clinical entity (2004) J Med Genet, 41. , COI: 1:STN:280:DC%2BD2c%2Fls1KlsQ%3D%3D; Ishihara, N., Yamada, K., Yamada, Y., Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFHX1B mutations and deletions at 2q22-q24.1 (2004) J Med Genet, 41, pp. 387-393. , COI: 1:CAS:528:DC%2BD2cXkvFChtL4%3D; Garavelli, L., Cerruti-Mainardi, P., Virdis, R., Genitourinary anomalies in Mowat-Wilson syndrome with deletion/mutation in the zinc finger homeo box 1B gene (ZFHX1B). Report of three Italian cases with hypospadias and review (2005) Horm Res., 63, pp. 187-192. , COI: 1:CAS:528:DC%2BD2MXlt1Snu7w%3D, PID: 15908750; Zweier, C., Thiel, C.T., Dufke, A., Clinical and mutational spectrum of Mowat-Wilson syndrome (2005) Eur J Med Genet, 48, pp. 97-111; Adam, M.P., Schelley, S., Gallagher, R., Clinical features and management issues in Mowat-Wilson syndrome (2006) Am J Med Genet A, 140, pp. 2730-2741; Dastot-Le Moal, F., Wilson, M., Mowat, D., Collot, N., Niel, F., Goossens, M., ZFHX1B mutations in patients with Mowat-Wilson syndrome (2007) Hum Mutat., 28, pp. 313-321. , COI: 1:CAS:528:DC%2BD2sXltVWls7g%3D; Garavelli, L., Zollino, M., Mainardi, P.C., Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature (2009) Am J Med Genet A, 149A, pp. 417-426. , COI: 1:CAS:528:DC%2BD1MXjvVyks7w%3D; Yamada, Y., Nomura, N., Yamada, K., The spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations (2014) Am J Med Genet A, 164A, pp. 1899-1908; Coyle, D., Puri, P., Hirschsprung’s disease in children with Mowat-Wilson syndrome (2015) Pediatr Surg Int, 31, pp. 711-717; Cecconi, M., Forzano, F., Garavelli, L., Recurrence of Mowat-Wilson syndrome in siblings with a novel mutation in the ZEB2 gene (2008) Am J Med Genet A, 146A, pp. 3095-3099. , COI: 1:CAS:528:DC%2BD1MXnsV2mtQ%3D%3D; McGaughran, J., Sinnott, S., Dastot-Le Moal, F., Recurrence of Mowat-Wilson syndrome in siblings with the same proven mutation (2005) Am J Med Genet A, 137A, pp. 302-304; Ohtsuka, M., Oguni, H., Ito, Y., Mowat-Wilson syndrome affecting 3 siblings (2008) J Child Neurol, 23, pp. 274-278; Garavelli, L., Ivanovski, I., Caraffi, S.G., Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients (2017) Genet Med., 19, pp. 691-700; Zweier, C., Horn, D., Kraus, C., Rauch, A., Atypical ZFHX1B mutation associated with a mild Mowat-Wilson syndrome phenotype (2006) Am J Med Genet A, 140, pp. 869-872; Yu, J.M., Liao, C.P., Ge, S., The prevalence and clinical impact of pulmonary artery sling on school-aged children: a large-scale screening study (2008) Pediatr Pulmonol., 43, pp. 656-661; Bourchany, A., Giurgea, I., Thevenon, J., Clinical spectrum of eye malformations in four patients with Mowat-Wilson syndrome (2015) Am J Med Genet A, 167, pp. 1587-1592. , COI: 1:CAS:528:DC%2BC2MXhtVegsrzK; Evans, E., Einfeld, S., Mowat, D., Taffe, J., Tonge, B., Wilson, M., The behavioral phenotype of Mowat-Wilson syndrome (2012) Am J Med Genet A, 158A, pp. 358-366; Pradier, B., Jeub, M., Markert, A., Smad-interacting protein 1 affects acute and tonic, but not chronic pain (2014) Eur J Pain, 18, pp. 249-257. , COI: 1:CAS:528:DC%2BC2cXlvFWmsw%3D%3D; Garavelli, L., Mainardi, P.C., Mowat-Wilson syndrome (2007) Orphanet J Rare Dis, 2, p. 42; Cordelli, D.M., Garavelli, L., Savasta, S., Epilepsy in Mowat-Wilson syndrome: delineation of the electroclinical phenotype (2013) Am J Med Genet A, 161A, pp. 273-284; Cordelli, D.M., Pellicciari, A., Kiriazopulos, D., Franzoni, E., Garavelli, L., Epilepsy in Mowat-Wilson syndrome: is it a matter of GABA? (2013) Epilepsia., 54, pp. 1331-1332. , COI: 1:CAS:528:DC%2BC3sXht1amu7rO; Beltran, M., Puig, I., Pena, C., A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition (2008) Genes Dev., 22, pp. 756-769. , COI: 1:CAS:528:DC%2BD1cXjvFeqs74%3D; Ghoumid, J., Drevillon, L., Alavi-Naini, S.M., ZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat-Wilson syndrome (2013) Hum Mol Genet, 22, pp. 2652-2661. , COI: 1:CAS:528:DC%2BC3sXptVOitrw%3D; Heinritz, W., Zweier, C., Froster, U.G., A missense mutation in the ZFHX1B gene associated with an atypical Mowat-Wilson syndrome phenotype (2006) Am J Med Genet A, 140, pp. 1223-1227

PY - 2018

Y1 - 2018

N2 - Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. Conclusion: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care. © 2018, American College of Medical Genetics and Genomics.

AB - Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. Conclusion: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care. © 2018, American College of Medical Genetics and Genomics.

KW - Hirschsprung

KW - intellectual disability

KW - management

KW - Mowat–Wilson syndrome

KW - ZEB2

KW - zinc finger E box binding homeobox 2

KW - adolescent

KW - adult

KW - age

KW - Article

KW - brain malformation

KW - cardiovascular malformation

KW - child

KW - clinical feature

KW - correlational study

KW - disease severity

KW - epilepsy

KW - family history

KW - female

KW - gene

KW - gene deletion

KW - gene locus

KW - genetic association

KW - genetic variation

KW - genotype

KW - genotype phenotype correlation

KW - growth curve

KW - head circumference

KW - human

KW - infant

KW - intellectual impairment

KW - major clinical study

KW - male

KW - mental disease

KW - missense mutation

KW - Mowat Wilson syndrome

KW - musculoskeletal system malformation

KW - patient care

KW - phenotype

KW - prediction

KW - prevalence

KW - protein function

KW - ZEB2 gene

U2 - 10.1038/gim.2017.221

DO - 10.1038/gim.2017.221

M3 - Article

VL - 20

SP - 965

EP - 975

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 9

ER -