Research Overview

We are studying patients with Angelman syndrome (AS), a developmental disorder that affects movement, speech and social behavior, and investigating interventions that could potentially improve the care of patients with this condition. AS is caused by a deficiency of a maternally-expressed gene and is manifested at birth. Symptoms may include, but are not limited to, functionally severe developmental delay, speech impairments, movement or balance problems, and behavioral uniqueness, including a combination of frequent laughter or smiling, apparent happy demeanor, easily excitable personality, hand flapping movements and short attention span.

Current Projects:

Characterization of Angelman syndrome

We are conducting an observational study, following children with AS over 5 to 10 years to gain a better understanding of disease progression and the clinical features of AS's four molecular subclasses. The study will also attempt to establish genotype-phenotype correlations, which might aid in clinical care of AS patients.

To learn more, please click here.

A trial of levodopa in Angelman syndrome

Levodopa is a drug commonly used in adults with Parkinson disease to control tremors and involuntary movements. Levodopa is not FDA-approved for use in children, but many children have used this drug for a variety of medical conditions over the last 30 years. Parents who put their children with AS on levodopa have reported improvements in cognition and abnormal movements, but the drug has not been rigorously studied in AS. Therefore, the goal of this study is to understand the efficacy of levodopa in these children.

Angelman syndrome clinical research studies

Gene identification for rare Mendelian disorders in collaboration with various basic science laboratories Clinical trials in rare Mendelian disorders

To learn more, please click here.

 

Research Background

Dr. Tan is a clinical geneticist with an interest in a broad range of rare and ultra-rare Mendelian disorders, including pediatric cancer predisposition syndromes. He is also interested in the design of clinical trials for rare genetic syndromes. After graduating from medical school in Nottingham (United Kingdom), he undertook training in pediatrics and clinical genetics in Nottingham, Bury St. Edmunds, Cambridge (Cambridgeshire), and Boston. He has been on the faculty at Boston Children’s Hospital since 2006 and has been actively involved in clinical research studies on Angelman syndrome since then. He leads the Boston site of the Angelman Syndrome Natural History study and was the overall principal investigator of a multi-center phase II/III clinical trial of levodopa in Angelman syndrome.

He is also interested in Bohring-Opitz syndrome and serves on the Medical Advisory Board of the Bohring- Opitz Syndrome Foundation.

In addition, he now serves as the site PI of a gene therapy trial in adults with ornithine transcarbamylase deficiency.

Selected Publications

  1. Tan WH, Bacino CA, Skinner SA, Anselm I, Barbieri-Welge R, Bauer-Carlin A, Beaudet AL, Bichell TJ, Gentile JK, Glaze DG, Horowitz LT, Kothare SV, Lee HS, Nespeca MP, Peters SU, Sahoo T, Sarco D, Waisbren SE, Bird LM. Angelman syndrome: Mutations influence features in early childhood. Am J Med Genet A. 2011; 155A(1):81-90.
  2. Bird LM, Tan WH, Bacino CA, Peters SU, Skinner SA, Anselm I, Barbieri-Welge R, Bauer-Carlin A, Gentile JK, Glaze DG, Horowitz LT, Mohan KN, Nespeca MP, Sahoo T, Sarco D, Waisbren SE, Beaudet AL. A therapeutic trial of pro-methylation dietary supplements in Angelman syndrome. Am J Med Genet A. 2011; 155A(12):2956-63.
  3. Tan WH, Bird LM, Thibert RL, Williams CA. If not Angelman, what is it? A review of Angelman-like syndromes. Am J Med Genet A. 2014; 164A(4):975- 92.
  4. von Oettingen JE, Tan WH, Dauber A. Skeletal dysplasia, global developmental delay, and multiple congenital anomalies in a 5 year-old boy – Report of the second family with B3GAT3 mutation and expansion of the phenotype. Am J Med Genet A. 2014; 164A(6):1580-6.
  5. Smpokou P, Fox VL, Tan WH. PTEN hamartoma tumour syndrome: early tumour development in children. Arch Dis Child. 2015; 100(1):34-7.
  6. Tan WH, Bird LM. Angelman syndrome: Current and emerging therapies in 2016. Am J Med Genet C Semin Med Genet. 2016 Nov 8. doi: 10.1002/ajmg.c.31536. [Epub ahead of print]
  7. Bird LM, Tan WH. Treatment of genetic disorders-A vision coming into focus. Am J Med Genet C Semin Med Genet. 2016 Nov 3. doi: 10.1002/ajmg.c.31535. [Epub ahead of print]
  8. Lamont RE, Tan WH, Innes AM, Parboosingh JS, Schneidman-Duhovny D, Rajkovic A, Pappas J, Altschwager P, DeWard S, Fulton A, Gray KJ, Krall M, Mehta L, Rodan LH, Saller DN Jr, Steele D, Stein D, Yatsenko SA, Bernier FP, Slavotinek AM. Expansion of phenotype and genotypic data in CRB2-related syndrome. Eur J Hum Genet. 2016 Oct;24(10):1436-44.

Education

Medical School

University of Nottingham Medical School
1998 Nottingham United Kingdom

Internship

Internal Medicine/General Surgery/Pediatrics University Hospital
1999 Nottingham United Kingdom

Residency

General Pediatrics West Suffolk Hospital & Addenbrooke's Hospital
2001 East Anglia United Kingdom

Residency

Pediatrics Massachusetts General Hospital
2003 Boston MA

Fellowship

Clinical Genetics Harvard Medical School Genetics Training Program
2006 Boston MA

Publications

  1. Developmental milestones and daily living skills in individuals with Angelman syndrome. J Neurodev Disord. 2024 Jun 15; 16(1):32. View Abstract
  2. Gaboxadol in angelman syndrome: A double-blind, parallel-group, randomized placebo-controlled phase 3 study. Eur J Paediatr Neurol. 2023 Nov; 47:6-12. View Abstract
  3. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications. Brain. 2022 09 14; 145(9):2991-3009. View Abstract
  4. DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes. Eur J Hum Genet. 2022 06; 30(6):695-702. View Abstract
  5. Methylation analysis and developmental profile of two individuals with Angelman syndrome due to mosaic imprinting defects. Eur J Med Genet. 2022 Apr; 65(4):104456. View Abstract
  6. Anxiety in Angelman Syndrome. Am J Intellect Dev Disabil. 2022 01 01; 127(1):1-10. View Abstract
  7. KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum. Brain. 2021 12 31; 144(12):3635-3650. View Abstract
  8. Proposed criteria for nevoid basal cell carcinoma syndrome in children assessed using statistical optimization. Sci Rep. 2021 10 05; 11(1):19791. View Abstract
  9. Clinical Characterization of Epilepsy in Children With Angelman Syndrome. Pediatr Neurol. 2021 11; 124:42-50. View Abstract
  10. Evaluating Sleep Disturbances in Children With Rare Genetic Neurodevelopmental Syndromes. Pediatr Neurol. 2021 10; 123:30-37. View Abstract
  11. The Unrecognized Mortality Burden of Genetic Disorders in Infancy. Am J Public Health. 2021 07; 111(S2):S156-S162. View Abstract
  12. Electrophysiological Abnormalities in Angelman Syndrome Correlate With Symptom Severity. Biol Psychiatry Glob Open Sci. 2021 Sep; 1(3):201-209. View Abstract
  13. Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability. Hum Mutat. 2021 06; 42(6):762-776. View Abstract
  14. Developmental Skills of Individuals with Angelman Syndrome Assessed Using the Bayley-III. J Autism Dev Disord. 2023 Feb; 53(2):720-737. View Abstract
  15. A dyadic approach to the delineation of diagnostic entities in clinical genomics. Am J Hum Genet. 2021 01 07; 108(1):8-15. View Abstract
  16. The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome. Neurology. 2021 02 16; 96(7):e1024-e1035. View Abstract
  17. Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis. Am J Med Genet A. 2021 01; 185(1):203-207. View Abstract
  18. Cleft Lip and Palate in Ectodermal Dysplasia. Cleft Palate Craniofac J. 2021 02; 58(2):237-243. View Abstract
  19. Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment. Mol Psychiatry. 2021 07; 26(7):3625-3633. View Abstract
  20. Genetic diagnoses and associated anomalies in fetuses prenatally diagnosed with esophageal atresia. Am J Med Genet A. 2020 08; 182(8):1890-1895. View Abstract
  21. Impaired dentin mineralization, supernumerary teeth, hypoplastic mandibular condyles with long condylar necks, and a TRPS1 mutation. Arch Oral Biol. 2020 Aug; 116:104735. View Abstract
  22. De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy. Genet Med. 2020 08; 22(8):1413-1417. View Abstract
  23. Imprinted genes in clinical exome sequencing: Review of 538 cases and exploration of mouse-human conservation in the identification of novel human disease loci. Eur J Med Genet. 2020 Jun; 63(6):103903. View Abstract
  24. ZMYND11-related syndromic intellectual disability: 16 patients delineating and expanding the phenotypic spectrum. Hum Mutat. 2020 05; 41(5):1042-1050. View Abstract
  25. Neurodevelopmental profile of siblings with Angelman syndrome due to pathogenic UBE3A variants. J Intellect Disabil Res. 2020 03; 64(3):246-250. View Abstract
  26. TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities. Am J Hum Genet. 2019 12 05; 105(6):1126-1147. View Abstract
  27. An observational study of pediatric healthcare burden in Angelman syndrome: results from a real-world study. Orphanet J Rare Dis. 2019 11 04; 14(1):239. View Abstract
  28. Infant mortality: the contribution of genetic disorders. J Perinatol. 2019 12; 39(12):1611-1619. View Abstract
  29. Genome Sequencing Identifies the Pathogenic Variant Missed by Prior Testing in an Infant with Marfan Syndrome. J Pediatr. 2019 10; 213:235-240. View Abstract
  30. Healthcare burden among individuals with Angelman syndrome: Findings from the Angelman Syndrome Natural History Study. Mol Genet Genomic Med. 2019 07; 7(7):e00734. View Abstract
  31. Maladaptive behaviors in individuals with Angelman syndrome. Am J Med Genet A. 2019 06; 179(6):983-992. View Abstract
  32. Prenatal imaging throughout gestation in Beckwith-Wiedemann syndrome. Prenat Diagn. 2019 08; 39(9):792-795. View Abstract
  33. Electrophysiological Phenotype in Angelman Syndrome Differs Between Genotypes. Biol Psychiatry. 2019 05 01; 85(9):752-759. View Abstract
  34. Clinical diversity of MYH7-related cardiomyopathies: Insights into genotype-phenotype correlations. Am J Med Genet A. 2019 03; 179(3):365-372. View Abstract
  35. Two Angelman families with unusually advanced neurodevelopment carry a start codon variant in the most highly expressed UBE3A isoform. Am J Med Genet A. 2018 07; 176(7):1641-1647. View Abstract
  36. Recognizing and Managing Children with a Pediatric Cancer Predisposition Syndrome: A Guide for the Pediatrician. Pediatr Ann. 2018 May 01; 47(5):e204-e216. View Abstract
  37. Acute Pancreatitis in a Patient with Maple Syrup Urine Disease: A Management Paradox. J Pediatr. 2018 07; 198:313-316. View Abstract
  38. Defining the phenotypic spectrum of SLC6A1 mutations. Epilepsia. 2018 02; 59(2):389-402. View Abstract
  39. Expanding the neurodevelopmental phenotype of PURA syndrome. Am J Med Genet A. 2018 01; 176(1):56-67. View Abstract
  40. A randomized controlled trial of levodopa in patients with Angelman syndrome. Am J Med Genet A. 2018 05; 176(5):1099-1107. View Abstract
  41. Liver Failure as the Presentation of Ornithine Transcarbamylase Deficiency in a 13-Month-Old Female. JIMD Rep. 2018; 40:17-22. View Abstract
  42. Treatment of ADCY5-Associated Dystonia, Chorea, and Hyperkinetic Disorders With Deep Brain Stimulation: A Multicenter Case Series. J Child Neurol. 2016 07; 31(8):1027-35. View Abstract
  43. Pharmacological therapies for Angelman syndrome. Wien Med Wochenschr. 2017 Jun; 167(9-10):205-218. View Abstract
  44. Clinical heterogeneity associated with KCNA1 mutations include cataplexy and nonataxic presentations. Neurogenetics. 2016 Jan; 17(1):11-6. View Abstract
  45. Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance. Am J Med Genet A. 2015 Sep; 167A(9):2122-31. View Abstract
  46. Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination. Am J Hum Genet. 2015 May 07; 96(5):709-19. View Abstract
  47. Commentary. Clin Chem. 2015 Jan; 61(1):54. View Abstract
  48. PTEN hamartoma tumour syndrome: early tumour development in children. Arch Dis Child. 2015 Jan; 100(1):34-7. View Abstract
  49. Copy number variation plays an important role in clinical epilepsy. Ann Neurol. 2014 Jun; 75(6):943-58. View Abstract
  50. If not Angelman, what is it? A review of Angelman-like syndromes. Am J Med Genet A. 2014 Apr; 164A(4):975-92. View Abstract
  51. Skeletal dysplasia, global developmental delay, and multiple congenital anomalies in a 5-year-old boy-report of the second family with B3GAT3 mutation and expansion of the phenotype. Am J Med Genet A. 2014 Jun; 164A(6):1580-6. View Abstract
  52. Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities. Mol Psychiatry. 2014 Mar; 19(3):368-79. View Abstract
  53. In: Rimoin DL, Pyeritz RE, Korf BR, editors. Emery and Rimoin's Principles and Practice of Medical Genetics. Human Developmental Genetics. 2013. View Abstract
  54. CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development. Nat Genet. 2012 Nov; 44(11):1260-4. View Abstract
  55. Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database. Hum Mutat. 2012 Mar; 33(3):457-66. View Abstract
  56. Pitt-Hopkins syndrome should be in the differential diagnosis for males presenting with an ATR-X phenotype. Clin Genet. 2011 Dec; 80(6):600-1. View Abstract
  57. A therapeutic trial of pro-methylation dietary supplements in Angelman syndrome. Am J Med Genet A. 2011 Dec; 155A(12):2956-63. View Abstract
  58. Angelman syndrome: Mutations influence features in early childhood. Am J Med Genet A. 2011 Jan; 155A(1):81-90. View Abstract
  59. A homozygous mutation in the tight-junction protein JAM3 causes hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Am J Hum Genet. 2010 Dec 10; 87(6):882-9. View Abstract
  60. A neurodevelopmental survey of Angelman syndrome with genotype-phenotype correlations. J Dev Behav Pediatr. 2010 Sep; 31(7):592-601. View Abstract
  61. Epilepsy in Prader-Willi syndrome: clinical characteristics and correlation to genotype. Epilepsy Behav. 2010 Nov; 19(3):306-10. View Abstract
  62. Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders. Am J Med Genet B Neuropsychiatr Genet. 2010 Jun 05; 153B(4):937-47. View Abstract
  63. Developmental and degenerative features in a complicated spastic paraplegia. Ann Neurol. 2010 Apr; 67(4):516-25. View Abstract
  64. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet. 2009 Apr; 46(4):242-8. View Abstract
  65. Diagnostic utility of array-based comparative genomic hybridization in a clinical setting. Am J Med Genet A. 2007 Nov 01; 143A(21):2523-33. View Abstract
  66. The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management. J Med Genet. 2007 Sep; 44(9):594-602. View Abstract
  67. Identification of a novel polymorphism--the duplication of the NPHP1 (nephronophthisis 1) gene. Am J Med Genet A. 2006 Sep 01; 140A(17):1876-9. View Abstract
  68. Proton magnetic resonance spectroscopy and diffusion-weighted imaging in isolated sulfite oxidase deficiency. J Child Neurol. 2006 Sep; 21(9):801-5. View Abstract
  69. Isolated sulfite oxidase deficiency: a case report with a novel mutation and review of the literature. Pediatrics. 2005 Sep; 116(3):757-66. View Abstract
  70. A putative new locus for an autosomal recessive cerebellar ataxia syndrome on chromosome 22q11. Clin Genet. 2005 Aug; 68(2):185-7. View Abstract
  71. Cockayne syndrome: the developing phenotype. Am J Med Genet A. 2005 Jun 01; 135(2):214-6. View Abstract
  72. Hypothelia, syndactyly, and ear malformation--a variant of the scalp-ear-nipple syndrome?: Case report and review of the literature. Am J Med Genet A. 2005 Apr 15; 134A(2):220-2. View Abstract
  73. Dose regimen for vancomycin not needing serum peak levels? Arch Dis Child Fetal Neonatal Ed. 2002 Nov; 87(3):F214-6. View Abstract
  74. Bohring-Opitz Syndrome. GeneReviews®. 1993. View Abstract

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