DOCSLIB.ORG

Adults with Sotos Syndrome: Review of 21 Adults with Molecularly Confirmed NSD1 Alterations, Including a Detailed Case Report of the Oldest Person Matthew R

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Adults with Sotos Syndrome: Review of 21 Adults with Molecularly Confirmed NSD1 Alterations, Including a Detailed Case Report of the Oldest Person Matthew R RESEARCH ARTICLE Adults With Sotos Syndrome: Review of 21 Adults With Molecularly Confirmed NSD1 Alterations, Including a Detailed Case Report of the Oldest Person Matthew R. Fickie,1,2* Pablo Lapunzina,3,4,5 Jennifer K. Gentile,6 Nina Tolkoff-Rubin,7 Daniela Kroshinsky,8 Enrique Galan,9 Esther Gean,10 Loreto Martorell,11 Valeria Romanelli,12 Joaquın Fernandez Toral,13 and Angela E. Lin1 1Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts 2Harvard Medical School Genetics Training Program, Boston, Massachusetts 3Instituto de Genetica Medica y Molecular (INGEMM), Instituto de Investigacion del Hospital Universitario La Paz (IdiPAZ), Madrid, Spain 4Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain 5Registro Espa~nol de Sındromes de Sobrecrecimiento (RESSC), Madrid, Spain 6Department of Psychiatry, Children’s Hospital Boston, Boston, Massachusetts 7Department of Nephrology, Massachusetts General Hospital, Boston, Massachusetts 8Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts 9Departamento de Pediatria, Hospital Materno Infatil de Badajoz, Badajoz, Spain 10Seccion de Genetica Medica, Hospital Sant Joan de Deu, Barcelona, Spain 11Seccion de Genetica Molecular, Hospital Sant Joan de Deu, Barcelona, Spain 12INGEMM, Hospital Universitario La Paz, Madrid, Spain 13Seccion de Genetica Pediatrica, Hospital Universitario Central de Asturias, Oviedo, Spain Received 19 September 2010; Accepted 30 May 2011 Sotos syndrome is a well-described multiple anomaly syndrome characterized by overgrowth, distinctive craniofacial appear- How to Cite this Article: ance, and variable learning disabilities. The diagnosis of Sotos Fickie MR, Lapunzina P, Gentile JK, Tolkoff- syndrome relied solely on these clinical criteria until haploin- Rubin N, Kroshinsky D, Galan E, Gean E, sufficiency of the NSD1 gene was identified as causative. We Martorell L, Romanelli V, Toral JF, Lin AE. describe a 63-year-old woman with classic features and a patho- 2011. Adults with Sotos syndrome: Review of genic NSD1 mutation, who we believe to be the oldest reported 21 adults with molecularly confirmed NSD1 person with Sotos syndrome. She is notable for the diagnosis of alterations, including a detailed case report of Sotos syndrome late in life, mild cognitive limitation, and the oldest person. chronic kidney disease attributed to fibromuscular dysplasia Am J Med Genet Part A 155:2105–2111. for which she recently received a transplant. She has basal cell and squamous cell carcinoma for which her lifetime of sun exposure and fair cutaneous phototype are viewed as risk factors. We also reviewed previous literature reports (n ¼ 11) for adults with Sotos syndrome, and studied patients ascertained in the Spanish Overgrowth Syndrome Registry (n ¼ 15). Analysis was limited to 21/27 (78%) total patients who had molecular con- firmation of Sotos syndrome (15 with a mutation, 6 with a *Correspondence to: microdeletion). With a mean age of 26 years, the most common Matthew R. Fickie, M.D., Division of Genetics, Baystate Children’s features were learning disabilities (90%), scoliosis (52%), eye Hospital, 795 Chestnut Street, Springfield, MA 01199. problems (43%), psychiatric issues (30%), and brain imaging E-mail: matthew.fi[email protected] anomalies (28%). Learning disabilities were more severe in Published online 10 August 2011 in Wiley Online Library patients with a microdeletion than in those with a point muta- (wileyonlinelibrary.com). tion. From this small study with heterogeneous ascertainment DOI 10.1002/ajmg.a.34156 Ó 2011 Wiley-Liss, Inc. 2105 2106 AMERICAN JOURNAL OF MEDICAL GENETICS PART A we suggest modest adjustments to the general healthcare CLINICAL REPORT monitoring of individuals with Sotos syndrome. Although this A 63-year-old white woman with tall stature was referred by the series includes neoplasia in four cases, this should not be nephrology service for evaluation of possible Marfan syndrome. interpreted as incidence. Age-appropriate cancer surveillance The past medical history was provided by the patient’s sister, her should be maintained. Ó 2011 Wiley-Liss, Inc. ‘‘guardian’’ since their mother had severe Alzheimer disease, and their father was living out of state; over the period of this evaluation Key words: adults with genetic disorders; familial gigantism; and manuscript submission: both parents have since died. The overgrowth syndrome; NSD1; Sotos syndrome; transitional care patient was the first of four pregnancies delivered by cesarean section and not known to be premature. She was described by her father as ‘‘spastic’’ at birth, referring to contractures. From early INTRODUCTION childhood she was developmentally delayed and had positional lower extremity deformities (pes planus) for which she wore braces. In the 47 years since Sotos et al. [1964] reported five children at the The patient had ‘‘fluid tapped from the brain,’’ which may have Massachusetts General Hospital with a distinctive overgrowth been for presumed hydrocephalus since she had a pneumoence- syndrome, more than 400 cases of Sotos syndrome have been phalogram. Medical records refer to a ‘‘tumor in her chest’’ which reported [Baujat and Cormier-Daire, 2007; Tatton-Brown et al., was later found to be an enlarged thymus. She resided at a private 2009]. The cardinal features include rapid early growth, advanced school for persons with learning disabilities, though she was aware bone age, head circumference and height >2 SD above the mean, a they were more disabled than herself. She reports with insight and typical craniofacial gestalt (macrocephaly, high prominent fore- sadness, that she was considered ‘‘retarded’’ during her childhood. head, sparse frontal hairline, inverted triangular face, pointed chin), She eventually completed high school, attended a vocational and learning disabilities ranging from mild to severe [Allanson and school for 3 years, and lived with her maternal aunt. In addition to Cole, 1996; Cole, 2005; Tatton-Brown et al., 2009]. Although these this history from the patient and her sister, the family album (Fig. 1) features have been well-described throughout childhood, little is provided a rich photographic history of a healthy-appearing girl known about the identification, clinical manifestations and with a distinct facial appearance (large head, thin hair, high fore- management of individuals diagnosed with Sotos syndrome later head, elongated face, prominent chin, wide-spaced eyes), tall in life. stature, and long limbs compared to siblings. The diagnosis of Sotos syndrome relied solely on clinical criteria In her third decade of life the patient had a bowel obstruction. until haploinsufficiency of the NSD1 (nuclear receptor SET Surgery for a poorly defined indication included a hysterectomy domain-containing protein) gene was identified as causative and oophorectomy. The patient enjoyed many outdoor activities [Kurotaki et al., 2002]. The NSD1 gene is located at 5q35, the and lived in Bermuda for 8 years prior to moving to Southern site of a common microdeletion in Japanese patients [Kurotaki California where she was told that she had features of Marfan et al., 2003], whereas non-Japanese patients are more likely to have a syndrome. In her twenties she was diagnosed with anemia and point mutation in NSD1 [Douglas et al., 2003]. NSD1 is known to hypertension which led to a diagnosis of renal disease. A renal artery encode a histone methyltransferase involved in chromatin regu- biopsy showed fibromuscular dysplasia at age 24 years, treated with lation whose epigenetic effects not only cause Sotos syndrome, but a right renal artery bypass with vein graft at age 30. Subsequent may be implicated in sporadic neuroblastoma [Berdasco et al., angiography showed a ‘‘diminutive left upper pole with fibromus- 2009]. The facial appearance changes with time. Specifically, as the cular dysplasia and patent right renal bypass.’’ She underwent a face lengthens the forehead becomes less prominent and the cholecystectomy at that time as well. The patient transferred care at mandible and chin become the dominant facial features age 58 for treatment of renal insufficiency, which was viewed as [Allanson and Cole, 1996]. This facial gestalt, tall stature, and chronic kidney disease, stage V. She underwent a successful lack of awareness of the disease among adult medicine physicians deceased donor kidney transplant at age 63 years. makes ‘‘possible Marfan syndrome’’ an occasional referring Her tall stature and habitus had been described by others as diagnosis [Maves et al., 2007]. The differential diagnosis of ‘‘marfanoid.’’ Echocardiogram at age 64 showed a normal aortic Sotos syndrome in adulthood also includes Weaver syndrome, diameter, no evidence of mitral valve prolapse, and mild aortic Simpson–Golabi–Behmel syndrome, and Gorlin syndrome. Caring insufficiency. When examined in the genetics clinic she was a well- for adults with genetic syndromes is increasingly recognized as an groomed, tall, and thin female who moved slowly. She was quietly important part of transitional care and internal medicine but engaging, speaking in a soft voice. She appeared older than her guidelines for screening and managing individuals with Sotos chronologic age, frail, with uremia. syndrome are not available [Cole, 2005]. Her weight was 64.1 kg (75th centile), height 177.4 cm (>97th We report on a 63-year-old woman who may be the oldest person centile), upper: lower segment ratio 1.03, BMI 20.4, head circum- with
Load more

Recommended publications
  • Tall Stature: a Difficult Diagnosis? Cristina Meazza1* , Chiara Gertosio2, Roberta Giacchero3, Sara Pagani1 and Mauro Bozzola1
    Meazza et al. Italian Journal of Pediatrics (2017) 43:66 DOI 10.1186/s13052-017-0385-5 REVIEW Open Access Tall stature: a difficult diagnosis? Cristina Meazza1* , Chiara Gertosio2, Roberta Giacchero3, Sara Pagani1 and Mauro Bozzola1 Abstract Referral for an assessment of tall stature is less common than for short stature. Tall stature is defined as a height more than two standard deviations above the mean for age. The majority of subjects with tall stature show a familial tall stature or a constitutional advance of growth (CAG), which is a diagnosis of exclusion. After a careful physical evaluation, tall subjects may be divided into two groups: tall subjects with normal appearance and tall subjects with abnormal appearance. In the case of normal appearance, the paediatric endocrinologist will have to evaluate the growth rate. If it is normal for age and sex, the subject may be classified as having familial tall stature, CAG or obese subject, while if the growth rate is increased it is essential to evaluate pubertal status and thyroid status. Tall subjects with abnormal appearance and dysmorphisms can be classified into those with proportionate and disproportionate syndromes. A careful physical examination and an evaluation of growth pattern are required before starting further investigations. Physicians should always search for a pathological cause of tall stature, although the majority of children are healthy and they generally do not need treatment to cease growth progression. The most accepted and effective treatment for an excessive height prediction is inducing puberty early and leading to a complete fusion of the epiphyses and achievement of final height, using testosterone in males and oestrogens in females.
    [Show full text]
  • Genetic Investigation of Patients with Tall Stature
    2 182 E Vasco de Albuquerque Genetic investigation of tall 182:2 139–147 Clinical Study Albuquerque and others stature patients Genetic investigation of patients with tall stature Edoarda Vasco de Albuquerque Albuquerque1, Mariana Ferreira de Assis Funari2, Elisângela Pereira de Souza Quedas1, Rachel Sayuri Honjo Kawahira3, Raquel Soares Jallad4, Thaís Kataoka Homma1, Regina Matsunaga Martin2,5, Vinicius Nahime Brito2, Alexsandra Christianne Malaquias1,6, Antonio Marcondes Lerario1,7, Carla Rosenberg8, Ana Cristina Victorino Krepischi8, Chong Ae Kim3, Ivo Jorge Prado Arnhold2 and Alexander Augusto de Lima Jorge1 1Unidade de Endocrinologia Genética (LIM25), 2Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (LIM42), Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brasil, 3Unidade de Genética do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil, 4Unidade de Neuroendocrinologia, 5Unidade de Doenças Osteometabólicas, Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brasil, 6Unidade de Endocrinologia Pediátrica, Correspondence Departamento de Pediatria, Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo, Brasil, 7Division of should be addressed Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, to A A L Jorge Michigan, USA, and 8Instituto de Biociências (IB), Universidade de São Paulo (USP), São Paulo, Brasil Email [email protected] Abstract Context: Patients with tall stature often remain undiagnosed after clinical investigation and few studies have genetically assessed this group, most of them without a systematic approach. Objective: To assess prospectively a group of individuals with tall stature, with and without syndromic features, and to establish a molecular diagnosis for their growth disorder.
    [Show full text]
  • Megalencephaly and Macrocephaly
    277 Megalencephaly and Macrocephaly KellenD.Winden,MD,PhD1 Christopher J. Yuskaitis, MD, PhD1 Annapurna Poduri, MD, MPH2 1 Department of Neurology, Boston Children’s Hospital, Boston, Address for correspondence Annapurna Poduri, Epilepsy Genetics Massachusetts Program, Division of Epilepsy and Clinical Electrophysiology, 2 Epilepsy Genetics Program, Division of Epilepsy and Clinical Department of Neurology, Fegan 9, Boston Children’s Hospital, 300 Electrophysiology, Department of Neurology, Boston Children’s Longwood Avenue, Boston, MA 02115 Hospital, Boston, Massachusetts (e-mail: [email protected]). Semin Neurol 2015;35:277–287. Abstract Megalencephaly is a developmental disorder characterized by brain overgrowth secondary to increased size and/or numbers of neurons and glia. These disorders can be divided into metabolic and developmental categories based on their molecular etiologies. Metabolic megalencephalies are mostly caused by genetic defects in cellular metabolism, whereas developmental megalencephalies have recently been shown to be caused by alterations in signaling pathways that regulate neuronal replication, growth, and migration. These disorders often lead to epilepsy, developmental disabilities, and Keywords behavioral problems; specific disorders have associations with overgrowth or abnor- ► megalencephaly malities in other tissues. The molecular underpinnings of many of these disorders are ► hemimegalencephaly now understood, providing insight into how dysregulation of critical pathways leads to ►
    [Show full text]
  • Level Estimates of Maternal Smoking and Nicotine Replacement Therapy During Pregnancy
    Using primary care data to assess population- level estimates of maternal smoking and nicotine replacement therapy during pregnancy Nafeesa Nooruddin Dhalwani BSc MSc Thesis submitted to the University of Nottingham for the degree of Doctor of Philosophy November 2014 ABSTRACT Background: Smoking in pregnancy is the most significant preventable cause of poor health outcomes for women and their babies and, therefore, is a major public health concern. In the UK there is a wide range of interventions and support for pregnant women who want to quit. One of these is nicotine replacement therapy (NRT) which has been widely available for retail purchase and prescribing to pregnant women since 2005. However, measures of NRT prescribing in pregnant women are scarce. These measures are vital to assess its usefulness in smoking cessation during pregnancy at a population level. Furthermore, evidence of NRT safety in pregnancy for the mother and child’s health so far is nebulous, with existing studies being small or using retrospectively reported exposures. Aims and Objectives: The main aim of this work was to assess population- level estimates of maternal smoking and NRT prescribing in pregnancy and the safety of NRT for both the mother and the child in the UK. Currently, the only population-level data on UK maternal smoking are from repeated cross-sectional surveys or routinely collected maternity data during pregnancy or at delivery. These obtain information at one point in time, and there are no population-level data on NRT use available. As a novel approach, therefore, this thesis used the routinely collected primary care data that are currently available for approximately 6% of the UK population and provide longitudinal/prospectively recorded information throughout pregnancy.
    [Show full text]
  • Macrocephaly Information Sheet 6-13-19
    Next Generation Sequencing Panel for Macrocephaly Clinical Features: Macrocephaly refers to an abnormally large head, OFC greater than 98th percentile, inclusive of the scalp, cranial bone and intracranial contents. Megalencephaly, brain weight/volume ratio greater than 98th percentile, results from true enlargement of the brain parenchyma [1]. Megalencephaly is typically accompanied by macrocephaly, however macrocephaly can occur in the absence of megalencephaly [2]. Both macrocephaly and megalencephaly can been seen as isolated clinical findings as well as clinical features of a mutli-systemic syndromic diagnosis. Our Macrocephaly Panel includes analysis of the 36 genes listed below. Macrocephaly Sequencing Panel ASXL2 GLI3 MTOR PPP2R5D TCF20 BRWD3 GPC3 NFIA PTEN TBC1D7 CHD4 HEPACAM NFIX RAB39B UPF3B CHD8 HERC1 NONO RIN2 ZBTB20 CUL4B KPTN NSD1 RNF125 DNMT3A MED12 OFD1 RNF135 EED MITF PIGA SEC23B EZH2 MLC1 PPP1CB SETD2 Gene Clinical Features Details ASXL2 Shashi-Pena Shashi et al. (2016) found that six patients with developmental delay, syndrome macrocephaly, and dysmorphic features were found to have de novo truncating variants in ASXL2 [3]. Distinguishing features were macrocephaly, absence of growth retardation, and variability in the degree of intellectual disabilities The phenotype also consisted of prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties and hypotonia. BRWD3 X-linked intellectual Truncating mutations in the BRWD3 gene have been described in males with disability nonsyndromic intellectual disability and macrocephaly [4]. Other features include a prominent forehead and large cupped ears. CHD4 Sifrim-Hitz-Weiss Weiss et al., 2016, identified five individuals with de novo missense variants in the syndrome CHD4 gene with intellectual disabilities and distinctive facial dysmorphisms [5].
    [Show full text]
  • The First Non-Invasive Prenatal Test That Screens for Single-Gene Disorders
    The first non-invasive prenatal test that screens for single-gene disorders the evolution of NIPT A non-invasive prenatal test that screens multiple genes for mutations causing severe genetic disorders in the fetus analyses circulating cell- free fetal DNA (cfDNA) from a maternal blood sample. The test is performed after 10 weeks of pregnancy. works as a complementary screen to traditional and genome- wide NIPT . It screens for several life-altering genetic disorders that are not screened with current NIPT technology, allowing a complete picture of the risk of a pregnancy being affected by a genetic disorder. 2 facilitates early diagnosis of single-gene disorders. It involves 3 different levels of screening: This test screens for 5 common inherited recessive genetic disorders, such as Cystic Fibrosis, Beta-Thalassemia, Sickle INHERITED cell anaemia, Deafness autosomal recessive type 1A, Deafness autosomal recessive type 1B. Genes screened: CFTR, CX26 (GJB2), CX30 (GJB6), HBB This test screens for 44 severe genetic disorders due to de novo mutations (a gene mutation that is not inherited) in 25 genes DE NOVO Genes screened: ASXL1, BRAF, CBL, CHD7, COL1A1, COL1A2 , COL2A1, FGFR2, FGFR3, HDAC8, JAG1, KRAS, MAP2K1, MAP2K2, MECP2, NIPBL, NRAS, NSD1, PTPN11, RAF1, RIT1, SETBP1, SHOC2, SIX3, SOS1 This test screens for both inherited and de novo single-gene disorders and represents a combination of the tests INHERITED COMPLETE and DE NOVO providing a complete picture of the pregnancy risk. 3 allows detection of common inherited genetic disorders in INHERITED the fetus GENE GENETIC DISORDER CFTR Cystic Fibrosis CX26 (GJB2) Deafness autosomal recessive type 1A CX30 (GJB6) Deafness autosomal recessive type 1B HBB Beta-Thalassemia HBB Sickle cell anemia The inherited recessive disorders screened by INHERITED are the most common in the European population 4 identifies fetal conditions that could be missed by traditional DE NOVO prenatal screening.
    [Show full text]
  • Orphanet Report Series Rare Diseases Collection
    Marche des Maladies Rares – Alliance Maladies Rares Orphanet Report Series Rare Diseases collection DecemberOctober 2013 2009 List of rare diseases and synonyms Listed in alphabetical order www.orpha.net 20102206 Rare diseases listed in alphabetical order ORPHA ORPHA ORPHA Disease name Disease name Disease name Number Number Number 289157 1-alpha-hydroxylase deficiency 309127 3-hydroxyacyl-CoA dehydrogenase 228384 5q14.3 microdeletion syndrome deficiency 293948 1p21.3 microdeletion syndrome 314655 5q31.3 microdeletion syndrome 939 3-hydroxyisobutyric aciduria 1606 1p36 deletion syndrome 228415 5q35 microduplication syndrome 2616 3M syndrome 250989 1q21.1 microdeletion syndrome 96125 6p subtelomeric deletion syndrome 2616 3-M syndrome 250994 1q21.1 microduplication syndrome 251046 6p22 microdeletion syndrome 293843 3MC syndrome 250999 1q41q42 microdeletion syndrome 96125 6p25 microdeletion syndrome 6 3-methylcrotonylglycinuria 250999 1q41-q42 microdeletion syndrome 99135 6-phosphogluconate dehydrogenase 67046 3-methylglutaconic aciduria type 1 deficiency 238769 1q44 microdeletion syndrome 111 3-methylglutaconic aciduria type 2 13 6-pyruvoyl-tetrahydropterin synthase 976 2,8 dihydroxyadenine urolithiasis deficiency 67047 3-methylglutaconic aciduria type 3 869 2A syndrome 75857 6q terminal deletion 67048 3-methylglutaconic aciduria type 4 79154 2-aminoadipic 2-oxoadipic aciduria 171829 6q16 deletion syndrome 66634 3-methylglutaconic aciduria type 5 19 2-hydroxyglutaric acidemia 251056 6q25 microdeletion syndrome 352328 3-methylglutaconic
    [Show full text]
  • Metacarpophalangeal Pattern Profile Analysis in Sotos Syndrome
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE HHS Public Access provided by IUPUIScholarWorks Author manuscript Author ManuscriptAuthor Manuscript Author Am J Med Manuscript Author Genet. Author Manuscript Author manuscript; available in PMC 2017 September 12. Published in final edited form as: Am J Med Genet. 1985 April ; 20(4): 625–629. doi:10.1002/ajmg.1320200408. Metacarpophalangeal Pattern Profile Analysis in Sotos Syndrome Merlin G. Butler, Department of Biology, University of Notre Dame and North Central Regional Genetics Center, Memorial Hospital, South Bend, Indiana Department of Medical Genetics, Indiana University School of Medicine F. John Meaney, Department of Medical Genetics, Indiana University School of Medicine Genetic Diseases Section, Indiana State Board of Health, Indianapolis Smita Kittur, Pediatric Genetics Department, Children’s Medical and Surgical Center, Johns Hopkins Hospital, Baltimore Joseph H. Hersh, and Child Evaluation Center, Department of Pediatrics, University of Louisville School of Medicine Lusia Hornstein Cincinnati Center for Developmental Disorders, Children’s Hospital Medical Center Abstract The metacarpophalangeal pattern profile (MCPP) was analyzed on 16 Sotos syndrome patients. A mean Sotos syndrome profile was produced. Correlation studies confirm clinical homogeneity of Sotos syndrome individuals. Discriminant analysis of Sotos syndrome patients and normal individuals produces a function of two MCPP variables and age, which may provide a useful tool for diagnosis. Keywords Sotos syndrome; metacarpophalangeal pattern profile (MCPP); discriminant analysis; correlation studies INTRODUCTION Sotos syndrome, or cerebral gigantism, was first described by Sotos et al [1964]; at least 100 cases were reported subsequently. This syndrome is characterized by large size at birth, large hands and feet, advanced osseous maturation, macrocephaly with prominent forehead and Address reprint requests to Merlin G.
    [Show full text]
  • Diagnostic Utility of Genome-Wide DNA Methylation Analysis in Mendelian Neurodevelopmental Disorders
    International Journal of Molecular Sciences Review Diagnostic Utility of Genome-Wide DNA Methylation Analysis in Mendelian Neurodevelopmental Disorders Sadegheh Haghshenas 1,2 , Pratibha Bhai 2, Erfan Aref-Eshghi 3 and Bekim Sadikovic 1,2,4,* 1 Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada; [email protected] 2 Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A 5W9, Canada; [email protected] 3 Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; [email protected] 4 Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada * Correspondence: [email protected] Received: 22 November 2020; Accepted: 4 December 2020; Published: 6 December 2020 Abstract: Mendelian neurodevelopmental disorders customarily present with complex and overlapping symptoms, complicating the clinical diagnosis. Individuals with a growing number of the so-called rare disorders exhibit unique, disorder-specific DNA methylation patterns, consequent to the underlying gene defects. Besides providing insights to the pathophysiology and molecular biology of these disorders, we can use these epigenetic patterns as functional biomarkers for the screening and diagnosis of these conditions. This review summarizes our current understanding of DNA methylation episignatures in rare disorders and describes the underlying technology and analytical approaches. We discuss the computational parameters, including statistical and machine learning methods, used for the screening and classification of genetic variants of uncertain clinical significance. Describing the rationale and principles applied to the specific computational models that are used to develop and adapt the DNA methylation episignatures for the diagnosis of rare disorders, we highlight the opportunities and challenges in this emerging branch of diagnostic medicine.
    [Show full text]
  • Sotos Syndrome
    European Journal of Human Genetics (2007) 15, 264–271 & 2007 Nature Publishing Group All rights reserved 1018-4813/07 $30.00 www.nature.com/ejhg PRACTICAL GENETICS In association with Sotos syndrome Sotos syndrome is an autosomal dominant condition characterised by a distinctive facial appearance, learning disability and overgrowth resulting in tall stature and macrocephaly. In 2002, Sotos syndrome was shown to be caused by mutations and deletions of NSD1, which encodes a histone methyltransferase implicated in chromatin regulation. More recently, the NSD1 mutational spectrum has been defined, the phenotype of Sotos syndrome clarified and diagnostic and management guidelines developed. Introduction In brief Sotos syndrome was first described in 1964 by Juan Sotos Sotos syndrome is characterised by a distinctive facial and the major diagnostic criteria of a distinctive facial appearance, learning disability and childhood over- appearance, childhood overgrowth and learning disability growth. were established in 1994 by Cole and Hughes.1,2 In 2002, Sotos syndrome is associated with cardiac anomalies, cloning of the breakpoints of a de novo t(5;8)(q35;q24.1) renal anomalies, seizures and/or scoliosis in B25% of translocation in a child with Sotos syndrome led to the cases and a broad variety of additional features occur discovery that Sotos syndrome is caused by haploinsuffi- less frequently. ciency of the Nuclear receptor Set Domain containing NSD1 abnormalities, such as truncating mutations, protein 1 gene, NSD1.3 Subsequently, extensive analyses of missense mutations in functional domains, partial overgrowth cases have shown that intragenic NSD1 muta- gene deletions and 5q35 microdeletions encompass- tions and 5q35 microdeletions encompassing NSD1 cause ing NSD1, are identifiable in the majority (490%) of 490% of Sotos syndrome cases.4–10 In addition, NSD1 Sotos syndrome cases.
    [Show full text]
  • Regional Genetic Consultation Service
    Regional Genetic Consultation Service Contract 5889BD01 July 1, 2018 through June 30, 2019 Congenital & Inherited Disorders Division of Health Promotion & Chronic Disease Prevention, Phone: 1-800-383-3826 http://idph.iowa.gov/genetics Regional Genetic Consultation Service: A contract established by IDPH in the Division of Health Promotion & Chronic Disease Prevention, Contract # 5888BD01 Administrative Code, Chapter 4:641-4.5(136A) Iowa Department of Public Health Advancing Health Through the Generations Kimberly Reynolds Adam Gregg Gerd Clabaugh Governor Lt. Governor Director Authorized State Official for this contract: Brenda Dobson, Director, Division of Health Promotion and Chronic Disease Prevention (515) 281-7769 University of Iowa Stead Family Department of Pediatrics (319) 356-2675 Hatem El-Shanti, MD, Division Director John A. Bernat, MD, PhD, Clinical Director Hannah Bombei, MS, CGC, Program Coordinator Page | 2 Congenital & Inherited Disorders Division of Health Promotion & Chronic Disease Prevention, Phone: 800-383-3826 http://idph.iowa.gov/genetics In collaboration with the Iowa Department of Public Health & The Stead Family Department of Pediatrics Division of Medical Genetics & Genomics University of Iowa Stead Family Children’s Hospital & Clinical Outreach Services University of Iowa Hospitals and Clinics Page | 3 What is the Regional Genetic Consultation Service? Iowa Administrative Code 641—4.5(136A) Regional Genetic Consultation Service (RGCS). This program provides comprehensive genetic and genomic services statewide through outreach clinics. 4.5(1) Provision of comprehensive genetic and genomic services. The department shall contract with the Division of Medical Genetics & Genomics within the Stead Family Department of Pediatrics at the University of Iowa to provide genetic and genomic health care and education outreach services for individuals and families within Iowa.
    [Show full text]
  • Abstracts Books 2014
    TWENTY-FIFTH EUROPEAN MEETING ON DYSMORPHOLOGY 10 – 12 SEPTEMBER 2014 25th EUROPEAN MEETING ON DYSMORPHOLOGY LE BISCHENBERG WEDNESDAY 10th SEPTEMBER 5 p.m. to 7.30 p.m. Registration 7.30 p.m. to 8.30 p.m. Welcome reception 8.30 p.m. Dinner 9.30 p.m. Unknown THURSDAY 11th SEPTEMBER 8.15 a.m. Opening address 8.30 a.m. to 1.00 p.m. First session 1.00 p.m. Lunch 2.30 p.m. to 7.00 p.m. Second and third sessions 8.00 p.m. Dinner 9.00 p.m. to 11.00 p.m. Unknown FRIDAY 12th SEPTEMBER 8.30 a.m. to 1.00 p.m. Fourth and fifth sessions 1.00 p.m. Lunch 2.30 p.m. to 6.00 p.m. Sixth and seventh sessions 7.30 p.m. Dinner SATURDAY 13th SEPTEMBER Breakfast – Departure Note: This program is tentative and may be modified. WEDNESDAY 10th SEPTEMBER 9.30 UNKNOWN SESSION Chair: FRYNS J.P. H. VAN ESCH Case 1 H. VAN ESCH Case 2 H. JILANI, S. HIZEM, I. REJEB, F. DZIRI AND L. BEN JEMAA Developmental delay, dysmorphic features and hirsutism in a Tunisian girl. Cornelia de Lange syndrome? L. VAN MALDERGEM, C. CABROL, B. LOEYS, M. SALEH, Y. BERNARD, L. CHAMARD AND J. PIARD Megalophthalmos and thoracic great vessels aneurisms E. SCHAEFER AND Y. HERENGER An unknown diagnosis associating facial dysmorphism, developmental delay, posterior urethral valves and severe constipation P. RUMP AND T. VAN ESSEN What’s in the name G. MUBUNGU, A. LUMAKA, K.
    [Show full text]