Atlas of X-Linked Intellectual Disability Syndromes

Charles E. Schwartz, Ph.D - As research fellow at the Department of Haematology at University of Utah, Dr. Schwartz laid the groundwork for the discovery of both breast and colon cancer genes. He established the molecular genetics laboratory at the Greenwood Genetic Center in 1985. Until his retirement in May 2019, Dr. Schwartz's research interests focused on the causes of intellectual disabilities (ID) and autism. Besides identifying over 27 XLID genes, his group established abnormal tryptophan metabolism as one feature associated with ASD. He is currently an Adjunct Professor in the Department of Pediatrics and Human Development at Michigan State University, Grand Rapids.Roger E. Stevenson, M.D. - In 1974, Dr. Stevenson left a faculty position at the University of Texas Medical School in Houston to return to his home state of South Carolina to establish the Greenwood Genetic Center. In its 50 years, the GGC has become the state's premier genetic institution with medical genetics trainingprograms, clinics, diagnostic laboratories, and research program. Stevenson's career has been focused on birth defects, intellectual disability, autism, and related disorders. He established the South Carolina Neural Tube Defect Surveillance and Prevention Program in 1992, and has collaborated with Charles Schwartz in Research on X-linked intellectual disabilities since 1985.Tao Wang, M.D., Ph.D.- Dr. Wang is a pediatric and biochemical geneticist, and physician scientist in the McKusick-Nathans Department of Genetic Medicine at Johns Hopkins University School of Medicine. Dr. Wang's clinical and research interests center around understanding genetic basis and mechanism of developmental brain disorders including X-linked intellectual disability and autism, and inborn errors of metabolism including phenylketonuria and gyrate atrophy of the choroid and retina. In collaboration with Drs. Stevenson and Schwartz of Greenwood Genetic Center, Dr. Wang's research team has contributed to clinical,genetic, and/or functional characterization of over 20 X-linked intellectual disability genes.

This new 3rd Edition of the Atlas of X-Linked Intellectual Disability Syndromes is a markedly expanded version of the 2 previous editions. The format defines each entity and discusses clinical, neurological, neuropathological, and genetic expression, along with growth and development, clinical photos, and differential diagnosis in a pithy outline format with useful references. There are also many useful appendices, new information regarding methylation signatures (when available) to assist in resolving troublesome VUS findings encountered during gene sequencing, as well as various treatment options, which is a growing body of knowledge. John M Graham Jr MD, ScD Clinical Genetics Consultant, Cedars-Sinai Medical Center, Emeritus Professor of Pediatrics, David Geffen Medical School at UCLA, Los Angeles CA

• FOREWORD INTRODUCTIONAARSKOG SYNDROMEABIDI SYNDROME ADRENOLEUKODYSTROPHYAGENESIS OF THE CORPUS CALLOSUM, X-LINKED AHMAD SYNDROME AICARDI SYNDROME ALG13 CONGENITAL DISORDER OF GLYCOSYLATIONALLAN-HERNDON-DUDLEY SYNDROME ALPHA-THALASSEMIA INTELLECTUAL DISABILITY (SEE ALSO ATRX-ASSOCIATED XLID) AP1S2-ASSOCIATED XLIDAPAK ATAXIA-SPASTIC DIPLEGIA SYNDROME ARMFIELD SYNDROME ARTS SYNDROME ARX-ASSOCIATED XLID ATAXIA-DEAFNESS-DEMENTIA, X-LINKED ATAXIA-SEIZURES-HEARING LOSSATKIN-FLAITZ SYNDROME ATP6AP2 CONGENITAL DISORDER OF GLYCOSYLATIONATRX-ASSOCIATED XLID BERGIA CARDIOMYOPATHY BERTINI SYNDROME BÖRJESON-FORSSMAN-LEHMANN SYNDROME BRANCHIAL ARCH SYNDROME, X-LINKED C1GALT1C1 CHAPERONOPATHYCANTU SYNDROME CARPENTER-WAZIRI SYNDROME (SEE ALSO ATRX-ASSOCIATED XLID) CEREBRO-CEREBELLO-COLOBOMA SYNDROME CEREBRO-OCULO-GENITAL SYNDROME CEREBRO-PALATO-CARDIAC SYNDROME (SEE ALSO RENPENNING SYNDROME) CHARCOT-MARIE-TOOTH NEUROPATHY, COWCHOCK VARIANTCHASSAING-LACOMBE CHONDRODYSPLASIA CHRISTIAN SYNDROME CHRISTIANSON SYNDROME CHUDLEY-LOWRY SYNDROME (SEE ALSO ATRX-ASSOCIATED XLID) CK SYNDROME COFFIN-LOWRY SYNDROME CORNELIA DE LANGE SYNDROME 2CORNELIA DE LANGE SYNDROME 5 CRANIOFACIOSKELETAL SYNDROME CREATINE TRANSPORTER DEFICIENCY DEAD/H-BOX-RELATED XLIDDEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85DHSRX CONGENITAL DISORDER OF GLYCOSYLATIONDUCHENNE MUSCULAR DYSTROPHY DYSKERATOSIS CONGENITA EPILEPSY-INTELLECTUAL DISABILITY IN FEMALES FITZSIMMONS SYNDROME FLNA-ASSOCIATED XLID FRAGILE X SYNDROME GABRA3-RELATED XLID-SEIZURESGALLOWAY-MOWAT SYNDROME 2 GIUFFRÈ-TSUKAHARA SYNDROME GLRA2-RELATED XLID GLYCEROL KINASE DEFICIENCY GOLABI-ITO-HALL SYNDROME: (SEE ALSO RENPENNING SYNDROME) GOLDBLATT SPASTIC PARAPLEGIA SYNDROME GOLTZ SYNDROME GPKOW-RELATED XLIDGRAHAM ANOPHTHALMIA SYNDROME GUSTAVSON SYNDROME HALL OROFACIAL SYNDROME HEREDITARY BULLOUS DYSTROPHY, X-LINKED HNRNPH2-RELATED XLID HOLMES-GANG SYNDROME (SEE ALSO ATRX-ASSOCIATED XLID) HOMFRAY SEIZURES-CONTRACTURES HUTCHINSON SYNDROMEHYDE-FORSTER SYNDROME HYDRANENCEPHALY WITH ABNORMAL GENITALIA (SEE ALSO ARX-ASSOCIATED XLID) HYDROCEPHALY-CEREBELLAR AGENESIS SYNDROME HYDROCEPHALY-MASA SPECTRUM HYPOPARATHYROIDISM, X-LINKED INCONTINENTIA PIGMENTI JUBERG-MARSIDI-BROOKS SYNDROME KABUKI SYNDROME 2KANG SYNDROME KCND1-RELATED XLIDKDM5C-RELATED XLIDKEIPERT SYNDROMELENZ MICROPHTHALMIA SYNDROME LESCH-NYHAN SYNDROME LINEAR SKIN DEFECTS-MULTIPLE ANOMALIESLISSENCEPHALY AND ABNORMAL GENITALIA, X-LINKED (SEE ALSO ARX-ASSOCIATED XLID) LISSENCEPHALY, X-LINKED LOWE SYNDROME LUJAN SYNDROME MAGT1 CONGENITAL DISORDER OF GLYCOSYLATIONMARTIN-PROBST SYNDROME MED12-RELATED XLIDMEHMO SYNDROME MEND SYNDROMEMENKES SYNDROME MICROPHTHALMIA 2MICROPHTHALMIA 13MIDAS SYNDROME MILES-CARPENTER SYNDROME MOHR-TRANEBJAERG SYNDROME MONOAMINE OXIDASE-A DEFICIENCY MSL3-RELATED XLIDMUCOPOLYSACCHARIDOSIS IIA MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 2 MYOTUBULAR MYOPATHY NAA10-ASSOCIATED XLIDN-ALPHA-ACETYLTRANSFERASE DEFICIENCY NANCE-HORAN SYNDROMENEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5NEURODEVELOPMENTAL DISORDER WITH EPILEPSY AND HEMOCHROMATOSIS NKAP-RELATED XLIDNONO-RELATED XLIDNORRIE DISEASE O-GlcNAc TRANSFERASE DEFICIENCYOGDEN SYNDROME (SEE ALSO NAA10-ASSOCIATED XLID)OPITZ FG SYNDROME OPTIC ATROPHY, X-LINKED ORAL-FACIAL-DIGITAL SYNDROME I ORNITHINE TRANSCARBAMOYLASE DEFICIENCY OSTEOPATHIA STRIATA WITH CRANIAL SCLEROSISOTOPALATODIGITAL SYNDROME I (SEE ALSO FLNA-ASSOCIATED XLID) OTOPALATODIGITAL SYNDROME II (SEE ALSO FLNA-ASSOCIATED XLID) PAINE SYNDROME PALLISTER W SYNDROME PARTINGTON SYNDROME (SEE ALSO ARX-ASSOCIATED XLID) PELIZAEUS-MERZBACHER SYNDROME PERIVENTRICULAR NODULAR HETEROTOPIA (SEE ALSO FLNA-ASSOCIATED XLID) PETTIGREW SYNDROME PHOSPHOGLYCERATE KINASE DEFICIENCY PIGA-ASSOCIATED XLIDPLOTT SYNDROME PORTEOUS SYNDROME (SEE ALSO RENPENNING SYNDROME) PPM-X PRIETO SYNDROME PROUD SYNDROME (SEE ALSO ARX-ASSOCIATED XLID) PYRUVATE DEHYDROGENASE DEFICIENCY RAYMOND TYPE XLIDRENPENNING SYNDROME RETT SYNDROME RETT-LIKE SEIZURES-HYPOTONIA RITSCHER-SCHINZEL SYNDROME 2RNF113A-RELATED XLIDSAY-MEYER SYNDROME SCHIMKE SYNDROME SH3KBP1-RELATED XLIDSHASHI SYNDROME SHRIMPTON SYNDROME SHUKLA-VERNON SYNDROMESIMPSON-GOLABI-BEHMEL SYNDROME SLC35A2 CONGENITAL DISORDER OF GLYCOSYLATION SLITRK2-RELATED XLIDSMARCA1-RELATED XLIDSMITH-FINEMAN-MYERS SYNDROME SNYDER-ROBINSON SYNDROME SSR4 CONGENITAL DISORDER OF GLYCOSYLATIONSTAG-RELATED HOLOPROSENCEPHALY STAG2-RELATED XLIDSTOCCO DOS SANTOS SYNDROME STOLL SYNDROME SUTHERLAND-HAAN SYNDROME (SEE ALSO RENPENNING SYNDROME) TARP SYNDROME TCEAL1-RELATED XLIDTELECANTHUS-HYPOSPADIAS SYNDROME TURNER XLID (SEE ALSO AP1S2-ASSOCIATED XLID) URBAN SYNDROMEUSP9X-RELATED XLIDVACTERL-HYDROCEPHALUS SYNDROME VASQUEZ SYNDROME WAISMAN-LAXOVA SYNDROME WARKANY SYNDROME WDR44 CILIOPATHYWIEACKER-WOLFF SYNDROME WIEACKER-WOLFF SYNDROME, FEMALE RESTRICTED WILSON-TURNER SYNDROME XLID-ARCH FINGERPRINTS-HYPOTONIA SYNDROME (SEE ALSO ATRX-ASSOCIATED XLID) XLID-ATAXIA-APRAXIA XLID-ATAXIA-DEMENTIA XLID-ATAXIA-SEIZURESXLID-BLINDNESS-SEIZURES-SPASTICITY XLID-BRAIN ANOMALIES-ATAXIAXLID-CHOREOATHETOSIS XLID-CHOROIDEREMIA-ECTODERMAL DYSPLASIA XLID-CLEFT LIP/CLEFT PALATE XLID-EPILEPSY (XIDE) XLID-HYDROCEPHALY-BASAL GANGLIA CALCIFICATIONS (SEE ALSO AP1S2-ASSOCIATED XLID) XLID-HYPEREKPLEXIA-SEIZURESXLID-HYPOGAMMAGLOBULINEMIA XLID-HYPOGONADISM-TREMOR XLID-HYPOSPADIAS XLID-HYPOTONIA-RECURRENT INFECTIONS XLID-INFANTILE SPASMS (SEE ALSO ARX-ASSOCIATED XLID) XLID-ISOLATED GROWTH HORMONE DEFICIENCY XLID-MACROCEPHALY XLID-MACROCEPHALY-MACROORCHIDISM XLID-MICROCEPHALY-TESTICULAR FAILURE XLID-MITOCHONDRIAL MYOPATHYXLID-MULTIPLE ANOMALIES-EARLY LETHALITYXLID-NAIL DYSTROPHY-SEIZURES XLID-NYSTAGMUS-SEIZURES XLID-PANHYPOPITUITARISM XLID-PIGMENTARY MOSAICISMXLID-PSORIASIS XLID-RETICULATE HYPERPIMENTATIONXLID-RETINITIS PIGMENTOSA XLID-RETINOPATHY-SEIZURESXLID-ROLANDIC SEIZURES XLID-SEIZURES-APHASIA XLID-SPASTIC PARAPLEGIA, TYPE 7 XLID-SPASTIC PARAPLEGIA-ATHETOSIS XLID-SPONDYLOEPIMETAPHYSEAL DYSPLASIA XLID-TRIGONOCEPHALYX-LINKED OHDO SYNDROME X-LINKED OLIVOPONTOCEREBELLAR ATROPHYYOUNG-HUGHES SYNDROME ZC4H2-ASSOCIATED XLID ZFP92-RELATED XLIDZFX-RELATED XLIDZMYM3-RELATED XLID APPENDICESI. GENES INVOLVED IN X-LINKED INTELLECTUAL DISABILITY (BY ORDER OF DISCOVERY) II. XLID SYNDROMES WITH MICROCEPHALY III. XLID SYNDROMES WITH MACROCEPHALY IV. XLID SYNDROMES WITH OCULAR ANOMALIES AND/OR VISUAL IMPAIRMENT V. XLID SYNDROME WITH HEARING LOSS VI. XLID SYNDROMES WITH FACIAL CLEFTING VII. XLID SYNDROMES WITH CARDIAC MALFORMATIONS OR OTHER CARDIOVASCULAR ABNORMALITIES VIII. XLID SYNDROMES WITH UROGENITAL ANOMALIES IX. XLID SYNDROMES WITH NEURONAL MIGRATION DISTURBANCE X. XLID SYNDROMES WITH SPASTIC PARAPLEGIA XI. XLID SYNDROMES WITH SEIZURES XII. XLID SYNDROMES WITH HYPOTONIA XIII. XLID SYNDROMES PREDOMINANTLY AFFECTING FEMALES XIV. DUPLICATION OF XLID GENES AND REGIONS OF THE X-CHROMOSOME GENOME XV. X-INACTIVATION XVI A. Xp SYNDROMAL XLID GENESXVI B. Xq SYNDROMAL XLID GENES XVI C. SYNDROMAL XLID GENESXVII. SYNDROMAL XLID (LINKAGE LIMITS) XVIII. NONSYNDROMAL XLID FAMILIES (LINKAGE LIMITS)XIX. NONSYNDROMAL XLID FAMILIES XX. X-LINKED DISORDERS WITH INTELLECTUAL DISABILITY AND AUTISM INDEX