2. Academic Validation
  3. Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation

Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation

  • Hum Mutat. 2004 Feb;23(2):147-159. doi: 10.1002/humu.10310.
Mitsuhiro Kato 1 2,  Soma Das 1,  Kristin Petras 1,  Kunio Kitamura 3,  Ken-Ichirou Morohashi 4,  Diane N Abuelo 5,  Mason Barr 6,  Dominique Bonneau 7,  Angela F Brady 8,  Nancy J Carpenter 9,  Karen L Cipero 10,  Francesco Frisone 11,  Takayuki Fukuda 4,  Renzo Guerrini 12,  Eri Iida 3,  Masayuki Itoh 13,  Amy Feldman Lewanda 14 15,  Yukiko Nanba 16,  Akira Oka 16,  Virginia K Proud 17,  Pascale Saugier-Veber 18,  Susan L Schelley 19,  Angelo Selicorni 20,  Rachel Shaner 5,  Margherita Silengo 21,  Fiona Stewart 22,  Noriyuki Sugiyama 4,  Jun Toyama 23,  Annick Toutain 24,  Ana Lía Vargas 25,  Masako Yanazawa 3,  Elaine H Zackai 10,  William B Dobyns 1
Affiliations

Affiliations

  • 1 Department of Human Genetics, The University of Chicago, Chicago, Illinois.
  • 2 Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.
  • 3 Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan.
  • 4 Department of Developmental Biology, National Institute for Basic Biology, Okazaki, Japan.
  • 5 Department of Pediatrics, Rhode Island Hospital, Providence, Rhode Island.
  • 6 Teratology Unit, Departments of Pediatrics, Pathology, and Obstetrics, University of Michigan, Ann Arbor, Michigan.
  • 7 Service de Génétique Médicale, Centre Hospitalier Universitaire d'Angers, Angers, France.
  • 8 North West Thames Regional Genetics Service, Kennedy-Galton Centre, North West London Hospitals NHS Trust, London, UK.
  • 9 HA Chapman Institute of Medical Genetics, University of Oklahoma Health Science Center, Tulsa, Oklahoma.
  • 10 Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania.
  • 11 Congregazione Suore Infermiere dell'Addolorata, Ospedale Generale di Zona "Valduce", Divisione di Patologia Neonatale, Como, Italy.
  • 12 INPE Istituto di Neuropsichiatria e Psicopedagogia dellíeta evolutiva, Universita degli Studi di Pisa-IRCCS Stella Maris, Pisa, Italy.
  • 13 National Center of Neurology and Psychiatry, National Institute of Neuroscience, Tokyo, Japan.
  • 14 Division of Genetics, Inova Fairfax Hospital for Children, Falls Church, Virginia.
  • 15 Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • 16 Tottori University School of Medicine, Yonago, Japan.
  • 17 Department of Pediatrics (Medical Genetics), Eastern Virginia Medical School; Norfolk, Virginia.
  • 18 Service de Médecine Néonatale et Service de Génétique, Centre Hospitalier Universitaire de Rouen, Rouen, France.
  • 19 Department of Pediatrics (Genetics), Stanford University, Stanford, California.
  • 20 Centro di Genetica Clinica per l'Infanzia, I Clinica Pediatrica Università di Milano, Milan, Italy.
  • 21 Department of Pediatrics, University of Torino, Torino, Italy.
  • 22 Department of Medical Genetics, Belfast City Hospital, Belfast, UK.
  • 23 Department of Pediatrics, Okinawa Child Development Center, Okinawa, Japan.
  • 24 Service de Génétique et Service de Neuropédiatrie, Centre Hospitalier Universitaire de Tours, Tours, France.
  • 25 Instituto de Genética; Universidad Nacional de Cuyo, Mendoza, Argentina.
PMID: 14722918 DOI: 10.1002/humu.10310
Abstract

We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.

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