Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation.
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.
Kato
Mitsuhiro
M
Department of Human Genetics, The University of Chicago, Chicago, Illinois.|Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.
Das
Soma
S
Department of Human Genetics, The University of Chicago, Chicago, Illinois.
Petras
Kristin
K
Department of Human Genetics, The University of Chicago, Chicago, Illinois.
Kitamura
Kunio
K
Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan.
Morohashi
Ken-Ichirou
KI
Department of Developmental Biology, National Institute for Basic Biology, Okazaki, Japan.
Abuelo
Diane N
DN
Department of Pediatrics, Rhode Island Hospital, Providence, Rhode Island.
Barr
Mason
M
Teratology Unit, Departments of Pediatrics, Pathology, and Obstetrics, University of Michigan, Ann Arbor, Michigan.
Bonneau
Dominique
D
Service de Génétique Médicale, Centre Hospitalier Universitaire d'Angers, Angers, France.
Brady
Angela F
AF
North West Thames Regional Genetics Service, Kennedy-Galton Centre, North West London Hospitals NHS Trust, London, UK.
Carpenter
Nancy J
NJ
HA Chapman Institute of Medical Genetics, University of Oklahoma Health Science Center, Tulsa, Oklahoma.
Cipero
Karen L
KL
Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania.
Frisone
Francesco
F
Congregazione Suore Infermiere dell'Addolorata, Ospedale Generale di Zona "Valduce", Divisione di Patologia Neonatale, Como, Italy.
Fukuda
Takayuki
T
Department of Developmental Biology, National Institute for Basic Biology, Okazaki, Japan.
Guerrini
Renzo
R
INPE Istituto di Neuropsichiatria e Psicopedagogia dellíeta evolutiva, Universita degli Studi di Pisa-IRCCS Stella Maris, Pisa, Italy.
Iida
Eri
E
Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan.
Itoh
Masayuki
M
National Center of Neurology and Psychiatry, National Institute of Neuroscience, Tokyo, Japan.
Lewanda
Amy Feldman
AF
Division of Genetics, Inova Fairfax Hospital for Children, Falls Church, Virginia.|Johns Hopkins University School of Medicine, Baltimore, Maryland.
Nanba
Yukiko
Y
Tottori University School of Medicine, Yonago, Japan.
Oka
Akira
A
Tottori University School of Medicine, Yonago, Japan.
Proud
Virginia K
VK
Department of Pediatrics (Medical Genetics), Eastern Virginia Medical School; Norfolk, Virginia.
Saugier-Veber
Pascale
P
Service de Médecine Néonatale et Service de Génétique, Centre Hospitalier Universitaire de Rouen, Rouen, France.
Schelley
Susan L
SL
Department of Pediatrics (Genetics), Stanford University, Stanford, California.
Selicorni
Angelo
A
Centro di Genetica Clinica per l'Infanzia, I Clinica Pediatrica Università di Milano, Milan, Italy.
Shaner
Rachel
R
Department of Pediatrics, Rhode Island Hospital, Providence, Rhode Island.
Silengo
Margherita
M
Department of Pediatrics, University of Torino, Torino, Italy.
Stewart
Fiona
F
Department of Medical Genetics, Belfast City Hospital, Belfast, UK.
Sugiyama
Noriyuki
N
Department of Developmental Biology, National Institute for Basic Biology, Okazaki, Japan.
Toyama
Jun
J
Department of Pediatrics, Okinawa Child Development Center, Okinawa, Japan.
Toutain
Annick
A
Service de Génétique et Service de Neuropédiatrie, Centre Hospitalier Universitaire de Tours, Tours, France.
Vargas
Ana Lía
AL
Instituto de Genética; Universidad Nacional de Cuyo, Mendoza, Argentina.
Yanazawa
Masako
M
Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan.
Zackai
Elaine H
EH
Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania.
Dobyns
William B
WB
Department of Human Genetics, The University of Chicago, Chicago, Illinois.
D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D061085:Agenesis of Corpus Callosum; D002478:Cells, Cultured; D003337:Corpus Callosum / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D005836:Genitalia, Female / Q000002:abnormalities / Q000473:pathology; D005837:Genitalia, Male / Q000002:abnormalities / Q000473:pathology; D005838:Genotype; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008214:Lymphocytes / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D025064:Sex Chromosome Disorders / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
C469264:ARX protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors