An Emerging Female Phenotype with Loss-of-Function Mutations in the Aristaless-Related Homeodomain Transcription Factor ARX.
The devastating clinical presentation of X-linked lissencephaly with abnormal genitalia (XLAG) is invariably caused by loss-of-function mutations in the Aristaless-related homeobox (ARX) gene. Mutations in this X-chromosome gene contribute to intellectual disability (ID) with co-morbidities including seizures and movement disorders such as dystonia in affected males. The detection of affected females with mutations in ARX is increasing. We present a family with multiple affected individuals, including two females. Two male siblings presenting with XLAG were deceased prior to full-term gestation or within the first few weeks of life. Of the two female siblings, one presented with behavioral disturbances, mild ID, a seizure disorder, and complete agenesis of the corpus callosum (ACC), similar to the mother's phenotype. A novel insertion mutation in Exon 2 of ARX was identified, c.982delCinsTTT predicted to cause a frameshift at p.(Q328Ffs*37). Our finding is consistent with loss-of-function mutations in ARX causing XLAG in hemizygous males and extends the findings of ID and seizures in heterozygous females. We review the reported phenotypes of females with mutations in ARX and highlight the importance of screening ARX in male and female patients with ID, seizures, and in particular with complete ACC.
Department of Paediatrics, School of Medicine, University of Adelaide, Adelaide, SA, Australia.|Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
Tessa
T
Mattiske
Department of Paediatrics, School of Medicine, University of Adelaide, Adelaide, SA, Australia.|Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
Ching
C
Moey
Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
Lisenka E
LE
Vissers
Murdoch Children's Research Institute, Melbourne, Australia.|University of Melbourne, Melbourne, Australia.|Melbourne Genomics Health Alliance, Melbourne, Australia.
Natalie
N
Thorne
Melbourne Genomics Health Alliance, Melbourne, Australia.|Victorian Life Sciences Computation Initiative, The University of Melbourne, Melbourne, Australia.
Peter
P
Georgeson
Department of Clinical Genetics, Liverpool Hospital, Liverpool, NSW, Australia.
Madhura
M
Bakshi
Department of Paediatrics, School of Medicine, University of Adelaide, Adelaide, SA, Australia.|Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
Cheryl
C
Shoubridge
D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D050172:Genes, X-Linked; D056726:Genetic Association Studies; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
C469264:ARX protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors
ARX; Aristaless-related homeobox; LISX2; X-linked lissencephaly; X-linked lissencephaly-2; XLAG; intellectual disability; seizure