Aicardi Syndrome without CDKL5 Gene Mutation

Pai, Cheng Pin; Wang, Chuan Yu; Kuo, Yung Ting; Liang, Jao Shwann

doi:10.1016/j.jecm.2013.02.011

Cited by 1 publication

(1 citation statement)

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“…Early investigations into the genetics of AIC were predominantly focused on the X chromosome for three reasons [ 5 , 6 , 7 , 8 , 9 , 10 ]. Firstly, an X-linked, male-lethal cause best explains the greater than 99% female predominance of the disease; secondly, all affected males identified to date have a 47, XXY karyotype [ 11 , 12 , 13 , 14 ]; and thirdly, serendipitously the first chromosomal aberration reported in a girl with AIC was a 46,X,t(X;3)(p22;q12) translocation [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Aicardi Syndrome Is a Genetically Heterogeneous Disorder

Ha,

Burgess,

Newman

et al. 2023

Genes

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Aicardi Syndrome (AIC) is a rare neurodevelopmental disorder recognized by the classical triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile epileptic spasms syndrome. The diagnostic criteria of AIC were revised in 2005 to include additional phenotypes that are frequently observed in this patient group. AIC has been traditionally considered as X-linked and male lethal because it almost exclusively affects females. Despite numerous genetic and genomic investigations on AIC, a unifying X-linked cause has not been identified. Here, we performed exome and genome sequencing of 10 females with AIC or suspected AIC based on current criteria. We identified a unique de novo variant, each in different genes: KMT2B, SLF1, SMARCB1, SZT2 and WNT8B, in five of these females. Notably, genomic analyses of coding and non-coding single nucleotide variants, short tandem repeats and structural variation highlighted a distinct lack of X-linked candidate genes. We assessed the likely pathogenicity of our candidate autosomal variants using the TOPflash assay for WNT8B and morpholino knockdown in zebrafish (Danio rerio) embryos for other candidates. We show expression of Wnt8b and Slf1 are restricted to clinically relevant cortical tissues during mouse development. Our findings suggest that AIC is genetically heterogeneous with implicated genes converging on molecular pathways central to cortical development.

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