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.
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).
Mutations in the Aristaless-related homeobox (ARX) gene are associated with a broad spectrum of disorders including X-linked lissencephaly with abnormal genitalia (XLAG) and absent corpus callosum.
KCC3 mutations have been associated with hereditary motor and sensory polyneuropathy with corpus callosum agenesis (Andermann syndrome) that often manifests with epileptic seizures.
Peripheral neuropathy with or without agenesis of the corpus callosum (ACCPN [MIM 2180000]) is an autosomal recessive disease characterised by progressive sensorimotor neuropathy, mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum.
Notably, we found mutations in genes encoding chromatin-state regulators, such as SMARCA2, CREBBP and KDM6A, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis.
FOXG1B (forkhead box G1B) is a very intriguing candidate gene since it is known to promote neuronal progenitor proliferation and to suppress premature neurogenesis and its disruption is reported in a patient with postnatal microcephaly, corpus callosum agenesis, seizures, and severe mental retardation.
In the present report, we describe a case of a 2-year-old female with RSTS who, besides most of the typical features of RSTS has corpus callosum dysgenesis and a Chiari type I malformation which required neurosurgical decompression.
Incomplete penetrance or haploinsufficiency of other genes from the critical region may explain the absence of corpus callosum agenesis in this patient with a ZBTB18 point mutation.
We resequenced DISC1 in a cohort of 144 well-characterized AgCC individuals and identified 20 sequence changes, of which 4 are rare potentially pathogenic variants.