An Emerging Female Phenotype with Loss‐of‐Function Mutations in the Aristaless‐ Related Homeodomain Transcription Factor ARX

Abstract

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.

Deleterious de novo variants of X‐linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita

“…The striking phenotypic differences between females with inherited X‐linked recessive ZC4H2 missense variants versus de novo X‐linked dominant deleterious ZC4H2 nonsense, frameshifting or Xq11.2 microdeletions is similar to that seen for a few other X‐linked genes, such as ARX (Bienvenu et al, ; Mattiske et al, ; Stromme et al, ), HDAC8 (Kaiser et al, ), PHF6 (Lower et al, ; Zweier et al, ), IQSEC2 (Ewans et al, ; O'Rawe et al, ; Shoubridge et al, ; Zerem et al, ), and CLCN4 (Hu et al, ; Palmer et al, ). Also gender‐specific pathogenicity differences of inherited variants in males and de novo variants in females have been reported for other XLID genes, for example, DDX3X (Dikow et al, ; Snijders Blok et al, ), KIAA2022 (Lorenzo et al, ; Van Maldergem et al, ), MTM1 (Schara, Kress, Tucke, & Mortier, ), and CASK (Moog et al, ).…”

Heterozygous nonsense ARX mutation in a family highlights the complexity of clinical and molecular diagnosis in case of chromosomal and single gene disorder co‐inheritance

“…A milder phenotype has been recently delineated in females with heterozygous XLAG mutations, with 31 affected carriers reported (Mattiske et al, 2017), which is additionally influenced by skewed X-inactivation, at least in brain (Marsh et al, 2009(Marsh et al, , 2016. Clinical manifestations mainly include ID and/or developmental delay (around half of the heterozygous female patients), partial or total ACC (around 73% of patients who underwent MRI), epilepsy (around 35%), and movement disorders (hypotonia/dystonia/ataxia, around 26%) (Mattiske et al, 2017). Behavioral disturbances and psychiatric features are also reported, such as autistic behavior, depression and anxiety.…”

Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females

“…As a consequence, heterozygous females typically have a milder disease phenotype or are not affected. Despite this, there is a growing list of X-chromosome genes which are subject to X-inactivation or escape X-inactivation, including, for example, PHF6, CLCN4, ALG13, ARX, or USP9X, DDX3X , which display distinct phenotypes in males and females depending on the functional severity of the variant, as well as manifesting in a more severe female phenotype than the heterozygous state would predict (4, 5, 6, 7, 8, 9, 10). We contend that the IQ motif and Sec7 domain 2 protein ( IQSEC2 ) (NM_001111125) (MIM 300522) is another X-chromosome disease gene in which we see a severe female phenotype because of heterozygous loss-of-function mutation.…”