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.

Background: Corpus callosum agenesis (ACC) is one of the most frequent Central Nervous System (CNS) malformations. However, genetics underlying isolated forms is still poorly recognized. Here, we report on two female familial cases with partial ACC. The proband shows isolated partial ACC and a mild neurodevelopmental phenotype. A fetus from a previous interrupted pregnancy exhibited a complex phenotype including partial ACC and the occurrence of a de novo 17q12 microduplication, which was interpreted as probably disease-causing.

Methods: A trio-based clinical exome sequencing (CES) was performed.

Results: Clinical exome sequencing data analysis led to identifying a heterozygous nonsense variant (NM_139058.3:c.922G>T; NP_620689.1:p.Glu308Ter) in the aristaless related homeobox gene (ARX) in the proband, with a putative de novo occurrence, producing a hypothetical protein lacking two essential domains. Sanger analysis confirmed the wild-type status of both parents in different tissues, and disclosed the occurrence of the nonsense variant in the fetus of the interrupted pregnancy, suggesting a formerly unrecognized contribution of the ARX mutation to the fetus' phenotype and gonadal or gonadosomatic mosaicism in one of the parents.

Conclusion: This study describes the phenotype associated with a heterozygous loss of function variant in ARX. Moreover, it highlights the importance of investigating both chromosomal and genetic contributions in cases of complex syndromic phenotypes involving CNS.