Exome sequencing in a child with neurodevelopmental disorder and epilepsy: Variant analysis of the AHNAK2 gene

Abstract

Background:The AHNAK2 gene encodes a large nucleoprotein expressed in several tissues, including brain, squamous epithelia, smooth muscle, and neuropil. Its role in calcium signaling has been suggested and to date, clear evidence about its involvement in the pathogenesis of clinical disorders is still lacking.Methods: Here, we report a female 24-year-old patient diagnosed with a cardiofacio-cutaneous-like phenotype (CFC-like), characterized by epilepsy, psychomotor development delay, atopic dermatitis, congenital heart disease, hypotonia, and facial dysmorphism, who is compound heterozygote for two missense mutations in the AHNAK2 gene detected by exome sequencing. Results:This patient had no detectable variant in any of the genes known to be associated with the cardio-facio-cutaneous syndrome. Moreover, the mode of inheritance does not appear to be autosomal dominant, as it is in typical CFC syndrome. We have performed in silico assessment of mutation severity separately for each missense mutation, but this analysis excludes a severe effect on protein function. Protein structure predictions indicate the mutations are located in flexible regions possibly involved in molecular interactions. Conclusion:We discuss an alternative interpretation on the potential involvement of the two missense mutations in the AHNAK2 gene on the expression of CFC-like phenotype in this patient based on inter-allelic complementation.

A de novo ARIH2 gene mutation was detected in a patient with autism spectrum disorders and intellectual disability

“…Within this context, it is essential to acknowledge that while Whole Exome Sequencing (WES) is a powerful tool for identifying coding mutations, it may not capture genetic variations in non-coding regions or complex polygenic interactions 1 , 57 . These undetected mutations, including those in non-coding regions and polygenic risks arising from inter-allelic complementation, could potentially play significant roles in shaping the patient's phenotype 58 . A limitation of our WES analysis is the filtering out of polymorphisms with Minor Allele Frequencies (MAF) higher than 1%, which may contribute to polygenic risk.…”