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

• Published in: Molecular genetics & genomic medicine Vol. 10; no. 9; pp. e2012 - n/a
• Main Authors: Vinci, Mirella, Kursula, Petri, Greco, Donatella, Elia, Maurizio, Vetri, Luigi, Schepis, Carmelo, Chiavetta, Valeria, Donadio, Serena, Roccella, Michele, Carotenuto, Marco, Romano, Valentino, Calì, Francesco
• Format: Journal Article
• Language: English
• Published: Bognor Regis John Wiley & Sons, Inc 01.09.2022; John Wiley and Sons Inc; Wiley
• Subjects: Age; AHNAK2; Amino acids; Atopic dermatitis; borderline intellectual functioning; Calcium signalling; Cardiovascular diseases; Clinical Report; Clinical Reports; Complementation; Convulsions & seizures; Coronary artery disease; Dermatitis; Epilepsy; facio‐cardio‐cutaneous‐like phenotype; Gene expression; Genes; Genomics; Heart diseases; Heredity; Heterozygotes; Hypotonia; Missense mutation; Molecular interactions; Muscles; Mutation; Neurodevelopmental disorders; Neuropil; NGS exome; Pathogenesis; Patients; Phenotypes; Protein structure; Proteins; Smooth muscle; Structure-function relationships
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.2012

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 cardio‐facio‐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. The AHNAK2 gene encodes a large nucleoprotein expressed in several tissues, including brain, squamous epithelia, smooth muscle and neuropil. Here, we report a female patient diagnosed with a cardio‐facio‐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 mis‐sense mutations in the AHNAK2 gene detected by exome sequencing.