Recurrent C.‐11c>t Change Located Upstream of the Normal ATG Initiation Codon of ANKH Causes Self‐limited Familial Infantile Epilepsy

OBJECTIVE:Pathogenic ANKH variants are a known cause of chondrocalcinosis (Online Mendelian Inheritance in Man [OMIM] #118600) and craniometaphyseal dysplasia (OMIM #123000). Here, we describe the phenotype and genotype of autosomal dominant infantile epilepsy caused by a c.-11C>T change upstream of the gene's normal ATG initiation codon of ANKH in a family of southern Italian descent; we correlate the phenotype with known epilepsy syndromes and provide the first evidence of recurrence of this particular ANKH variant. METHODS:Phenotyping and genotyping (short-read exome/genome sequencing) was performed on six members of a family with self-limited familial infantile epilepsy (SeLFIE). RESULTS:We describe a family with six individuals who presented with infantile onset epilepsy. All affected family members experienced focal and/or bilateral tonic-clonic seizures, sometimes triggered by fever or infection, with seizure onset predominantly before the age of 2 years. Patients responded well to antiseizure medication, and seizures resolved completely before the age of 4 years. Short-read genome/exome sequencing and comparative bioinformatic analysis of the variants of five affected individuals and one unaffected individual revealed ANKH c.-11C>T as the causative pathogenic variant in this family, segregating with the disease. SIGNIFICANCE:To our knowledge, we report the second family with autosomal dominant epilepsy caused by an ANKH c.-11C>T variant. The pediatric phenotype closely resembles that of the previously reported British family, suggesting low phenotypic heterogeneity, and aligns with SeLFIE. ANKH-associated epilepsy should be considered in SeLFIE, especially in cases with a family history of chondrocalcinosis or recurrent acute joint pain episodes.