# Recurrent c.‐11C>T change located upstream of the normal ATG initiation codon of ANKH causes self‐limited familial infantile epilepsy

## TL;DR

A specific genetic change in the ANKH gene is linked to a rare form of infantile epilepsy that resolves by age 4 and runs in families.

## Contribution

This study reports the second family with autosomal dominant infantile epilepsy caused by the ANKH c.-11C>T variant and highlights its association with SeLFIE.

## Key findings

- ANKH c.-11C>T variant causes autosomal dominant infantile epilepsy with early onset and spontaneous resolution.
- The epilepsy phenotype is consistent with SeLFIE and shows low phenotypic heterogeneity across families.
- ANKH-associated epilepsy should be considered in infants with familial chondrocalcinosis or joint pain history.

## Abstract

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.

Phenotyping and genotyping (short‐read exome/genome sequencing) was performed on six members of a family with self‐limited familial infantile epilepsy (SeLFIE).

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.

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.