Chromosome 14 deletions, rings, and epilepsy genes: A riddle wrapped in a mystery inside an enigma

Abstract

The ring 14 syndrome is a rare condition caused by the rearrangement of one chromosome 14 into a ring‐like structure. The formation of the ring requires two breakpoints and loss of material from the short and long arms of the chromosome. Like many other chromosome syndromes, it is characterized by multiple congenital anomalies and developmental delays. Typical of the condition are retinal anomalies and drug‐resistant epilepsy. These latter manifestations are not found in individuals who are carriers of comparable 14q deletions without formation of a ring (linear deletions). To find an explanation for this apparent discrepancy and gain insight into the mechanisms leading to seizures, we reviewed and compared literature cases of both ring and linear deletion syndrome with respect to both their clinical manifestations and the role and function of potentially epileptogenic genes. Knowledge of the epilepsy‐related genes in chromosome 14 is an important premise for the search of new and effective drugs to combat seizures. Current clinical and molecular evidence is not sufficient to explain the known discrepancies between ring and linear deletions.

Live‐born autosomal ring chromosomes at the Johns Hopkins Hospital Cytogenomics Laboratory: Case series—Spanning 52 years of experience in a single center

“…To date, copy number gain as a mechanism has not been associated with disease, nor are these genes predicted to be dosage sensitive. However, dysregulation of PACS2 , a gene associated with autosomal dominant Developmental and Epileptic Encephalopathy 66 (MIM: 618067), might occur via position effect due to an altered chromosomal topology of the RC (Vaisfeld et al, 2021).…”

“…The patient exhibited severe cognitive impairment and epilepsy, among other features, and was prescribed medication to control their seizures. Reports of cases with pure terminal deletions identified by array are noted in the literature (Vaisfeld et al, 2021); however, their features differ significantly from those seen in association with RC14 (Vaisfeld et al, 2021). A research SNP array (Illumina 850k v1.2) performed on cultured skin fibroblasts shows a 1.7 Mb adjacent duplication and a 577 kb deletion at the terminal end of chromosome 14q32.33.…”

“…A research SNP array (Illumina 850k v1.2) performed on cultured skin fibroblasts shows a 1.7 Mb adjacent duplication and a 577 kb deletion at the terminal end of chromosome 14q32.33. Epilepsy‐candidate genes, including AKT1 and PACS2 , may be implicated in cases with linear deletions (Vaisfeld et al, 2021); both epilepsy‐candidate genes are wholly contained in this individual's gain. To date, copy number gain as a mechanism has not been associated with disease, nor are these genes predicted to be dosage sensitive.…”

“…It should be noted that the wide range of phenotypes (growth restriction and variable intellectual disability) associated with RCs could be explained by additional factors consistent with a complex disease beyond gene dosage imbalance. Notably, the genetic and genomic factor(s) affecting RC instability and intolerance are incompletely understood (Guilherme et al, 2011; Li et al, 2022; López‐Uriarte et al, 2013; Vaisfeld et al, 2021).…”