Expanding the genotype–phenotype correlation ofde novoheterozygous missense variants inYWHAGas a cause of developmental and epileptic encephalopathy

Abstract

Developmental and Epileptic encephalopathies (DEE) describe heterogeneous epilepsy syndromes, characterized by early‐onset, refractory seizures and developmental delay (DD). Several DEE associated genes have been reported. With increased access to whole exome sequencing (WES), new candidate genes are being identified although there are fewer large cohort papers describing the clinical phenotype in such patients. We describe 6 unreported individuals and provide updated information on an additional previously reported individual with heterozygous de novo missense variants in YWHAG. We describe a syndromal phenotype, report 5 novel, and a recurrent p.Arg132Cys YWHAG variant and compare developmental trajectory and treatment strategies in this cohort. We provide further evidence of causality in YWHAG variants. WES was performed in five patients via Deciphering Developmental Disorders Study and the remaining two were identified via Genematcher and AnnEX databases. De novo variants identified from exome data were validated using Sanger sequencing. Seven out of seven patients in the cohort have de novo, heterozygous missense variants in YWHAG including 2/7 patients with a recurrent c.394C > T, p.Arg132Cys variant; 1/7 has a second, pathogenic variant in STAG1. Characteristic features included: early‐onset seizures, predominantly generalized tonic–clonic and absence type (7/7) with good response to standard anti‐epileptic medications; moderate DD; Intellectual Disability (ID) (5/7) and Autism Spectrum Disorder (3/7). De novo YWHAG missense variants cause EE, characterized by early‐onset epilepsy, ID and DD, supporting the hypothesis that YWHAG loss‐of‐function causes a neurological phenotype. Although the exact mechanism of disease resulting from alterations in YWHAG is not fully known, it is possible that haploinsufficiency of YWHAG in developing cerebral cortex may lead to abnormal neuronal migration resulting in DEE.

Epilepsy and electroencephalogram evolution in YWHAG gene mutation: A new phenotype and review of the literature

“…EEG became normal. Furthermore, this case expands the phenotypic spectrum associated with the YWHAG gene that was recently described in this journal (Kanani et al, 2020) in seven patients with YWHAG mutation. In this series, average age of seizure onset was 2 years (ranging from 4 months to 16 years), seizure type was predominantly generalized tonic clonic, and in most of these cases, multiple antiepileptic drugs were required to control their seizures.…”

“…YWHAG is one such new gene that has been implicated in developmental and epileptic encephalopathies (Aghazadeh & Papadopoulos, 2016). It is located on chromosome 7q11.23 and encodes a member of the 14‐3‐3 protein family, which is involved in intracellular signaling pathways and plays an important role in signal transduction (Kanani et al, 2020).…”

“…After a comprehensive work‐up, a likely pathogenic variant was found in the YWHAG gene. To date, in the literature, missense mutation was reported in 4 patients by Guella et al (2017), in 12 patients in a study by Balasubramanian et al (2019), and an additional 7 cases were described in detail in this journal recently (Kanani et al, 2020).…”

A Novel Heterozygous Missense Variant in YWHAG Gene Cause Early-Onset Epilepsy in a Chinese Family

“…Usually seizure control can be achieved by sodium valproate and levetiracetam, and ethosuximide, stiripentol. One patient was found to be no response to lamotrigine 8 . The proband in our study achieve seizure control after 4 months of treatment with sodium valproate.…”

“…Until now, there have been ten variants in fteen patients were found to be affected by YWHAG de ciency (including our patients) 3,8−11 . Twelve of the patients were described with detailed clinical manifestation (Table.1 (Table.1) 3,8 . Both of our patients experienced multiple GTCSs, and the family did not report other types of seizure.…”