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Case Reports
. 2020 Apr;182(4):713-720.
doi: 10.1002/ajmg.a.61483. Epub 2020 Jan 11.

Expanding the genotype-phenotype correlation of de novo heterozygous missense variants in YWHAG as a cause of developmental and epileptic encephalopathy

Farah Kanani  1 , Hannah Titheradge  2 , Nicola Cooper  2 , Frances Elmslie  3 , Melissa M Lees  4 , Jane Juusola  5 , Laura Pisani  6 , Carolyn McKenna  6 , Cyril Mignot  7 , Stephanie Valence  8 , Boris Keren  9 , Katherine Lachlan  10 ; DDD Study  11 ; Meena Balasubramanian  1   12
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Case Reports

Expanding the genotype-phenotype correlation of de novo heterozygous missense variants in YWHAG as a cause of developmental and epileptic encephalopathy

Farah Kanani et al. Am J Med Genet A. 2020 Apr.

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.

Keywords: YWHAG; developmental delay; early-onset seizures; epileptic encephalopathy; intellectual disability.

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