The YWHAG gene (OMIM∗ 605,356) resides on Chr 7q11.23 and encodes the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (14–3–3γ), which is highly expressed in the brain. This protein regulates neuronal migration and its abnormal activity may cause morphological defects in the developing cortex. The scientific interest in the YWHAG gene firstly started in 1999, when the clinical influence was presumed due to the YWHAG location at the most telomeric end of the deletion region founded in Williams–Beuren syndrome (WBS) [
]. Later, in 2010, a study in YWHAG knockdown zebrafish confirmed the link between gene mutation, brain size and epileptic seizures [
- Horie M.
- Suzuki M.
- Takahashi E.
- Tanigami A.
Cloning, expression, and chromosomal mapping of the human 14-3-3 gamma gene (YWHAG) to 7q11.
23 Genomics. 1999; 60 (Sep 1): 241-243https://doi.org/10.1006/geno.1999.5887
- Komoike Y.
- Fujii K.
- Nishimura A.
- Hiraki Y.
- Hayashidani M.
- Shimojima K.
- et al.
Zebrafish gene knockdowns imply roles for human YWHAG in infantile spasms and cardiomegaly.
Genesis. 2010; 4: 233-243
In recent years, only 14 subjects were described carrying de novo variants in YWHAG gene and epilepsy, basically recognized as developmental and epileptic encephalopathy (DEE) (Table 1).
Table 1Phenotypic features of our case compared to patients from the literature.
|This report||Stern T et al. Am J Med Genet A 2021||Ye XG et al. Frontiers in Genetics 2021||Kim SY et al. Clinical Genetics 2021||Kanani F et al. Am J Med Genet A 2020||Guella I et al. American Journal of Human Genetics 2017|
|N° of pts||1||1||2||1||6||4|
|Age at last FU (y)||5||5||3||na||3||15||16||7||4||10||7.5||23||18||16||10|
|Sz onset (mo)||24||9||7||na||19||10||192||24||24||<60||na||<6||12||<72||6|
|Sz types||Myoclonic sz||Absences, myoclonic sz, focal-onset sz||Febrile sz, myoclonic sz||Febrile and afebrile GTC sz (DS)||Febrile sz, myoclonic sz||Absences, focal-onset and GTC sz||Isolated GTC sz||Absences||GTC sz||Frontal lobe sz||Absences||Absences, GTC and generalized myoclonic sz||Atypical absences, myoclonic and GTC sz||Absences, myoclonicsz, eyelid myoclonia||Focal-onset motor sz (febrile)|
|EEG findings||Generalized spike waves time-locked with myoclnic event||Generalized spike waves with bilateral frontal predominance||Generalized irregular polyspike-and-slow waves||na||Generalized spike-and-slow waves||na||na||Prolonged burst of generalized 2.5 Hz spike and wave activity||na||na||Normal||Generalized polyspike wave and slow wave discharges||Dysrhytmic background,sharp waves in bianterior quadrants||Bilateral fronto-temporal spike-waves||na|
|ASMs tested||VPA||VPA, LEV||VPA||na||VPA||LEV, ESM||None||VPA, LTG, ESM||VPA||VPA, CBZ||None||VPA, STP||CLZ, LTG, VPA, ESM||VPA, LTG||VPA|
|Speech/Language||Normal||Normal||Normal||na||Normal||Normal||Normal||Delayed, echolalial||Mildly delayed||Mildly delayed||Delayed||Delayed||Delayed||na||na|
|Developmental delay||Mild Global||No||No||Global||No||Moderate global||Global||Global||Mild global||Global||Mild global||Moderate-severe||Mild-moderate||Mild||Global|
|ASD||No||No||No||na||No||Yes||Yes||Yes||No||No||No||Yes||No, but ADHD||na||na|
|Dysmorphisms||Prominent forehead and spaced teeth||No||No||na||No||Down slating palpebral fissures, upturned nose, absent Cupid's bow, small ears, prominent forehead||Ptosis, down slating palpebral fissures, downturned corners of mouth||Upturned nose with thickened alae nasi, wide mouth||No||Upslanting palpebral fissures, short columella, broad mouth||Bulbous nose, thin upper lip, hypertelorism, prominenet forehead||Hypertelorism, down slating palpebral fissures, small ears||na||na||na|
|Brain MRI findings||Normal||Nonspecific white matter hyperintensities||Normal||na||Normal||Normal||Normal||Normal||Focus of hyperintensity frontal lobe||Subtle signal changes in frontal subcortical with matter||Normal||Normal||Normal||Normal||Generalized atrophy with loss of white matter|
|YWHAG variant||c.304del; p.Ser102Alafs*7||c.619G>A; p.Glu207Lys||c.124C>T; p.Arg42Ter||c.394C>T; p.Arg132Cys||c.373A>G; p.Lys125Glu||c.169C>G; p.Arg57Gly||c.398A>C; p.Tyr133Ser||c.532A>G; p.Asn178Asp||c.394C>T; p.Arg132Cys||c.169C>T; p.Arg57Cys||c.529C>A; p.Leu177Ile||c.394C>T; p.Arg132Cys||c.394C>T; pArg132Cys||c.394C>T; p.Arg132Cys||c.44A>C; p.Glu15Ala|
|Inheritance||De novo||De novo||Inherited (5 affected family members)||Inherited (mother with mosaicism)||De novo||De novo||De novo||De novo||De novo||De novo||De novo||De novo||De novo||De novo||De novo|
Legend: ASMs= anti-seizure medications; CBZ= Carbamazepine; CLZ= Clonazepam; DS= Dravet Syndrome; ESM= Ethosuximide; F= female; FU= follow-up; GTC= generalized tonic-clonic; LEV= Levetiracetam; LTG= Lamotrigine; M= male; mo= months; N°= number; na= not assessed; pts= patients; STP= Stiripentol; sz= seizures; VPA= valproic acid; y= years.
* the clinical features of this patient were updated in Kanani F. et al., 2020.
We would like to share our experience with the description of a previously unreported YWHAG mutation in a patient with a mild phenotype.
2. Case report
We report on a 5-year-old female, born from healthy unrelated parents. Developmental milestones were normally achieved until 2 years of age when the onset of myoclonic seizures with normal interictal background EEG and no auditory-tactile stimuli reflex was documented. Epileptic myoclonias were seen during wakefulness, but also during drowsiness and in the lighter stages (N1 and N2) of the N-REM sleep state (Fig. 1). Myoclonic events were more evident in the eyelids, neck and forearms. Spontaneous generalized discharges were not always accompanied by clinical manifestations. EEG-video with polygraphic recording confirmed generalized epileptic spikes time-locked with sudden, brief, synchronous upper limbs jerks and deltoids EMG dischareges (Fig 1). Biochemical investigations were scarcely contributory. Conventional Magnetic Resonance Imaging (MRI) 1.5 Tesla was normal.
Seizures transiently ceased within two months with valproic acid monotherapy. After one year of follow-up, the girl experienced polymorphic focal-onset seizures with impaired awareness interspersed between long seizure-free periods (range, 3–6 months); during these latter periods, hyperactivity was noticed.
Motor developmental milestones were achieved in the upper limit of a normal age range (sitting position at 8 months, able to walk alone at 18 months) despite normal skills in language development.
On the other hand, the Griffith Mental Development Scales III documented a global developmental delay (general age-equivalent scores of 38 months instead of the 57 months chronological age) and showed widespread weaknesses in all developmental areas, even if motor skills were less compromised than language and communication (age-equivalent scores: Locomotor 42 months, Personal-Social 40 months, Hearing and Language 35 months, Eye and Hand Coordination Performance 38 months, Practical Reasoning 39 months).
Initial genetic investigations comprising next-generation sequencing (NGS) epilepsy panel and Array-CGH were inconclusive.
The exome sequencing (ES), using NGS (NextSeq 550 Illumina), identified a de novo mutation c.304del on exon 2. This frameshift mutation leads to an early protein synthesis termination (p.Ser102Alafs*7). Genetic data analysis was performed with Sentieon and VarSeq (V2.1.0) software. In silico variant prediction tools such as SIFT, PolyPhen, MutationTaster were used to assist with variant classification. Finally, pathogenicithy of the variant was confirmed with bidirectional Sanger sequencing and it was classified as pathogenic according to the American College of Medical Genetics (ACMG) criteria [
- Richards S.
- Aziz N.
- Bale S.
- Bick D.
- Das S.
- Gastier-Foster J.
- Grody W.W.
- Hegde M.
- Lyon E.
- Spector E.
- Voelkerding K.
- Rehm H.L.
ACMG laboratory quality assurance committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology.
Genet Med. 2015; 17 (Epub 2015 Mar 5. PMID: 25741868; PMCID: PMC4544753): 405-424https://doi.org/10.1038/gim.2015.30
Since 2017, eleven de novo YWHAG mutations have been reported and they are mainly associated with a severe phenotype of DEE [
]. Only in two papers was recognized a milder phenotype with myoclonic epilepsy in three unrelated families (Table 1).
- Guella I.
- McKenzie M.B.
- Evans D.M.
- Buerki S.E.
- Toyota E.B.
- Van Allen M.I.
- et al.
De Novo mutations in YWHAG cause early-onset epilepsy.
Am J Hum Genet. 2017; 101: 300-310https://doi.org/10.1016/j.ajhg.2017.07.004
Our case supports the hypothesis of an epilepsy spectrum ranging from mild myoclonic epilepsy or febrile seizures up to severe DEE. Moreover, as depicted, myoclonic seizures could initially lead to a challenging diagnosis, misleading towards self-limited infantile seizures, although our case documented specific polymorphic seizures without auditory-tactile reflex and flares despite anti-seizure medication therapy [
- Zuberi S.M.
- O'Regan M.E.
Developmental outcome in benign myoclonic epilepsy in infancy and reflex myoclonic epilepsy in infancy: a literature review and six new cases.
Epilepsy Res. 2006; 70 (Epub 2006 Aug 10. PMID: 16904290): S110-S115https://doi.org/10.1016/j.eplepsyres.2006.01.014
Thirteen previously reported affected individuals had neurodevelopmental disorders including developmental delay, intellectual disability, or autism spectrum disorder (Table 1).
Only one subject was reported at the beginning with a mild motor delay with a gap of two months in normal development but without longterm follow-up [
]. We therfore hypotize a hierarchical continuum of learning disability rather than distinct entities being the most frequent pattern represented by a specific cognitive profile with motor skills less compromised than language and communication. Our case confirms the hypothesis of a mild phenotype with mioclonic epilepsy and neurodevelopmental delay even in the case of epilepsy-related to YWHAG mutation.
- Stern T.
- Orenstein N.
- Fellner A.
- Lev-El Halabi N.
- Shuldiner A.R.
- Gonzaga-Jauregui C.
- Lidzbarsky G.
- Basel-Salmon L.
- Goldberg-Stern H
Epilepsy and electroencephalogram evolution in YWHAG gene mutation: a new phenotype and review of the literature.
Am J Med Genet A. 2021; 185: 901-908https://doi.org/10.1002/ajmg.a.62026
Case Report written following the CARE guidelines
Declaration of Competing Interest
All authors disclose any financial and personal relationships with other people or organizations that could inappropriately influence the work. The work described has not been published previously and it is not under consideration elsewhere. None of the authors has any conflict of interest to disclose.
Appendix A. Supplementary materials
- Supplementary Data S1
Supplementary Raw Research Data. This is open data under the CC BY license http://creativecommons.org/licenses/by/4.0/
- Cloning, expression, and chromosomal mapping of the human 14-3-3 gamma gene (YWHAG) to 7q11.23 Genomics. 1999; 60 (Sep 1): 241-243https://doi.org/10.1006/geno.1999.5887
- Zebrafish gene knockdowns imply roles for human YWHAG in infantile spasms and cardiomegaly.Genesis. 2010; 4: 233-243
- ACMG laboratory quality assurance committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology.Genet Med. 2015; 17 (Epub 2015 Mar 5. PMID: 25741868; PMCID: PMC4544753): 405-424https://doi.org/10.1038/gim.2015.30
- De Novo mutations in YWHAG cause early-onset epilepsy.Am J Hum Genet. 2017; 101: 300-310https://doi.org/10.1016/j.ajhg.2017.07.004
- Developmental outcome in benign myoclonic epilepsy in infancy and reflex myoclonic epilepsy in infancy: a literature review and six new cases.Epilepsy Res. 2006; 70 (Epub 2006 Aug 10. PMID: 16904290): S110-S115https://doi.org/10.1016/j.eplepsyres.2006.01.014
- Epilepsy and electroencephalogram evolution in YWHAG gene mutation: a new phenotype and review of the literature.Am J Med Genet A. 2021; 185: 901-908https://doi.org/10.1002/ajmg.a.62026
Published online: December 08, 2021
Accepted: December 7, 2021
Received in revised form: December 3, 2021
Received: October 29, 2021
© 2021 British Epilepsy Association. Published by Elsevier Ltd.
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