Kozina et al. BMC Medical Genetics(2020) 21:209
https://doi.org/10.1186/s12881-020-01119-6

CASE REPORTOpen Access

Two novel PCDH19 mutations in Russianpatients with epilepsy with intellectual
disability limited to females: a case report
Anastasiya Aleksandrovna Kozina1,2, Elena Grigorievna Okuneva3, Natalia Vladimirovna Baryshnikova2,3,
Inessa Dmitrievna Fedonyuk4, Alexey Aleksandrovich Kholin2,4, Elena Stepanovna Il’ina4, Anna Yurievna Krasnenko3,
Ivan Fedorovich Stetsenko3, Nikolay Alekseevich Plotnikov3, Olesia Igorevna Klimchuk3,
Ekaterina Ivanovna Surkova3* and Valery Vladimirovich Ilinsky1,2,3,5Abstract
Background: Epilepsy with intellectual disability limited to females (Epileptic encephalopathy, early infantile, 9;
EIEE9) is a rare early infantile epileptic encephalopathy characterized by an unusual X-linked inheritance: femaleswith heterozygous mutations are affected, while hemizygous males are not.
Case presentation: We describe the clinical and molecular characteristics of 2 Russian patients with EIEE9 (females,
ages 3 years and 7 years). In these patients seizures developed at the age of 3 years. Additionally, for our patientsand for cases described in the literature we searched for a possible relationship between the type and localizationof the mutation and the EIEE9 clinical phenotype.
Conclusions: We identified two novel PCDH19 mutations in EIEE9 patients: a missense mutation in exon 1 (c.1236C >A, p.Asp412Glu) and a frameshift in exon 3 (c.2386_2387insGTCT, p.Thr796fs). We conclude that the age of seizure
onset and the presence of intellectual disability may depend not on the type and localization of PCDH19 mutations,but on the X-inactivation status. The study also highlights the need to screen for EIEE9 among young female epilepsy
patients.
Keywords: Epilepsy with intellectual disability limited to females, EIEE9, PCDH19, Protocadherin 19, Case report

Background
Epilepsy with intellectual disability limited to females(early infantile epileptic encephalopathy type 9, OMIM
300088, EIEE9) is a rare X-linked disease affecting heterozygous females and sparing hemizygous males. EIEE9
was first described by [1].
The main characteristic of EIEE9 is early infantile (6–36
months) onset of seizures of various types (tonic, clonic,
tonic-clonic, partial seizures) and severity [2]. Seizures
usually are provoked by fever and are resistant to anti* Correspondence: esurkova@genotek.ru
3
Genotek Ltd., Nastavnicheskii pereulok 17/1, 105120 Moscow, Russia
Full list of author information is available at the end of the article

epileptic drugs [3]. Additionally, patients often have cognitive impairment up to severe intellectual disability [4].
EIEE9 is caused by mutations in the PCDH19(protocadherin 19) gene [5]. This gene is located on the
X-chromosome, thus EIEE9 has an X-linked pattern ofinheritance. Disorders with the same type of inheritanceare typically characterized by affected males andunaffected carrier females. However, core clinical symptoms of EIEE9 manifest only in females, while carrier
males may have several neuropsychiatric features suchas obsessional tendencies [3]. Males with mosaic mutations can also be affected with a phenotype similar toaffected females [2, 6, 7]. Some authors explain this

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Kozina et al. BMC Medical Genetics(2020) 21:209

unique sex-limited expression pattern of EIEE9 by themechanism called “cellular interference” either due to Xchromosome inactivation in females or somatic mosaicism in males [8, 9]. However, experimental evidence forthe accuracy of this model remains insufficient.
The PCDH19 gene includes six exons and encodes the1148-amino-acid (AA) protein. PCDH19 protein belongs
to the protocadherin δ2 subgroup of the cadherin superfamily [10]. Protocadherins, including PCDH19, play arole in neuronal migration and formation of synaptic
connections in the brain [11, 12]. However, clear cellularfunctions, molecular mechanisms and signaling partners
have yet to be determined. Cooper and colleagues
showed that protocadherin-19 molecules from adjacentcells form adhesive connections between neurons. Someof the mutations that cause epilepsy occur in the region
responsible for what Cooper et al. characterize as a“forearm handshake” [13].
Dibbens et al. were first to identify mutations in the
PCDH19 gene in seven families with EIEE9 [5]. To date,more than 150 mutations in PCDH19 have been revealed. PCDH19 is currently considered the second mostclinically significant gene for epilepsy after SCN1A.
EIEE9-associated PCDH19 mutations can be missense or
have a truncating functional effect (nonsense, frameshift,splicing) [2]. Most of these mutations are de novo mutations in exon 1, which encodes the entire extracellulardomain of protocadherin 19. No mutations were foundin exon 2 and mutations are extremely rare in exons 3–
6 [2, 8, 14, 15].
Here, we describe clinical and genetic characteristics
of two Russian EIEE9patients. We identified two novel
PCDH19 mutations in these patients.

Case presentation
The study conforms to the Declaration of Helsinki. All
research was approved by the ethics committee of
Genotek Ltd. (05/2019). The patients’ parents provided
written informed consent to studies and publication ofclinical information and sequencing data.
Among all of the families there was no history of seizures or intellectual disability. All patients were diagnosed with EIEE9 when PCDH19 (NM_001184880.2)
mutations were found.
Patient 1 (3 years old, female, 23 kg, 103 cm)

The pregnancy and perinatal history were unremarkable.
The girl developed without abnormalities to the age of 3
years. At 3 years the girl developed generalized onset
motor tonic-clonic seizures with apnoea at night against
a background of fever. A month later the seizures wererepeated against the background of normal temperature.
Seizures during wakefulness first developed at 3 years

Page 2 of 7

and 2 months. Seizures persisted despite treatment withvalproic acid.
Intelligence was normal. Speech was restricted tophrases. Ophtalmologic examination revealed no pathology. Ultrasound examination revealed hepatosplenomegaly. A blood test showed elevated lactate level (2,6mmol/L, normal < 1,7 mmol/L).
Video electroencephalogram (VEEG) was performedfor 2.5 h in states of active and passive wakefulness,sleep, and during functional tests (Fig. 1). The basic
rhythm was represented by a regular, stable, modulatedalpha rhythm with a frequency of 7–8 Hz and an amplitude up to 70 μV. This rhythm was recorded in theoccipital regions with distribution to the posterior temporal and parietal regions of the hemispheres. Rhythmic
theta-activity with tendency to hypersynchronization
and regional delta-slow accentuation in the righttemporal region with polyphasic potentials, but with notypical epileptiform activity were revealed at wake state.
During rhythmic photostimulation, a rhythm following
reaction was not observed. Photoparoxysmal response
has not been recorded. A 3-min hyperventilation test revealed a moderate disorganization of cortical rhythm inthe form of diffuse slow-wave activity of the theta range
without a significant increase in amplitude. At the endof the test, there was rapid restoration of background.
Sleep was modulated in phases; physiological patterns of
sleep were differentiated. During sleep, regional epileptiform activity in the form of sharp-and-slow wave
discharges in the temporal regions was revealed. Kcomplexes in the form of high-amplitude flashes of slow
biphasic and polyphase waves with an amplitude of up
to 190 μV were periodically recorded.
The brain magnetic resonance imaging (MRI) revealeda region of gliosis in the left frontal lobe.
The patient received antiepileptic treatments (valproic
acid 600 mg/day, topiramate 25 mg/day, levetiracetam
1000 mg/day) without significant improvement.

Patient 2 (7 years old, female, 26 kg, 130 cm)

The pregnancy was complicated by a threat of preterm
birth at 16 weeks and chlamydia. Up to 3 years and 2
months, the girl developed according to her age withperiodic tension of the neck muscles which started at 7
months. At the age of 3 years and 2 months the first febrile seizure occurred in the form of tonic tension of theextremities at night (generalized onset motor tonicclonic seizures). Seizures persisted despite treatment
with valproic acid (500 mg/day). Clusters of seizures repeated every 5–10 days. Aggression and hysterical
reactions were observed after the seizures. However, intellectual abilities were age appropriate. Ophthalmologic
examination revealed no pathology.

Kozina et al. BMC Medical Genetics

Fig. 1 (See legend on next page.)(2020) 21:209

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Kozina et al. BMC Medical Genetics(2020) 21:209

Page 4 of 7

(See figure on previous page.)
Fig. 1 EEG for patient 1 during wakefulness and sleep. a. Waking EEG. Rhythmic theta-activity with tendency to hypersynchronization. Regional deltaslow accentuation in right temporal region with polyphasic potentials, but with no typical epileptiform activity at wake state. b. Sleep EEG. Regional
epileptiform activity – sharp-and-slow wave discharges in the left temporal region. Moderate fusiform brush-like beta-activity accentuations in frontocentro-temporal D > S regions. c. Sleep EEG. Regional epileptiform activity – sharp-and-slow wave discharges in the right temporal region. Preserved
sleep architectonics with the presence of physiological sleep patterns (K-complexes and “sleep spindles”)

The VEEG was performed for 2.5 h in states of active
and passive wakefulness, sleep, and functional tests(Fig. 2). The basic rhythm was represented by a regular,
stable, modulated alpha rhythm with a frequency of 8–9,
5 Hz. Rhythmic 5–6 Hz theta activity in the frontal regions and theta accentuation in the vertex region, butwith no typical epileptiform activity were revealed atwake state. Sleep was modulated in phases; physiologicalpatterns of sleep were differentiated (K-complexes,
vertex-potentials, sleep spindles). Moderate fusiform
brush-like beta-activity accentuations and atypical Kcomplexes with spike-like insertions were revealed in
frontal regions.
With antiepileptic (valproic acid 600 mg/day, levetiracetam 500 mg/day) and antipsychotic (aminophenylbutyric acid 250 mg/day) treatment at the time of analysis,
seizures were not observed.
Genetic studies

After obtaining informed consent for the genetic analyses, targeted exome enrichment and sequencing were
performed using patient and parental genomic DNA extracted from circulating leukocytes.
Exome sequencing

Exome sequencing of samples was carried out by Genotek
Ltd. Genomic DNA from peripherial blood samples was
extracted using QIAamp DNA Mini Kit (Qiagen, Hilden,
Germany) according to the manufacturerʼs protocol. DNA
libraries were prepared using the QIAseq FX DNA librarykit (Qiagen, Hilden, Germany). Target enrichment, sequencing and quality control were performed as described
previously [16]. To estimate pathogenicity, data were extracted from the dbNSFP, Clinvar, OMIM, and HGMD
databases. The variants were analyzed in silico using
Scale-Invariant Feature Transform (SIFT) and Polymorphism Phenotyping v2 (PolyPhen-2). Mutant allele frequencies were extracted from the 1000Genomes, ExAC, andGenotek databases. Pathogenicity was evaluated in accordance with international recommendations of ACMG
(American College of Medical Genetics and Genomics),
CAP (College of American Pathologists), and AMP (Association for Molecular Pathology).
Sanger sequencing

All variants found by exome sequencing were confirmed
by Sanger sequencing. Additionally, we used Sanger

sequencing to confirm the presence of PCDH19 mutations in the parents of probands. BigDye Terminator
Cycle Sequencing Kit v3.1 (Thermo Fisher Scientific)
was used to label amplicons with fluorescent labels.
Sanger sequencing was performed on ABI PRISM 3500
Genetic Analyzer (Applied Biosystems) in accordancewith the protocol of manufacturer.
All described variants are under consideration in the
ClinVar database.

Discussion and conclusions
We identified two novel heterozygous mutations in the
PCDH19 gene (NM_001184880.2) in two girls.
The c.2386_2387insGTCT mutation was not previously reported in literature and databases. This mutation
is an insertion of 4 nucleotides in exon 3 and is predicted to have caused a frameshift mutation at position
796 of the amino acid sequence. The mutation led to achange from Thr to Ser at position 796 and a translation
termination codon at position 19 of the new reading frame(p.Thr796SerfsTer19). Using the secondary structureof PCDH19, we revealed that this mutation is located in
the cytoplasmic domain and produces a truncated protein lacking the intracellular domain. According to the
ACMG criteria, this mutation can be classified as pathogenic (PVS1, PS2, PM2, PP3). The c.2386_2387insGTCT
mutation is absent in parents of the proband (de novo)(Fig. 3).
The c.1236C > A (p.Asp412Glu) mutation was not previously reported in literature and databases. This missense mutation results in a single amino acid change ina highly conserved extracellular protein domain. At themolecular level, this results in a negatively charged Glutamic acid instead of a negatively charged Aspartic acid.
This change does not potentially impair the electrostaticinteraction between the amino acid residues and does
not destabilize the β-chain structure. AA substitutions in
the cytoplasmic domain appear to have less or no deleterious effects on protein function. According to the
ACMG criteria, this mutation can be classified as likely
pathogenic (PM1, PM2, PP3, PP4). The mutation was
inherited from the paternal line. The girl’s father was
identified to be a hemizygote while the mother did notcarry this variant (Fig. 3). But the father of patient 2 ishealthy and had no seizures. There is no family historyof epilepsy on the father’s side.

Kozina et al. BMC Medical Genetics(2020) 21:209

Page 5 of 7

Fig. 2 EEG of patient 2 during wakefulness and sleep. a. Waking EEG. Physiological 8–9,5 Hz alpha rhythm in the posterior regions. Rhythmic 5–6
Hz theta activity in frontal regions and theta accentuation in the vertex region. b. Sleep EEG. Moderate fusiform brush-like beta-activity
accentuations in frontal (predominantly left frontopolar-inferior frontal regions). No epileptiform activity was identified. c. Sleep EEG. Atypical Kcomplexes with spike-like insertions in frontal regions. No typical epileptiform spike-wave discharges were identified

Kozina et al. BMC Medical Genetics(2020) 21:209

Page 6 of 7

Fig. 3 Pedigrees of Russian families with EIEE9. a: proband - patient 1 with heterozygous de novo PCDH19 mutation c.2386_2387insGTCT(p.Thr796fs). b: proband – patient 2 with heterozygous PCDH19 mutation c.1236C > A (p.Asp412Glu). The proband has inherited this mutationfrom the father. Black circle: affected mutation-carrying female; white circle: female without mutation; white square: male without mutation; dot
within a white square: asymptomatic mutation-carrying male

The PCDH19 mutations cause EIEE9, however, thedisease-causing mechanisms are not fully understood. It
has been hypothesized that the mosaicism of normal
PCDH19 and mutant-expressing cells results in “scrambling” of the neuronal brain circuitry in affected people(cellular interference).
The phenotype of EIEE9 can be different – girls withthe disorder have symptoms ranging from benign focal
epilepsy with normal cognitive abilities to severe seizures
and intellectual disability similar to Dravet syndrome.
PCDH19 is highly conserved across human, mouse,zebrafish, and chicken and has weak homophilic cell adhesion characteristics. It has been shown that PCDH19
interacts with N-cadherin and members of the WAVE
complex (Nap1 and Cyfip2) suggesting that each has arole in controlling cell movements during embryogenesis[17, 18]. The majority of the PCDH19 mutations wereobserved in a highly conserved extracellular protein domain (AA 1–678) that is essential for the normal function of cadherin [13]. These mutations are mostly

missense. Truncating mutations have been found in all
domains of the PCDH19 protein [15].
We identified two novel PCDH19 mutations in EIEE9
patients. We compared the clinical and genetic characteristics of these patients with those described previously(with different age of seizures and level of intellectual
disability) (Table 1) [19–23]. We expected to detect early
onset of seizures and intellectual disability only in patients with mutations in exon 1, as it is important for
the interaction of protocadherin with other molecules.
However, an analysis of the data did not confirm this.
We found that the severity of EIEE9 do not correlatewith the localization and type of the PCDH19 mutation.
The different level of intellectual disability in the described EIEE9 patients can be explained by the random
nature of X inactivation in the different parts of thebrain.
We also confirmed the suggestion of Kolc and colleagues that age at seizure onset determines the prognosis of the disease. An early onset of seizures (≤12

Table 1 Comparison of PCDH19 mutations identified in this study (bold) and previously described PCDH19 mutations in femaleswith EIEE9
Mutation

Exon

Type

Onset of seizures, months

Intelligence

Sourcec.445C > T p.Pro149Ser

1

Missense

17

normal[19]c.695A > G (p.Asn232Ser)

1

Missense

4

intellectual disability[20]c.918C > G, p.Tyr306*

1

Nonsense

20

normal[21]c.937G > A p.Glu307Lys

1

Missense

70

normal[19]c.919G > A p.Glu313Lys

1

Missense

32

normal[19]c.1183C > T (p.Arg395*)

1

Nonsense

8

intellectual disability[22]c.1236C > A (p.Asp412Glu)

1

Missense

38

normalThis study (Patient 2)c.1681C > T, p.Pro561Ser

1

Missense

14

normal[21]c.1765_1766delTG p.Val589CysfsX8

1

Frameshift

9

intellectual disability[19]c.2386_2387insGTCT (p.Thr796fs)

3

Frameshift

36

normalThis study (Patient 1)

c2468delT, p.L823fs

3

Frameshift

18

intellectual disability[23]

Kozina et al. BMC Medical Genetics(2020) 21:209

months) leads to more severe intellectual disability ascompared to onset at> 12 months [2].
Genetic testing could provide direct evidence of mutations associated with EIEE9. This analysis is a rapid andpractical tool to confirm the diagnosis of EIEE9. Genetic
testing should be considered for young female patientswith infantile onset seizures and developmental delay.
Abbreviations
ACMG: American College of Medical Genetics and Genomics;
AMP: Association for Molecular Pathology; CAP: College of American
Pathologists; EIEE9: Epileptic encephalopathy, early infantile, 9Acknowledgements
AAK and VVI acknowledge the Leading Scientific School of Prof. Andrey
Lisitsa (grant of the President of the Russian Federation NSH-6313.2018.4).
We gratefully express our appreciation for the important suggestions by T.
Gurbich in her review of an earlier version of this manuscript.
Authors’ contributions
AAK1, EGO, NVB, IDF, AAK2, ESI, AYK3, IFS, NAP, OIK, EIS, VVI met theInternational Committee of Medical Journal Editors (ICMJE) criteria for
authorship. AAK1, EGO, NVB, IDF, AAK2, ESI, and EIS contributed to datacollection and the first draft of the manuscript. AYK3, IFS, NAP and OIK
carried out the mutation analysis. AAK1, EGO, NVB, IDF, AAK2, and ESI cared
for the patients. VVI was a mentor who contributed to design of the work
and interpretation of data. All authors read and approved the final
manuscript.
Funding
The work was done within the framework of the State Academies of
Sciences Fundamental Scientific Research Program for 2013–2020. The fundplayed no direct role in the design of the study, the collection, analysis, orinterpretation of data, or the writing of the manuscript.

Page 7 of 7

2.

3.
4.

5.

6.
7.
8.
9.

10.
11.

12.
13.

14.

15.

16.
Availability of data and materials
The datasets generated and analyzed during the current study are available
in the Genotek repository, gf1232.1680CC36C.1.fastq.gzgf1232.1680CC36C.2.fa
stq.gztw8628.594DA854D.1.fastq.gztw8628.594DA854D.2.fastq.gzGRCh37.p13
genome assembly (https://www.ncbi.nlm.nih.gov/assembly/GCF_000001405.25/).

17.

18.
Ethics approval and consent to participate
All studies were approved by the Genotek’s Ethics Committee (05/2019). The
patients ‘parents have given written informed consent to these studies.
Consent for publication
The patients’ parents have given written informed consent to publication ofclinical information and sequencing data.
Competing interests
EGO, NVB, AYK, IFS, NAP, OIK, EIS, VVI are employees of Genotek Ltd. The
authors declare that they have no other competing interests.
Author details
1
Institute of Biomedical Chemistry, Pogodinskaya street 10/8, 119121
Moscow, Russia. 2Pirogov Russian National Research Medical University,
Ostrovitianova street 1, 117997 Moscow, Russia. 3Genotek Ltd.,
Nastavnicheskii pereulok 17/1, 105120 Moscow, Russia. 4Russian Children’sClinical Hospital of Pirogov Russian National Research Medical University,
Leniskiy prospekt 117, 117513 Moscow, Russia. 5Vavilov Institute of General
Genetics, Gubkina street 3, 119333 Moscow, Russia.
Received: 28 January 2020 Accepted: 3 September 2020

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