Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort
Journal of Human Genetics
Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort
Qi Zeng 0 2
? Xiaoling Yang 0 2
? Jing Zhang 0 2
? Aijie Liu 0 2
? Zhixian Yang 0 2
? Xiaoyan Liu 0 2
? Ye Wu 0 2
? Xiru Wu 0 2
? Liping Wei 0 2
? Yuehua Zhang 0 2
0 Department of Pediatrics, Peking University First Hospital , Beijing , China
1 Yuehua Zhang
2 Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University , Beijing , China
Benign familial epilepsies that present themselves in the first year of life include benign familial neonatal epilepsy (BFNE), benign familial neonatal-infantile epilepsy (BFNIE) and benign familial infantile epilepsy (BFIE). We used Sanger sequencing and targeted next-generation sequencing to detect gene mutations in a Chinese cohort of patients with these three disorders. A total of 79 families were collected, including 4 BFNE, 7 BFNIE, and 68 BFIE. Genetic testing led to the identification of gene mutations in 60 families (60 out of 79, 75.9%). A total of 42 families had PRRT2 mutations, 9 had KCNQ2 mutations, 8 had SCN2A mutations, and 1 had a GABRA6 mutation. In total three of four BFNE families were detected with KCNQ2 mutations. Mutations were detected in all BFNIE families, including 3 KCNQ2 mutations, 3 SCN2A mutations, and 1 PRRT2 mutation. Gene mutations were identified in 50 out of 68 BFIE families (73.5%), including 41 PRRT2 mutations (41 out of 68, 60.3%), 5 SCN2A mutations, 3 KCNQ2 mutations, and 1 GABRA6 mutation. Our results confirmed that mutations in KCNQ2, SCN2A, and PRRT2 are major genetic causes of benign familial epilepsy in the first year of life in the Chinese population. KCNQ2 is the major gene related to BFNE. PRRT2 is the main gene responsible for BFIE.
Benign familial epilepsy with onset in the first year of life is
an autosomal dominant form of genetic epilepsy
characterized by unprovoked partial or secondary generalized
seizures in neonates or infants with remission at a young age,
and a generally benign outcome [
]. All patients have a
family history of early onset seizure. Three epileptic
syndromes have been delineated so far, including benign
familial neonatal epilepsy (BFNE: OMIM 121200), benign
familial neonatal-infantile epilepsy (BFNIE: OMIM 607745)
and benign familial infantile epilepsy (BFIE: OMIM
605751). These conditions are differentiated mainly for the
age of onset. BFNE usually starts in neonatal period,
typically before 5 days of life . The seizure onset age is
usually from 2 days to 3.5 months of age in BFNIE [
BFIE tend to occur between 3 and 20 months of onset age,
mostly between 4 and 7 months [
]. During childhood or
adolescence, family members in BFIE may develop
paroxysmal kinesigenic dyskinesias (PKD). This clinical subtype
of BFIE is known as infantile convulsions with paroxysmal
choreoathetosis syndrome [
] (ICCA: OMIM 602066).
Defects in the genes encoding the voltage-gated
potassium channel subunits KCNQ2 and KCNQ3 are responsible
for BFNE [
]. The voltage-gated sodium channel gene
SCN2A was identified as the major causative gene for
]. Recently studies also led to the
identification of mutations in the proline-rich transmembrane protein
2 gene PRRT2 in BFIE [
]. However, for some
families, the causative genes have not been identified.
Although these three disorders show a significant clinical
overlap, a comprehensive mutational screening of the
candidate genes on a large set of families has been not yet
explored in the Chinese population. In this study, we
performed genetic analysis of families diagnosed as BFNE,
BFNIE, and BFIE in the Chinese Han population, and to
explore genetic background behind them.
Materials and methods
This study was approved by the Ethics Committee of
Peking University First Hospital. Written informed consent
for the analysis and publication of clinical and genetic
details was obtained from the patients or their parents. We
recruited families with at least two family members affected
by focal seizures starting within the first year of life at
Peking University First Hospital from September 2006 to
November 2016. Clinical information about age of seizure
onset, seizure types, developmental milestones, and
neurologic status of the patients and their relatives was collected
using a pre-test questionnaire completed by the recruiting
clinician by telephone or from medical records. Patients
were followed up at a pediatric neurology clinic at our
hospital or by telephone.
The diagnostic criterias for benign familial epilepsy were
as follows [
]: (1) unprovoked focal seizures with or
without secondary generalization, usually manifesting
motor arrest, deviation of the head and eyes to one side,
generalized hypertonia, cyanosis, and limb jerks; (2) normal
interictal electroencephalography; (3) normal brain
imaging; (4) no underlying disorders or neurological
disabilities; (5) normal psychomotor development before,
during and after the onset of seizures; (6) family history of
seizures (similar age at onset); (7) good response to
treatment and, in many cases, cessation of seizures before the
age of 2 years.
Seizures with onset in the first 28 days of life were
defined as neonatal, and from the second month to 1 year,
they were defined as infantile. Families were classified as
BFNE, when all affected family members experienced
neonatal seizures, BFNIE when the onset of seizures in
family members was between 1 and 3 months of age or
showed both neonatal and infantile seizures, and BFIE
when all family members showed infantile seizures and at
least one experienced seizure onset beyond 3 months of age.
BFIE families with affected individuals showing PKD later
in life were subclassified as ICCA.
Blood samples were obtained from these probands and their
family members when possible. Genomic DNA was
extracted from peripheral blood by a standard method.
Mutation screening of PRRT2 was performed by using the
polymerase chain reaction (PCR) and Sanger sequencing.
The method has been described in our previous study [
Mutation found in a proband was examined for
cosegregation in other family members.
Targeted next-generation sequencing
PRRT2 mutation negative probands were further screened
for pathogenic mutations through a custom-designed gene
panel in which a total of 149 candidate genes associated
with epilepsy were selected as the genes of interest
(Supplementary Appendix 1).
The target regions included all exons and the adjacent
+50 bp and ?50 bp segments of the introns of the selected
genes. The DNA of peripheral blood was fragmented, and
libraries were prepared following recommended protocols
of Illumina; The library DNA was captured by using a
GenCap exome capture kit (MyGenostics). The
capture experiment was conducted according to the
manufacturer?s protocol. Enriched capture libraries were
sequenced on a HiSeq X-ten or HiSeq 2500 platform
(Illumina) for 150 bp pair-end sequencing. The average
sequencing depth on the target regions was ?200, and the
coverage of the target regions (introns and exons) was
Raw sequencing data were saved in FASTQ format, then
analyzed using the following bioinformatics workflow:
First, Illumina sequencing adapters and low quality reads
(<80 bp) were filtered by using fastq_mcf. After quality
control, the clean reads were mapped to the UCSC hg19
human reference genome using BWA. Duplicated reads
were removed using Picard Tools, and only uniquely
mapping reads were used for variation detection. Second,
SNP and indel variants were detected by using the GATK
HaplotypeCaller. Then, the GATK VariantFiltration tool
was used to filter the variants. The filtered standards were
described as follows: (a) variants with mapping qualities
<30; (b) the Total Mapping Quality Zero Reads < 4; (c)
approximate read depth <5; (d) QUAL <50.0; (e)
phredscaled p-value using Fisher?s exact test to detect strand bias
>10.0. After these two steps, the data were transformed to
VCF format, and variants were further annotated by
ANNOVAR and associated with multiple databases, such as
the 1000 genomes project, ESP6500, dbSNP, EXAC,
Inhouse (MyGenostics), and HGMD. Variant functions
were predicted by SIFT, PolyPhen-2, MutationTaster, and
GERP++. The related software and database are available
in Supplementary Appendix 2.
Five steps were used to select potential pathogenic
mutations in the downstream analysis: (a) Mutation reads
should be >5, and the fraction of mutant alleles should be
no <30%; (b) Common variants with alternative allele
frequencies greater than 5% in the 1000 Genomes,
ESP6500, or Inhouse database were removed; (c) Variants
present in the InNormal database (MyGenostics) were
removed; (d) Synonymous variants were labeled. (e) After
(a), (b), and (c), only synonymous variants reported in
HGMD were kept. After the above filters, the remaining
variants were considered to be potential pathogenic
Fig. 1 Sequence
chromatograms. a Sequence
chromatograms showing the 14
novel gene mutations detected in
families with benign familial
epilepsies in the first year of life,
compared with wild-type traces.
b Sequence chromatograms of
family 50. The proband was
found with a compound
heterozygous mutation of
PRRT2 which consists of
c.649dupC inherited from his
father and c.593_594delCT from
his mother. The arrow shows the
position of the mutation
Copy number variants (CNVs) were also detected by
using the next-generation sequencing capture panel. Copy
numbers were first determined from the clean bam files.
Then, the copy numbers were corrected for GC content and
normalized according to population information. CNV
candidates satisfying the combined statistical tests were
annotated by using information from OMIM,
GeneReviewer, Decipher, and ClinVar. CNV candidates were also
filtered by using the DGV and MyGenostics control
databases. CNV candidates reported in Decipher and those
overlapping with the Decipher database were determined to
be pathogenic CNVs. CNV candidates annotated as
pathogenic or likely pathogenic in dbVAR, and those covering
functionally related genes, were determined to be likely
pathogenic. Other CNVs were uncertain. The related
software and database are also available in Supplementary
The potential pathogenic variations and CNVs suggested
by the targeted next-generation sequencing were validated
using Sanger sequencing, multiplex ligation-dependent
probe amplification (MLPA), or Real-time Quantitative
PCR (qPCR). The DNA of other family members was only
analyzed for potentially pathogenic variants and CNVs.
Next, we performed segregation analysis in these families.
For novel variants, we analyzed the variant in 104 healthy
Chinese controls. Variations and CNVs that showed
evidence of cosegregation with the families? phenotypes or
fulfilled genetic models were considered very likely to be
A total of 79 unrelated families with benign familial
epilepsies in the first year of life were collected. Of the 79
families, 255 family members were affected, with a range of
2?19 affected individuals per family (average 3.2). Seizure
onset beyond 1 year of age in some affected members was
found in 3 families (family 37, 47, and 58). The latest onset
age of seizure in these 3 families were 13 months, 3 years
and 14 months, respectively. Of the 79 families, 4 were
classified as BFNE, 7 as BFNIE, and 68 as BFIE. A total of
15 out of 68 BFIE families were subclassified as ICCA.
Family pedigrees of all 79 families are shown in
Supplementary Appendix 3.
Gene mutations were found in 60 of 79 families (75.9%) .
Of the mutations found, 42 affected PRRT2, 9 affected
KCNQ2, 8 affected SCN2A, and one affected GABRA6. In
total 14 mutations were novel (14/60, 23.3%). Sequence
chromatograms of novel mutations are shown in Fig. 1a.
In the 4 BFNE families, causative mutations were only
found in KCNQ2, which was identified as the affected gene
in 3 of the families. All 7 BFNIE families had identifiable
gene mutations, PRRT2 was found in one family, KCNQ2
in 3 families, and SCN2A in 3 families. In the 68 BFIE
families, gene mutations were identified in 50 families (50
out of 68, 73.5%), with PRRT2 mutations found in 41
families (41 out of 68, 60.3%), SCN2A mutations found in 5
families, KCNQ2 mutations found in 3 families, and a
GABRA6 mutation found in one family. In total 14 of 15
ICCA families were found to have PRRT2 mutations (14
out of 15, 93.3%). The remaining ICCA family was not
detected with any pathogenic mutation. The detection rates
of PRRT2, KCNQ2, SCN2A, and GABRA6 mutations in
families with BFNE, BFNIE, and BFIE are shown in Fig. 2.
The clinical features and genetic testing results of all 79
families are summarized in Table 1.
Of the 42 families with PRRT2 mutations, 39 had
frameshift mutations, one had a nonsense mutation, one
showed a loss of a stop codon, and one was a microdeletion
of the gene (family 30). The size of the deletion detected by
the targeted next-generation sequencing was about 1583 bp
(chr16: 29824376-29825959). The deletion was verified by
qPCR (the qPCR results of the family members are shown
in Supplementary Appendix 4). The mutation c.649dupC[p.
Arg217Profs*8] and c.649delC[p.Arg217Glufs*12] were
hot spot mutations of PRRT2. The mutation c.649dupC was
found in 28 families (28 out of 42, 66.7%). The mutation
c.649delC was found in 6 families. In total 19 of the 42
families with PRRT2 mutation were described previously
]. The mutations c.560dupT[p.Gln188Alafs*4] and
c.679C>T[p.Arg227*] are novel. We found a proband from
an ICCA family (family 50) with a compound heterozygous
mutation of PRRT2 consisting of a mutation c.649dupC[p.
Arg217Profs*8] inherited from his father, who had PKD;
Fig. 2 Detection rates of PRRT2, KCNQ2, SCN2A, and GABRA6
mutations in families with BFNE, BFNIE, and BFIE
this proband also inherited a novel mutation
c.593_594delCT [p.Pro198Argfs*26] from his
asymptomatic mother, who did not have a family history of seizures
or PKD (see family pedigrees in Fig. 3a1 and a2). The
sequence chromatograms of the proband and her parents are
shown in Fig. 1b. The proband is a girl. She had seizure
onset in 2.5 months. Her seizures were well-controlled with
valproate until she was 2 years old, when the valproate
therapy stopped. The seizures relapsed 2 days after
valproate withdrawal. The duration of seizures were about
2?3 min. The seizures were so frequent that recurred once
every hour. Then carbamazepine was used for this patient
and her seizures were controlled. She was 28 months old at
last follow-up and had a light developmental delay in
Of the 9 families with KCNQ2 mutations, one had a
nonsense mutation, 7 had missense mutations, and one had
a gene deletions of KCNQ2, that also extended to the
adjacent gene, CHRNA4 (family 7). The deletions included
whole exons of KCNQ2 and CHRNA4 (MLPA results are
shown in Supplementary Appendix 5). Six KCNQ2
mutations in our study were novel mutations, including
mother who didn?t have any clinical history of seizure and PKD. b
Pedigree of family 6 which had an affected family member (IV7)
suffered from intractable epilepsy from the second day of life and
evolved to epileptic encephalopathy. c Pedigree of family 61 which
was detected with a GABRA6 mutation c.523G>T
c.2506G>T[p.Glu836*], c.958G>A[p.Val320Ile], c.237T>
G[p.Asn79Lys], and c.1510C>T[p.Arg504Trp]. Family 6,
with the reported KCNQ2 mutation c.998G>A[p.
Arg333Gln], was diagnosed as BFNIE, with 7 affected
members who experienced seizures within the first 2 days to
6 months of life and had seizure remission before 1 year of
life (see family pedigree in Fig. 3b). However, one affected
individual (IV7) in this family has suffered intractable
epilepsy from the second day after birth. The seizures were
resistant to multiple antiepileptic drugs and led to severe
developmental delay. He is 8 years old now and cannot
walk alone. He also carries the KCNQ2 mutation
Arg333Gln, which was inherited from his father, who had
benign neonatal epilepsy.
All 8 SCN2A mutations found in our study are missense
mutations. Five SCN2A mutations in our study were novel
mutations, including c.2872A>G[p.Met958Val], c.752T>C
[p.Val251Ala], c.1307T>C[p.Leu436Ser], c.4835C>G[p.
Ala1612Gly], and c.1737C>G[p.Ser579Arg].
We identified a BFIE family (family 61) with a novel
GABRA6 mutation c.523G>T[p. Gly175Trp]. The proband
and her mother showed seizure onset at 8.5?9 months of life
and showed remission before 1 year. The proband was 5
years old at last follow up. Both the proband and her mother
had no seizure relapsed and showed normal intelligence.
The clinical history of infantile seizure could not be
obtained for the grandmother of the proband, who also
carried the same mutation. The family pedigree is shown in
Fig. 3c. The position of p.G175 codes for a highly
conserved amino acid. The in silico analysis of the Gly175Trp
mutation based on SIFT (score 0.000), Polyphen-2 (score
0.99), and Mutation Taster (score 0.99) predicted that this
substitution at position 175 from Gly to Trp could be
pathogenic. The change is not reported in Single Nucleotide
Polymorphism database (dbSNP), and is neither found in
ExAC nor 1000 G. This mutation is also absent in the 104
healthy Chinese controls.
We aimed to establish the genetic spectrum in Chinese
families with benign familial epilepsies of the first year of
life. Our results showed that in 79 families, the detection
rate for gene mutations was 75.9%, which was lower than in
a study by Zara et al. [
], who had a rate of 89%. It might
be because the proportion of BFNE, BFNIE, and BFIE
families in our study were different from the study by Zara
KCNQ2 is the only gene related to BFNE in our study.
This indicates that KCNQ2 is a major causative gene of
BFNE. Although the sample size of our BFNE families was
small, this result was consistent with a larger study by
Grinton et al. [
], consisting of ~80% BFNE families with
KCNQ2 mutations. Grinton et al. also identified one BFNE
family with a KCNQ3 mutation and 2 families with SCN2A
mutations. However, we did not identify any mutations in
KCNQ3 or SCN2A in our BFNE families. This suggests that
BFNE families with causative mutations in KCNQ3 and
SCN2A are rare.
In our study, all 7 BFNIE families were detected with
gene mutations. The genes involved were KCNQ2, SCN2A,
and PRRT2. SCN2A had been proved to be a main causative
gene of BFNIE [
]. KCNQ2 mutations were previously
identified in several families fulfill the diagnosis of BFNIE
]. We identified 3 families with SCN2A mutations
and 3 families with KCNQ2 mutations in our BFNIE
families. This indicates that both SCN2A and KCNQ2 are
important genes in BFNIE families. KCNQ2 and CHRNA4
deletions have been reported in typical BFNE families, as
well as patients with neonatal seizures and developmental
delay in previous studies [
]. We found one BFNIE
family with KCNQ2 and CHRNA4 deletions. Both of the
two affected members in this family showed typical benign
neonatal or infantile epilepsy. We found one BFNIE family
with a PRRT2 hotspot mutation, c.649dupC. The onset of
seizures in affected members was between 2 and 2.5 months
of age in this family. The earliest age of onset of seizures in
individuals with PRRT2 mutations in a previous study was
during the first few days of life [
BFIE families were the most genetically heterogeneous.
PRRT2, KCNQ2, SCN2A, and GABRA6 were found to be
involved. The rate of identifiable gene mutations in the
BFIE families was 73.5% in our study. PRRT2 mutations
were clustered in families with BFIE (41 out of 68, 60.3%).
It may be due to regional and racial differences, however,
our rate was lower than those rates found by other research
11, 12, 14, 21
]. In our study, most PRRT2
mutations were frameshift mutations. And we did not find
any missense mutation in PRRT2. Both c.649dupC[p.
Arg217Profs*8] and c.649delC[p.Arg217Glufs*12] were
hot spot mutations of PRRT2. The mutation c.649dupC was
most common in PRRT2 mutations, accounting for 66.7%
(28 out of 42) families with PRRT2 mutations in our study.
The ICCA families exhibited only PRRT2 mutations. The
positive rate of PRRT2 mutations in our ICCA families was
93.3%. This result was consistent with the rate that had been
reported by other research groups [
identification of SCN2A mutations in 5 BFIE families in our
cohort further proved that this gene is also involved in
families with a delayed age of onset . KCNQ2 was the
only gene that could be related to these three benign familial
epilepsies in our study. However, KCNQ2 mutations
showed a progressively decreasing rate as the age of seizure
onset increased. We found 3 families with KCNQ2
mutations in our 68 BFIE families (4.4%, 3 out of 68). Zara et al.
] found one family with KCNQ2 mutation in 29 BFIE
families (3.4%, 1 out of 29). These two rates are similar. In
our study, 3 BFIE families have affected individuals with
seizure onset beyond 1 year of age. All three families were
found to have a mutation in PRRT2 or SCN2A.
Labate et al. [
] have reported homozygous mutation in
PRRT2 in a family with intellectual disability and seizures
with onset in infancy. Delcourt et al. [
] also reported that
patients with biallelic mutations in PRRT2 gene had diverse
forms of paroxysmal neurological disorders, including
status epilepticus, paroxysmal non-kinesigenic dyskinesia,
learning abilities, behavioural problems, episodes of ataxia,
and cerebellar atrophy. In our study, an affected member in
an ICCA family (family 50) was identified with a
compound heterozygous PRRT2 mutation. This patient was
more dependent on anti-epileptic drugs compared to the
other affected members with a heterozygous c.649dupC
mutation in her family and showed a slight language
development delay. It may due to our short follow-up time
(28 months at last follow up), however, this girl had not yet
showed a distinct phenotype of infantile epileptic
encephalopathy or other severe paroxysmal neurological
Both benign epilepsy and epileptic encephalopathy have
been reported to be associated with KCNQ2 mutations [
Families with KCNQ2 mutations and variable phenotypes
have been described previously [
]. We identified a
BFNIE family (family 6) with 7 affected members who
showed benign epilepsy as neonates or infants, and one
affected boy presented epileptic encephalopathy. This boy
was found to have a familial Arg333Gln mutation in
KCNQ2, which had been reported in BFNE . This
further demonstrates that the correlation between genotype
and phenotype is inconsistent, even within a family. Just as
most other epilepsy associated with ion channelopathies, the
genotype-phenotype relation for KCNQ2 can be
substantially modified by other genes and environmental
We detected a novel c.523 G > T[p. Gly175Trp] mutation
in the GABRA6 gene in a BFIE family. GABRA6 is a
member of the GABA-A receptor gene family of
heteromeric pentameric ligand-gated ion channels through which
GABA, the major inhibitory neurotransmitter in the
mammalian brain, acts. GABRA6 mutations have been shown to
be related to the childhood absence epilepsy in a previous
study and polymorphisms in this gene were important risk
factors for the development of the idiopathic generalized
]. As far as we know, we have identified the
first GABRA6 mutation in a BFIE family. Further functional
research is necessary to strongly associate the mutation with
the BFIE phenotype. However, the pathogenic
bioinformatics prediction and the cosegregation of mutation allow
us to speculate on a deleterious effect of this variation in our
family. The absence of the mutation in SNP/variant
databases, and in our control population also supports this
Previous studies showed that SCN8A and CHRNA2
mutations was identified in sporadic families with BFIE [
]. These two genes are also included in our gene panel.
However, we did not reveal any causative mutations in
these two genes in our BFNE, BFNIE, and BFIE families.
This suggests that mutations of these genes are rare as a
cause of benign familial epilepsies.
In summary, mutations in KCNQ2, SCN2A, and PRRT2
are major genetic causes of benign familial epilepsies of the
first year of life in Chinese population. KCNQ2 is the major
gene related to BFNE. PRRT2 is the main gene responsible
for BFIE. GABRA6 mutations might be involved in families
Acknowledgements This study was supported by grants from the
omics-based precision medicine of epilepsy being entrusted by Key
Research Project of the Ministry of Science and Technology of China
(2016YFC0904400 and 2016YFC0904401) and the Beijing Key
Laboratory of Molecular Diagnosis and Study on Pediatric Genetic
Diseases (Z141107004414036). We thank the patients and their family
members for taking part in this study.
Compliance with Ethical Standards
Conflict of Interest All authors declare that there is no conflict of
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