Chinese cases of early infantile epileptic encephalopathy: a novel mutation in the PCDH19 gene was proved in a mosaic male- case report

Chinese cases of early infantile epileptic encephalopathy: a novel mutation in the PCDH19 gene... Background: The link between the protocadherin-19 (PCDH19) gene and epilepsy suggests that an unusual form of X-linked inheritance affects females but is transmitted through asymptomatic males. Individuals with epilepsy associated with mutations in the PCDH19 gene display generalized or focal seizures with or without fever sensitivity. The clinical manifestation of the condition ranges from mild to severe, resulting in intellectual disability and behavioural disturbance. In the present study, we assessed mutations in the PCDH19 gene and the clinical features of a group of Chinese patients with early infantile epileptic encephalopathy and aimed to provide further insight into the understanding of epilepsy and mental retardation limited to females (EFMR; MIM 300088). Case Presentation: We described three variations in the PCDH19 gene in Chinese patients with epilepsy who developed generalized seizures occurring in clusters with or without triggering by fever. Candidate genes were screened for mutations that cause epilepsy and related paroxysmal or nervous system diseases in the coding exons and intron–exon boundaries using polymerase chain reaction (PCR) of genomic deoxyribonucleic acid (DNA) followed by sequencing. The variations were sequenced using next-generation sequencing technology and verified with first-generation sequencing. Exome sequencing of a multigene epilepsy panel revealed three mutations in the PCDH19 gene in a mosaic male and two unrelated females. These included a frameshift mutation c.1508_1509insT (p.Thr504HisfsTer19), a missense mutation c.1681C > T (p.Pro561Ser) and a nonsense mutation c.918C > G (p.Tyr306Ter). Of the three mutations in the PCDH19 gene associated with early infantile epileptic encephalopathy, the frameshift variation in a mosaic male is novel and de novo, the missense variation is de novo and is the second ever reported in females, and the nonsense variation was inherited from the paternal line and is the first example discovered in a female. Conclusions: The results from our current study provide new insight into and perspectives for the molecular genetic link between epilepsy and PCDH19 alterations. Moreover, our new findings of the male mosaic variant broaden the spectrum of PCDH19-related epilepsy and provide a new understanding of this complex genetic disorder. Keywords: PCDH19, Infantile epilepsy, Clinical manifestations, Gene variations * Correspondence: zbchen0532@126.com Yuxia Tan, Mei Hou and Shaochun Ma contributed equally to this work. Department of Pediatrics, The Affiliated Hospital of Qingdao University, No. 59, Haier Road, Qingdao 266000, China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tan et al. BMC Medical Genetics (2018) 19:92 Page 2 of 8 Background inheritance and the pathogenic hypothesis associated with Epilepsy and mental retardation limited to females the cellular interference mechanism. However, following (EFMR; MIM 300088), first reported by Juberg et al. the report of a male with a mosaic PCDH19 deletion [6], a (1971), affects females but is transmitted through un- small number of recent studies have described several al- affected males, following an unusual X-linked form of terations of the PCDH19 gene in mosaic male patients in inheritance [1]. EFMR, also known as early infantile epi- succession [14–17]. leptic encephalopathy-9 (EIEE9, OMIM# 300088), is a Here, we present evidence of three mutations of the genetic disorder, of which the de novo or familial hetero- PCDH19 gene in a mosaic male and two unrelated fe- zygous variation of the PCDH19 gene (OMIM 300460) males in Chinese individuals with epilepsy, further con- is forecasted to be the second most common cause in tributing to the clinical understanding of EFMR in addition to variations of the sodium voltage-gated chan- relation to the PCDH19 gene. nel alpha subunit 1 (SCN1A) gene [2–5]. Since the initial description of the PCDH19 gene, the evidence of a link Case presentation between the clinical features of epilepsy and de novo or We recruited three Chinese children with epilepsy familial mutations in the PCDH19 gene has increased. treated in the Qingdao Women & Children’s Hospital These links include infantile onset of multiple seizure between March 2016 and April 2017. The clinical diag- types, such as Dravet syndrome, generalized or focal nosis was made by clinical geneticists. Additional clinical epilepsy with or without fever sensitivity, and epilepsy information relevant to the diagnosis was provided by of variable severity in females with or without intel- the parents and the caregivers. The CARE guidelines lectual disability, behavioural disturbance or psychiatric were followed in reporting these cases. Two millilitres of symptoms [2, 6–8]. venous blood was collected from each patient and each The PCDH19 gene is located on the X chromosome parent of the subject upon signed informed consent. (Xq22.1) and encodes protocadherin-19. This is a Then, the blood samples were sent to Beijing Kangso calcium-dependent adhesion molecule belonging to the Medical Inspection for gene testing: nervous system dis- δ2-protocadherin (pcdhs) subclass of the cadherin eases “big bag” for patient 1 (a total of 1906 genes) and (cdhs) superfamily [9]. The PCDH19 gene shows an un- epilepsy and related paroxysmal diseases for patient 2 usual X-linked form of inheritance affecting only fe- and patient 3 (a total of 518 genes). Genomic DNA from males but being transmitted via asymptomatic males, blood samples was extracted using the Qiagen FlexiGene which implies that it is pathogenic in heterozygous mu- DNA kit (Qiagen, Germany) following the manufacture’s tated females but non-pathogenic in hemizygous mutated guidelines. Candidate genes were screened for mutations males [6, 10]. PCDH19 has been shown to be expressed in in the coding exons and intron–exon boundaries using the central nervous system and is possibly involved in a PCR of genomic DNA followed by sequencing. Primer se- cellular interference mechanism that affects brain devel- quences and PCR conditions are available upon request. opment, neuronal connections, and intracellular signal The variations were sequenced with next-generation transductions at the synaptic membrane [3, 11, 12]. sequencing and verified with first-generation sequen- Variations in the PCDH19 gene were first reported by cing. Detailed experimental methods can be found in Dibbens et al. (2008) in several families with the EFMR Additional file 1. disorder [10]. Depienne et al. (2009) discovered that sub- jects with PCDH19-related disease might be normal dur- Patient 1 ing early development but experience seizure onset Patient 1 is a 27-month-old male. He was born via nor- occurring in clusters with fever sensitivity, an observa- mal vaginal delivery at full-term. He weighed 3.0 kg at tion similarly seen with Dravet syndrome (DS) [6]. An birth. No neurological problems were noted during rou- increasing number of female epilepsy patients with tine examinations at birth. The pregnancy and perinatal PCDH19 mutations have been reported over recent history were unremarkable. He was the first child of years, and the clinical spectrum of diseases associated non-consanguineous parents. Family history was non- with PCDH19 gene mutations has also expanded, in- contributory. At the age of 7 months, his first recurrent, cluding patients displaying focal or generalized seizures afebrile generalized tonic seizures (TS) were noted. The recurring in clusters or isolation with or without febrile video electroencephalogram (VEEG) showed sharp, trigger, ranging from mild to severe, with or without spike waves with partial origin at right frontal regions cognitive impairment, behavioural disturbance, and psy- and high voltage slow background. The brain magnetic chiatric symptoms [2, 4, 11, 13]. resonance imaging (MRI) was normal. Following treat- Up to now, the molecular genetic study for PCDH19-re- ment with valproate (VPA) and topiramate (TPM) for lated epilepsy has been focused on females. Male subjects 5 months, his cluster seizures remained and occurred were generally excluded because of the unusual X-linked from time to time. After adjusting the antiepileptic Tan et al. BMC Medical Genetics (2018) 19:92 Page 3 of 8 drugs (AED) to VPA and phenobarbital (PB), the con- both strands covering the variant on Integrate Genome trol of seizures remained unsatisfactory. After 9 months Viewer are shown in more detail in Additional file 2. from the initial onset, oxcarbazepine (OXC) was added. Then, his seizures were gradually controlled with VPA, PB and OXC, and he remained seizure-free for 3 months till Patient 2 the last follow-up. Patient 2 is a 34-month-old female. She was born at In his development, his early psychomotor skills were full-term via normal vaginal delivery without distress unremarkable. However, he showed signs of intellectual and dysmorphic features. At birth, she weighed 3.3 kg, impairment and behavioural disturbance following the and neurologic examination suggested no abnormalities. onset of his seizures. His head control was complete at The perinatal history, pregnancy and neonatal course 2 months. He rolled at 4 months, sat up unsupported were all unremarkable. She is the only child to her healthy at 7 months, climbed at 11 months, and walked inde- parents. She had no family history of neurological disease. pendently at 13 months. At present, he runs unsteadily Her first seizure displaying a tonic seizure (TS) was noted and falls easily when standing up from squatting. He during a febrile illness at the age of 14 months; the EEG spoke his first word at age 15 months and had only and brain computed tomography (CT) then were normal. three purposeful words by 24 months. He was unable By 19 months of age, she developed a cluster of febrile sei- to act following orders or to express his wants accur- zures lasting for approximately 10 s each time, with sei- ately. He receives language training and physical therapy zures occurring 6 times in 36 h. At the age of 31 months, at present. a second cluster appeared, triggered by fever. The VEEG By clinical exome sequencing, patient 1 was found to and brain MRI were also normal at this onset. Her psy- have a frameshift mutation in the PCDH19 gene: a thy- chomotor development was unremarkable. Her seizure mine (T) inserted into the encoding region between nu- was gradually controlled after being given TPM. cleotides 1508 and 1509 (c.1508_1509insT), suggesting a Clinical exome sequencing revealed a missense muta- mosaic nucleotide mutation. The mutation led to the tion in the PCDH19 gene: a cytosine to thymine (C > T) synthesis of amino acid beginning from amino acid 504 nucleotide change at position 1681 (c.1681C > T) in pa- of Thr changed and ending in the nineteenth amino acid tient 2, a heterozygous nucleotide mutation causing after the change (p.Thr504HisfsTer19). This mutation amino acid 561 to change from Pro to Ser (p.Pro561Ser). was a de novo variation. The male’s parents showed no This mutation was de novo, and this alteration was not abnormalities (Fig. 1). The Sanger sequencing results of found in her parents (Fig. 2). Fig. 1 The genetic map and mutation sequence chromatograms in the PCDH19 gene of family 1. Black square: affected mutation-carrying male; white square: male without PCDH19 mutation; white circle: female without PCDH19 mutation. The red arrows indicate the location of the identified mutation Tan et al. BMC Medical Genetics (2018) 19:92 Page 4 of 8 Fig. 2 The genetic map and mutation sequence chromatograms in the PCDH19 gene of family 2. Black circle: affected mutation-carrying female; white circle: female without PCDH19 mutation; white square: male without PCDH19 mutation. The red arrows indicate the location of the identified mutation Patient 3 and epileptogenic characters of the three patients carry- Patient 3 is a 39-month-old female. She was born at ing PCDH19 variations are described in Table 1. full-term via a normal vaginal delivery. She weighed In a 2016 study, Terracciano et al. revealed a male pa- 3.18 kg at birth, with no apparent neurological abnormal- tient with the nonsense mutation c.918C > G (p.Tyr306- ities. The prenatal history and neonatal development were Ter), the same position as patient 3 in our cohort. Here, normal. She is the only child of non-consanguineous par- we compared the findings from our study with those of ents. Her grandmother has a history of seizures. Her seiz- Terracciano et al. [14]. Of the four patients, seizures ure onset was at 20 months when she experienced a started within the first year of life for two patients and cluster of afebrile generalized tonic and clonic seizures after the first year of life for the other two, with an aver- (GTCS), with seizures occurring 6 times in a day. The age age of onset of 12 months (6–20 months). All pa- VEEG and brain MRI showed no abnormality at that time. tients had generalized seizures or focal seizures with After a one-month seizure-free period, she presented with secondary generalization (SG), characterizing the onset a second cluster of afebrile generalized seizures. The of epilepsy. Cluster seizures occurred in all subjects, and VEEG showed sharp slow wave emission mainly in the patient 4 had confirmed epileptic status. Two patients right occipital region. Treatment with levetiracetam re- had seizures associated with fever sensitivity at onset, sulted in gradual control of seizures. She requires no other and the other two were afebrile onset. EEG was normal significant medical attention. in patients 2 and 4 but showed abnormality in patients 1 For patient 3, clinical exome sequencing suggested a and 3. Brain MRI had no special findings. Psychiatric nonsense mutation in the PCDH19 gene: acytosine to symptoms were absent from all the patients. However, guanine (C > G) nucleotide change at nucleotide 918 patients 1 and 4 developed intellectual impairment and (c.918C > G), a heterozygous nucleotide mutation. The behavioural disturbance. Patient 1 had recurrent epilepsy mutation changed amino acid 306 from Tyr into a ter- despite being treated with multiple anti-epileptic drugs, mination codon (p.Tyr306Ter). The mutation was inher- suggesting that the seizures related to PCDH19 varia- ited from the paternal line. The girl’s father was tions were difficult to control to a certain degree. identified to be a hemizygote, but her mother did not Despite the many clinical manifestations of PCDH19-re- carry this alteration (Fig. 3). lated epilepsy, the disease shares some common character- istics, namely, onset at the age of infancy and babyhood, generalized seizures and cluster seizures [3]. Generalized Discussion and Conclusions tonic seizures (TS), tonic-clonic seizures (GTCS) or focal We identified three mutations of PCDH19-related epi- seizures with SG occurring in clusters with or without lepsy in a cohort of Chinese children. The clinical data fever sensitivity are the common seizure types. Other Tan et al. BMC Medical Genetics (2018) 19:92 Page 5 of 8 Fig. 3 The genetic map and mutation sequence chromatograms in the PCDH19 gene of family 3. Black circle: affected mutation-carrying female; white circle: female without PCDH19 mutation; a dot in a white square: asymptomatic mutation-carrying male. The red arrows indicate the location of the identified mutation Table 1 Clinical data of patients with epilepsy carrying PCDH19 mutations Patient number Male patient 1 Female patient 2 Female patient 3 Male patient (Terracciano et al. 2016) [14] PCDH19 mutation c.1508_1509insT c.1681C > T c.918C > G c.918C > G p.Thr504HisfsTer19 p.Pro561Ser p.Tyr306Ter p.Tyr306* Mutation type Frameshift mutation Missense mutation Nonsense mutation Nonsense mutation Sex Male Female Female Male Present age 2 y 3 m 2 y 10 m 3 y 3 m 4 y Birth weight 3.0 kg 3.3 kg 3.18 kg Unknown Age at onset 7 m 1 y 2 m 1 y 8 m 9 m Type of seizures at onset TS TS GTCS Focal with SG Cluster occurrence Yes Yes Yes Yes Fever sensitivity No Yes No Yes Status epilepticus No No No Yes EEG Abnormal Normal Abnormal Normal MRI Normal Normal Normal Normal Intellectual disability Yes No No Borderline Psychiatric symptoms No No No No Behavioural disturbance Yes No No Yes Current AED Phenobarbital, valproate, Topiramate Levetiracetam Valproic acid oxcarbazepine Persistence of seizures with AED Yes No No No Transmission De novo De novo Paternal inheritance De novo Tan et al. BMC Medical Genetics (2018) 19:92 Page 6 of 8 seizure types, such as myoclonic seizures, atonic seizures in the splice site of intron 1 [14, 16, 17, 20]. Neverthe- and atypical absences, are rare. Intellectual development less, here, we attest the first male with the PCDH19 gene abnormalities vary from normal to severe impairment. Pa- pathogenic variant c.1508_1509insT, which contributes tients may or may not display psychiatric symptoms and to further explanation of this complex and an interesting behavioural disturbance [4, 13]. genetic disorder. Of the four patients, three genetic alterations were de The missense mutation c.1681C > T (p.Pro561Ser) was novo, and one was inherited from her asymptomatic reported in a female patient by Carvill in 2013 [21] and father. PCDH19 mutations in most patients are sporadic the nonsense mutation c.918C > G (p.Tyr306Ter) in a and de novo, whilst some are of paternal inheritance. mosaic male patient by Terracciano in 2016 [14]. These This makes it difficult to recognize the pattern of inher- reports together with our findings collectively suggest itance [18, 19]. To determine the complete feature of that PCDH19 gene mutations have a significant associ- EFMR, more patients need to be studied. ation with epilepsy. The missense alteration was de With the progress of genetic detection technology, novo. The nonsense mutation was transmitted from an thus far, over 150 PCDH19 mutations have been identi- asymptomatic father, but the transmitting male showed fied, featuring small deletion, small insertion, nonsense, no abnormalities because of the unusual X-linked inher- missense, microduplication, intragenic deletion, splice itance of PCDH19. site mutation and whole gene deletion. The great major- The full-length mRNA of the PCDH19 gene is 9765 ity of the variations (over 90%) are located in exon 1, the nucleotides, encoding a 1148 amino acid protein. The largest exon encoding the extracellular cadherin domain PCDH19 gene consists of six exons; exon 1 is the lar- [5]. In our study, we report three mutations located in gest exon encoding a signal peptide, the whole extra- exon 1, including a frameshift mutation, a missense mu- cellular domain and a short transmembrane domain tation and a nonsense mutation. One mutation was (TM), including six repeats of EC cadherin regulating novel, and two were reported recently. The frameshift al- cell-cell interactions [10]. All three mutations we iden- teration c.1508_1509insT (p.Thr504HisfsTer19) was tified in the present study were found in exon 1 of the identified in a mosaic male, which was a novel and de PCDH19 gene, with the nonsense mutation c.918C > G novo mutation. This discovery expands the spectrum of (p.Tyr306Ter) in EC3 and both the frameshift muta- PCDH19-related epilepsy in males. A brief review of mo- tion c.1508_1509insT (p.Thr504HisfsTer19) and the saic males in terms of the PCDH19 gene are as follows: missense mutation c.1681C > T (p.Pro561Ser) in EC5 Stosser et al. (2017) identified five males with mosaic (Fig. 4). The nonsense and missense mutations were pathogenic variants presenting with epilepsy with or predicted to be deleterious in our report and were pre- without signs of developmental delay, similar to female viously reported [14, 21]. Although the frameshift alter- patients with PCDH19 pathogenic variants [20]. Other ation was novel, the frameshift nature of c.1508_1509insT researchers also reported several variants in mosaic and the predicted introduction of a termination codon of males, and these male patients with mosaic mutations p.Thr504HisfsTer19 are predicted to be harmful. More- showed similar clinical features of epileptic encephalop- over, the extracellular domains of six EC cadherin repeats athy to those presented in PCDH19 affected females. were highly conserved in the amino acid sequence and The previously described pathogenic mutations in mo- shown to be critical for normal protein function. Hence, saic males contain frameshift mutation, nonsense vari- our study added further evidence to the pathology of ant, missense mutation of exon 1 and alteration located these mutations. Fig. 4 Schematic diagram of the point mutations identified in the PCDH19 gene. SP: signal peptide; EC: extracellular cadherin domain; TM: transmembrane domain; CM1 and CM2; cytoplasmic domains 1 and 2 Tan et al. BMC Medical Genetics (2018) 19:92 Page 7 of 8 In conclusion, we report three mutations in the Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in PCDH19 gene associated with early infantile epileptic en- published maps and institutional affiliations. cephalopathy. Of the three mutations, one variation was in a mosaic male and is a novel finding, the missense vari- Author details Department of Pediatrics, The Affiliated Hospital of Qingdao University, No. ation is de novo and is the second female case reported, 59, Haier Road, Qingdao 266000, China. Department of Pediatrics, Zibo City and the nonsense variation is of paternal inheritance and Maternal and Child Health Hospital, Zibo City 255029, Shandong Province, is the first report in a female. Our report provides further China. Department of Pediatric Rehabilitation, The Affiliated Qingdao Women & Children’s Hospital of Qingdao University, Qingdao 266034, China. proof and opens a new point of view for the molecular Department of Pediatric Neurology, The Affiliated Qingdao Women & genetic diagnosis of patients with a special type of epi- Children’s Hospital of Qingdao University, Qingdao 266034, China. lepsy. Perhaps more significantly is that the new mutation Received: 16 February 2018 Accepted: 30 May 2018 discovered in the mosaic male would expand the current knowledge about EIEE9 and guide diagnosis and targeted therapy in male patients. Finally, there are notable limita- References tions to this study, including the relatively small sample 1. Juberg RC, Hellman CD. A new familial form of convulsive disorder and size. However, this study has certainly opened a new fron- mental retardation limited to females. J Pediatr. 1971;79(5):726–32. tier for further investigation into early infantile epileptic 2. Depienne C, Trouillard O, Bouteiller D, et al. Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females. Hum encephalopathy related to the PCDH19 gene in the future. Mutat. 2011;32(1):E1959–75. 3. Depienne C, LeGuern E. PCDH19-related infantile epileptic Additional files encephalopathy: an unusual X-linked inheritance disorder. Hum Mutat. 2012;33(4):627–34. 4. van Harssel JJ, Weckhuysen S, van Kempen MJ, et al. Clinical and genetic Additional file 1: Detailed experimental methods for gene testing. aspects of PCDH19-related epilepsy syndromes and the possible role of (DOC 31 kb) PCDH19 mutations in males with autism spectrum disorders. Neurogenetics. Additional file 2: The Sanger sequencing results of both strands 2013;14(1):23–34. covering the variant on Integrate Genome Viewer for patient 1.(DOC 66 5. Duszyc K, Terczynska I, Hoffman-Zacharska D. Epilepsy and mental kb) retardation restricted to females: X-linked epileptic infantile encephalopathy of unusual inheritance. J Appl Genet. 2015;56(1):49–56. 6. Depienne C, Bouteiller D, Keren B, et al. Sporadic infantile epileptic Abbreviations encephalopathy caused by mutations in PCDH19 resembles Dravet AED: Antiepileptic drugs; CT: Computed tomography; DNA: Deoxyribonucleic syndrome but mainly affects females. PLoS Genet. 2009;5(2):e1000381. acid; EFMR: Epilepsy and mental retardation limited to females; 7. Marini C, Mei D, Parmeggiani L, et al. Protocadherin 19 mutations in girls GTCS: Generalized tonic and clonic seizures; MRI: Brain magnetic resonance with infantile-onset epilepsy. Neurology. 2010;75(7):646–53. imaging; OXC: Oxcarbazepine; PB: Phenobarbital; PCDH19: Protocadherin-19; PCR: Polymerase chain reaction; SCN1A: Sodium voltage-gated channel alpha sub- 8. Specchio N, Marini C, Terracciano A, et al. Spectrum of phenotypes in unit 1; TPM: Topiramate; TS: Tonic seizures; VEEG: Video electroencephalogram; female patients with epilepsy due to protocadherin 19 mutations. Epilepsia. VPA: Valproate 2011;52(7):1251–7. 9. Redies C, Vanhalst K, Fv R. delta-Protocadherins: unique structures and Acknowledgements functions. Cell Mol Life Sci. 2005;62(23):2840–52. This study was technically supported by Kangso Medical Inspection, Beijing, 10. Dibbens LM, Tarpey PS, Hynes K, et al. X-linked protocadherin 19 mutations China. The authors thank the patients and their parents. cause female-limited epilepsy and cognitive impairment. Nat Genet. 2008; 40(6):776–81. 11. Hynes K, Tarpey P, Dibbens LM, et al. Epilepsy and mental retardation Funding limited to females with PCDH19 mutations can present de novo or in single This study was financially supported by the Natural Science Fund of China generation families. J Med Genet. 2010;47(3):211–6. (grant number 31640047). 12. Dibbens LM, Kneen R, Bayly MA, et al. Recurrence risk of epilepsy and mental retardation in females due to parental mosaicism of PCDH19 Availability of data and materials The datasets used and/or analysed during the current study are available mutations. Neurology. 2011;76(17):1514–9. from the corresponding author upon reasonable request. 13. Marini C, Darra F, Specchio N, et al. Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy. Epilepsia. 2012;53(12): Authors’ contributions 2111–9. ZBC conceived the study. YXT wrote the manuscript. MH and SCM collected 14. Terracciano A, Trivisano M, Cusmai R, et al. PCDH19-related epilepsy in two patient data. PPL revised the manuscript. SGX, YW and LPC facilitated all mosaic male patients. Epilepsia. 2016;57(3):e51–5. project-related work. All authors have read and agreed to the manuscript. 15. Perez D, Hsieh DT, Rohena L. Somatic mosaicism of PCDH19 in a male with All authors declare responsibility for all aspects of this work. early infantile epileptic encephalopathy and review of the literature. Am J Med Genet A. 2017;173(6):1625–30. Ethics approval and consent to participate 16. Thiffault I, Farrow E, Smith L, et al. PCDH19-related epileptic encephalopathy This study was approved by the Ethics Committee of the Affiliated Hospital in a male mosaic for a truncating variant. Am J Med Genet A. 2016;170(6): of Qingdao University. Written informed consent for participating in the 1585–9. study was obtained from all the patients’ parents. 17. de Lange IM, Rump P, Neuteboom RF, et al. Male patients affected by mosaic PCDH19 mutations: five new cases. Neurogenetics. 2017;18(3): Consent for publication 147–53. Informed consent was obtained from all subjects’ parents in this study. All the 18. Scheffer IE, Turner SJ, Dibbens LM, et al. Epilepsy and mental retardation patients’ guardians agree to the publication. limited to females: an under-recognized disorder. Brain. 2008;131(Pt 4):918–27. 19. Tan C, Shard C, Ranieri E, et al. Mutations of protocadherin 19 in female Competing interests epilepsy (PCDH19-FE) lead to allopregnanolone deficiency. Hum Mol Genet. The authors declare that they have no competing interests. 2015;24(18):5250–9. Tan et al. BMC Medical Genetics (2018) 19:92 Page 8 of 8 20. Stosser MB, Lindy AS, Butler E, et al. High frequency of mosaic pathogenic variants in genes causing epilepsy-related neurodevelopmental disorders. Genet Med. 2018;20(4):403–10. 21. Carvill GL, Heavin SB, Yendle SC, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45(7):825–30. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Medical Genetics Springer Journals

Chinese cases of early infantile epileptic encephalopathy: a novel mutation in the PCDH19 gene was proved in a mosaic male- case report

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Abstract

Background: The link between the protocadherin-19 (PCDH19) gene and epilepsy suggests that an unusual form of X-linked inheritance affects females but is transmitted through asymptomatic males. Individuals with epilepsy associated with mutations in the PCDH19 gene display generalized or focal seizures with or without fever sensitivity. The clinical manifestation of the condition ranges from mild to severe, resulting in intellectual disability and behavioural disturbance. In the present study, we assessed mutations in the PCDH19 gene and the clinical features of a group of Chinese patients with early infantile epileptic encephalopathy and aimed to provide further insight into the understanding of epilepsy and mental retardation limited to females (EFMR; MIM 300088). Case Presentation: We described three variations in the PCDH19 gene in Chinese patients with epilepsy who developed generalized seizures occurring in clusters with or without triggering by fever. Candidate genes were screened for mutations that cause epilepsy and related paroxysmal or nervous system diseases in the coding exons and intron–exon boundaries using polymerase chain reaction (PCR) of genomic deoxyribonucleic acid (DNA) followed by sequencing. The variations were sequenced using next-generation sequencing technology and verified with first-generation sequencing. Exome sequencing of a multigene epilepsy panel revealed three mutations in the PCDH19 gene in a mosaic male and two unrelated females. These included a frameshift mutation c.1508_1509insT (p.Thr504HisfsTer19), a missense mutation c.1681C > T (p.Pro561Ser) and a nonsense mutation c.918C > G (p.Tyr306Ter). Of the three mutations in the PCDH19 gene associated with early infantile epileptic encephalopathy, the frameshift variation in a mosaic male is novel and de novo, the missense variation is de novo and is the second ever reported in females, and the nonsense variation was inherited from the paternal line and is the first example discovered in a female. Conclusions: The results from our current study provide new insight into and perspectives for the molecular genetic link between epilepsy and PCDH19 alterations. Moreover, our new findings of the male mosaic variant broaden the spectrum of PCDH19-related epilepsy and provide a new understanding of this complex genetic disorder. Keywords: PCDH19, Infantile epilepsy, Clinical manifestations, Gene variations * Correspondence: zbchen0532@126.com Yuxia Tan, Mei Hou and Shaochun Ma contributed equally to this work. Department of Pediatrics, The Affiliated Hospital of Qingdao University, No. 59, Haier Road, Qingdao 266000, China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tan et al. BMC Medical Genetics (2018) 19:92 Page 2 of 8 Background inheritance and the pathogenic hypothesis associated with Epilepsy and mental retardation limited to females the cellular interference mechanism. However, following (EFMR; MIM 300088), first reported by Juberg et al. the report of a male with a mosaic PCDH19 deletion [6], a (1971), affects females but is transmitted through un- small number of recent studies have described several al- affected males, following an unusual X-linked form of terations of the PCDH19 gene in mosaic male patients in inheritance [1]. EFMR, also known as early infantile epi- succession [14–17]. leptic encephalopathy-9 (EIEE9, OMIM# 300088), is a Here, we present evidence of three mutations of the genetic disorder, of which the de novo or familial hetero- PCDH19 gene in a mosaic male and two unrelated fe- zygous variation of the PCDH19 gene (OMIM 300460) males in Chinese individuals with epilepsy, further con- is forecasted to be the second most common cause in tributing to the clinical understanding of EFMR in addition to variations of the sodium voltage-gated chan- relation to the PCDH19 gene. nel alpha subunit 1 (SCN1A) gene [2–5]. Since the initial description of the PCDH19 gene, the evidence of a link Case presentation between the clinical features of epilepsy and de novo or We recruited three Chinese children with epilepsy familial mutations in the PCDH19 gene has increased. treated in the Qingdao Women & Children’s Hospital These links include infantile onset of multiple seizure between March 2016 and April 2017. The clinical diag- types, such as Dravet syndrome, generalized or focal nosis was made by clinical geneticists. Additional clinical epilepsy with or without fever sensitivity, and epilepsy information relevant to the diagnosis was provided by of variable severity in females with or without intel- the parents and the caregivers. The CARE guidelines lectual disability, behavioural disturbance or psychiatric were followed in reporting these cases. Two millilitres of symptoms [2, 6–8]. venous blood was collected from each patient and each The PCDH19 gene is located on the X chromosome parent of the subject upon signed informed consent. (Xq22.1) and encodes protocadherin-19. This is a Then, the blood samples were sent to Beijing Kangso calcium-dependent adhesion molecule belonging to the Medical Inspection for gene testing: nervous system dis- δ2-protocadherin (pcdhs) subclass of the cadherin eases “big bag” for patient 1 (a total of 1906 genes) and (cdhs) superfamily [9]. The PCDH19 gene shows an un- epilepsy and related paroxysmal diseases for patient 2 usual X-linked form of inheritance affecting only fe- and patient 3 (a total of 518 genes). Genomic DNA from males but being transmitted via asymptomatic males, blood samples was extracted using the Qiagen FlexiGene which implies that it is pathogenic in heterozygous mu- DNA kit (Qiagen, Germany) following the manufacture’s tated females but non-pathogenic in hemizygous mutated guidelines. Candidate genes were screened for mutations males [6, 10]. PCDH19 has been shown to be expressed in in the coding exons and intron–exon boundaries using the central nervous system and is possibly involved in a PCR of genomic DNA followed by sequencing. Primer se- cellular interference mechanism that affects brain devel- quences and PCR conditions are available upon request. opment, neuronal connections, and intracellular signal The variations were sequenced with next-generation transductions at the synaptic membrane [3, 11, 12]. sequencing and verified with first-generation sequen- Variations in the PCDH19 gene were first reported by cing. Detailed experimental methods can be found in Dibbens et al. (2008) in several families with the EFMR Additional file 1. disorder [10]. Depienne et al. (2009) discovered that sub- jects with PCDH19-related disease might be normal dur- Patient 1 ing early development but experience seizure onset Patient 1 is a 27-month-old male. He was born via nor- occurring in clusters with fever sensitivity, an observa- mal vaginal delivery at full-term. He weighed 3.0 kg at tion similarly seen with Dravet syndrome (DS) [6]. An birth. No neurological problems were noted during rou- increasing number of female epilepsy patients with tine examinations at birth. The pregnancy and perinatal PCDH19 mutations have been reported over recent history were unremarkable. He was the first child of years, and the clinical spectrum of diseases associated non-consanguineous parents. Family history was non- with PCDH19 gene mutations has also expanded, in- contributory. At the age of 7 months, his first recurrent, cluding patients displaying focal or generalized seizures afebrile generalized tonic seizures (TS) were noted. The recurring in clusters or isolation with or without febrile video electroencephalogram (VEEG) showed sharp, trigger, ranging from mild to severe, with or without spike waves with partial origin at right frontal regions cognitive impairment, behavioural disturbance, and psy- and high voltage slow background. The brain magnetic chiatric symptoms [2, 4, 11, 13]. resonance imaging (MRI) was normal. Following treat- Up to now, the molecular genetic study for PCDH19-re- ment with valproate (VPA) and topiramate (TPM) for lated epilepsy has been focused on females. Male subjects 5 months, his cluster seizures remained and occurred were generally excluded because of the unusual X-linked from time to time. After adjusting the antiepileptic Tan et al. BMC Medical Genetics (2018) 19:92 Page 3 of 8 drugs (AED) to VPA and phenobarbital (PB), the con- both strands covering the variant on Integrate Genome trol of seizures remained unsatisfactory. After 9 months Viewer are shown in more detail in Additional file 2. from the initial onset, oxcarbazepine (OXC) was added. Then, his seizures were gradually controlled with VPA, PB and OXC, and he remained seizure-free for 3 months till Patient 2 the last follow-up. Patient 2 is a 34-month-old female. She was born at In his development, his early psychomotor skills were full-term via normal vaginal delivery without distress unremarkable. However, he showed signs of intellectual and dysmorphic features. At birth, she weighed 3.3 kg, impairment and behavioural disturbance following the and neurologic examination suggested no abnormalities. onset of his seizures. His head control was complete at The perinatal history, pregnancy and neonatal course 2 months. He rolled at 4 months, sat up unsupported were all unremarkable. She is the only child to her healthy at 7 months, climbed at 11 months, and walked inde- parents. She had no family history of neurological disease. pendently at 13 months. At present, he runs unsteadily Her first seizure displaying a tonic seizure (TS) was noted and falls easily when standing up from squatting. He during a febrile illness at the age of 14 months; the EEG spoke his first word at age 15 months and had only and brain computed tomography (CT) then were normal. three purposeful words by 24 months. He was unable By 19 months of age, she developed a cluster of febrile sei- to act following orders or to express his wants accur- zures lasting for approximately 10 s each time, with sei- ately. He receives language training and physical therapy zures occurring 6 times in 36 h. At the age of 31 months, at present. a second cluster appeared, triggered by fever. The VEEG By clinical exome sequencing, patient 1 was found to and brain MRI were also normal at this onset. Her psy- have a frameshift mutation in the PCDH19 gene: a thy- chomotor development was unremarkable. Her seizure mine (T) inserted into the encoding region between nu- was gradually controlled after being given TPM. cleotides 1508 and 1509 (c.1508_1509insT), suggesting a Clinical exome sequencing revealed a missense muta- mosaic nucleotide mutation. The mutation led to the tion in the PCDH19 gene: a cytosine to thymine (C > T) synthesis of amino acid beginning from amino acid 504 nucleotide change at position 1681 (c.1681C > T) in pa- of Thr changed and ending in the nineteenth amino acid tient 2, a heterozygous nucleotide mutation causing after the change (p.Thr504HisfsTer19). This mutation amino acid 561 to change from Pro to Ser (p.Pro561Ser). was a de novo variation. The male’s parents showed no This mutation was de novo, and this alteration was not abnormalities (Fig. 1). The Sanger sequencing results of found in her parents (Fig. 2). Fig. 1 The genetic map and mutation sequence chromatograms in the PCDH19 gene of family 1. Black square: affected mutation-carrying male; white square: male without PCDH19 mutation; white circle: female without PCDH19 mutation. The red arrows indicate the location of the identified mutation Tan et al. BMC Medical Genetics (2018) 19:92 Page 4 of 8 Fig. 2 The genetic map and mutation sequence chromatograms in the PCDH19 gene of family 2. Black circle: affected mutation-carrying female; white circle: female without PCDH19 mutation; white square: male without PCDH19 mutation. The red arrows indicate the location of the identified mutation Patient 3 and epileptogenic characters of the three patients carry- Patient 3 is a 39-month-old female. She was born at ing PCDH19 variations are described in Table 1. full-term via a normal vaginal delivery. She weighed In a 2016 study, Terracciano et al. revealed a male pa- 3.18 kg at birth, with no apparent neurological abnormal- tient with the nonsense mutation c.918C > G (p.Tyr306- ities. The prenatal history and neonatal development were Ter), the same position as patient 3 in our cohort. Here, normal. She is the only child of non-consanguineous par- we compared the findings from our study with those of ents. Her grandmother has a history of seizures. Her seiz- Terracciano et al. [14]. Of the four patients, seizures ure onset was at 20 months when she experienced a started within the first year of life for two patients and cluster of afebrile generalized tonic and clonic seizures after the first year of life for the other two, with an aver- (GTCS), with seizures occurring 6 times in a day. The age age of onset of 12 months (6–20 months). All pa- VEEG and brain MRI showed no abnormality at that time. tients had generalized seizures or focal seizures with After a one-month seizure-free period, she presented with secondary generalization (SG), characterizing the onset a second cluster of afebrile generalized seizures. The of epilepsy. Cluster seizures occurred in all subjects, and VEEG showed sharp slow wave emission mainly in the patient 4 had confirmed epileptic status. Two patients right occipital region. Treatment with levetiracetam re- had seizures associated with fever sensitivity at onset, sulted in gradual control of seizures. She requires no other and the other two were afebrile onset. EEG was normal significant medical attention. in patients 2 and 4 but showed abnormality in patients 1 For patient 3, clinical exome sequencing suggested a and 3. Brain MRI had no special findings. Psychiatric nonsense mutation in the PCDH19 gene: acytosine to symptoms were absent from all the patients. However, guanine (C > G) nucleotide change at nucleotide 918 patients 1 and 4 developed intellectual impairment and (c.918C > G), a heterozygous nucleotide mutation. The behavioural disturbance. Patient 1 had recurrent epilepsy mutation changed amino acid 306 from Tyr into a ter- despite being treated with multiple anti-epileptic drugs, mination codon (p.Tyr306Ter). The mutation was inher- suggesting that the seizures related to PCDH19 varia- ited from the paternal line. The girl’s father was tions were difficult to control to a certain degree. identified to be a hemizygote, but her mother did not Despite the many clinical manifestations of PCDH19-re- carry this alteration (Fig. 3). lated epilepsy, the disease shares some common character- istics, namely, onset at the age of infancy and babyhood, generalized seizures and cluster seizures [3]. Generalized Discussion and Conclusions tonic seizures (TS), tonic-clonic seizures (GTCS) or focal We identified three mutations of PCDH19-related epi- seizures with SG occurring in clusters with or without lepsy in a cohort of Chinese children. The clinical data fever sensitivity are the common seizure types. Other Tan et al. BMC Medical Genetics (2018) 19:92 Page 5 of 8 Fig. 3 The genetic map and mutation sequence chromatograms in the PCDH19 gene of family 3. Black circle: affected mutation-carrying female; white circle: female without PCDH19 mutation; a dot in a white square: asymptomatic mutation-carrying male. The red arrows indicate the location of the identified mutation Table 1 Clinical data of patients with epilepsy carrying PCDH19 mutations Patient number Male patient 1 Female patient 2 Female patient 3 Male patient (Terracciano et al. 2016) [14] PCDH19 mutation c.1508_1509insT c.1681C > T c.918C > G c.918C > G p.Thr504HisfsTer19 p.Pro561Ser p.Tyr306Ter p.Tyr306* Mutation type Frameshift mutation Missense mutation Nonsense mutation Nonsense mutation Sex Male Female Female Male Present age 2 y 3 m 2 y 10 m 3 y 3 m 4 y Birth weight 3.0 kg 3.3 kg 3.18 kg Unknown Age at onset 7 m 1 y 2 m 1 y 8 m 9 m Type of seizures at onset TS TS GTCS Focal with SG Cluster occurrence Yes Yes Yes Yes Fever sensitivity No Yes No Yes Status epilepticus No No No Yes EEG Abnormal Normal Abnormal Normal MRI Normal Normal Normal Normal Intellectual disability Yes No No Borderline Psychiatric symptoms No No No No Behavioural disturbance Yes No No Yes Current AED Phenobarbital, valproate, Topiramate Levetiracetam Valproic acid oxcarbazepine Persistence of seizures with AED Yes No No No Transmission De novo De novo Paternal inheritance De novo Tan et al. BMC Medical Genetics (2018) 19:92 Page 6 of 8 seizure types, such as myoclonic seizures, atonic seizures in the splice site of intron 1 [14, 16, 17, 20]. Neverthe- and atypical absences, are rare. Intellectual development less, here, we attest the first male with the PCDH19 gene abnormalities vary from normal to severe impairment. Pa- pathogenic variant c.1508_1509insT, which contributes tients may or may not display psychiatric symptoms and to further explanation of this complex and an interesting behavioural disturbance [4, 13]. genetic disorder. Of the four patients, three genetic alterations were de The missense mutation c.1681C > T (p.Pro561Ser) was novo, and one was inherited from her asymptomatic reported in a female patient by Carvill in 2013 [21] and father. PCDH19 mutations in most patients are sporadic the nonsense mutation c.918C > G (p.Tyr306Ter) in a and de novo, whilst some are of paternal inheritance. mosaic male patient by Terracciano in 2016 [14]. These This makes it difficult to recognize the pattern of inher- reports together with our findings collectively suggest itance [18, 19]. To determine the complete feature of that PCDH19 gene mutations have a significant associ- EFMR, more patients need to be studied. ation with epilepsy. The missense alteration was de With the progress of genetic detection technology, novo. The nonsense mutation was transmitted from an thus far, over 150 PCDH19 mutations have been identi- asymptomatic father, but the transmitting male showed fied, featuring small deletion, small insertion, nonsense, no abnormalities because of the unusual X-linked inher- missense, microduplication, intragenic deletion, splice itance of PCDH19. site mutation and whole gene deletion. The great major- The full-length mRNA of the PCDH19 gene is 9765 ity of the variations (over 90%) are located in exon 1, the nucleotides, encoding a 1148 amino acid protein. The largest exon encoding the extracellular cadherin domain PCDH19 gene consists of six exons; exon 1 is the lar- [5]. In our study, we report three mutations located in gest exon encoding a signal peptide, the whole extra- exon 1, including a frameshift mutation, a missense mu- cellular domain and a short transmembrane domain tation and a nonsense mutation. One mutation was (TM), including six repeats of EC cadherin regulating novel, and two were reported recently. The frameshift al- cell-cell interactions [10]. All three mutations we iden- teration c.1508_1509insT (p.Thr504HisfsTer19) was tified in the present study were found in exon 1 of the identified in a mosaic male, which was a novel and de PCDH19 gene, with the nonsense mutation c.918C > G novo mutation. This discovery expands the spectrum of (p.Tyr306Ter) in EC3 and both the frameshift muta- PCDH19-related epilepsy in males. A brief review of mo- tion c.1508_1509insT (p.Thr504HisfsTer19) and the saic males in terms of the PCDH19 gene are as follows: missense mutation c.1681C > T (p.Pro561Ser) in EC5 Stosser et al. (2017) identified five males with mosaic (Fig. 4). The nonsense and missense mutations were pathogenic variants presenting with epilepsy with or predicted to be deleterious in our report and were pre- without signs of developmental delay, similar to female viously reported [14, 21]. Although the frameshift alter- patients with PCDH19 pathogenic variants [20]. Other ation was novel, the frameshift nature of c.1508_1509insT researchers also reported several variants in mosaic and the predicted introduction of a termination codon of males, and these male patients with mosaic mutations p.Thr504HisfsTer19 are predicted to be harmful. More- showed similar clinical features of epileptic encephalop- over, the extracellular domains of six EC cadherin repeats athy to those presented in PCDH19 affected females. were highly conserved in the amino acid sequence and The previously described pathogenic mutations in mo- shown to be critical for normal protein function. Hence, saic males contain frameshift mutation, nonsense vari- our study added further evidence to the pathology of ant, missense mutation of exon 1 and alteration located these mutations. Fig. 4 Schematic diagram of the point mutations identified in the PCDH19 gene. SP: signal peptide; EC: extracellular cadherin domain; TM: transmembrane domain; CM1 and CM2; cytoplasmic domains 1 and 2 Tan et al. BMC Medical Genetics (2018) 19:92 Page 7 of 8 In conclusion, we report three mutations in the Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in PCDH19 gene associated with early infantile epileptic en- published maps and institutional affiliations. cephalopathy. Of the three mutations, one variation was in a mosaic male and is a novel finding, the missense vari- Author details Department of Pediatrics, The Affiliated Hospital of Qingdao University, No. ation is de novo and is the second female case reported, 59, Haier Road, Qingdao 266000, China. Department of Pediatrics, Zibo City and the nonsense variation is of paternal inheritance and Maternal and Child Health Hospital, Zibo City 255029, Shandong Province, is the first report in a female. Our report provides further China. Department of Pediatric Rehabilitation, The Affiliated Qingdao Women & Children’s Hospital of Qingdao University, Qingdao 266034, China. proof and opens a new point of view for the molecular Department of Pediatric Neurology, The Affiliated Qingdao Women & genetic diagnosis of patients with a special type of epi- Children’s Hospital of Qingdao University, Qingdao 266034, China. lepsy. Perhaps more significantly is that the new mutation Received: 16 February 2018 Accepted: 30 May 2018 discovered in the mosaic male would expand the current knowledge about EIEE9 and guide diagnosis and targeted therapy in male patients. Finally, there are notable limita- References tions to this study, including the relatively small sample 1. Juberg RC, Hellman CD. A new familial form of convulsive disorder and size. However, this study has certainly opened a new fron- mental retardation limited to females. J Pediatr. 1971;79(5):726–32. tier for further investigation into early infantile epileptic 2. Depienne C, Trouillard O, Bouteiller D, et al. Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females. Hum encephalopathy related to the PCDH19 gene in the future. Mutat. 2011;32(1):E1959–75. 3. Depienne C, LeGuern E. PCDH19-related infantile epileptic Additional files encephalopathy: an unusual X-linked inheritance disorder. Hum Mutat. 2012;33(4):627–34. 4. van Harssel JJ, Weckhuysen S, van Kempen MJ, et al. Clinical and genetic Additional file 1: Detailed experimental methods for gene testing. aspects of PCDH19-related epilepsy syndromes and the possible role of (DOC 31 kb) PCDH19 mutations in males with autism spectrum disorders. Neurogenetics. Additional file 2: The Sanger sequencing results of both strands 2013;14(1):23–34. covering the variant on Integrate Genome Viewer for patient 1.(DOC 66 5. Duszyc K, Terczynska I, Hoffman-Zacharska D. Epilepsy and mental kb) retardation restricted to females: X-linked epileptic infantile encephalopathy of unusual inheritance. J Appl Genet. 2015;56(1):49–56. 6. Depienne C, Bouteiller D, Keren B, et al. Sporadic infantile epileptic Abbreviations encephalopathy caused by mutations in PCDH19 resembles Dravet AED: Antiepileptic drugs; CT: Computed tomography; DNA: Deoxyribonucleic syndrome but mainly affects females. PLoS Genet. 2009;5(2):e1000381. acid; EFMR: Epilepsy and mental retardation limited to females; 7. Marini C, Mei D, Parmeggiani L, et al. Protocadherin 19 mutations in girls GTCS: Generalized tonic and clonic seizures; MRI: Brain magnetic resonance with infantile-onset epilepsy. Neurology. 2010;75(7):646–53. imaging; OXC: Oxcarbazepine; PB: Phenobarbital; PCDH19: Protocadherin-19; PCR: Polymerase chain reaction; SCN1A: Sodium voltage-gated channel alpha sub- 8. Specchio N, Marini C, Terracciano A, et al. Spectrum of phenotypes in unit 1; TPM: Topiramate; TS: Tonic seizures; VEEG: Video electroencephalogram; female patients with epilepsy due to protocadherin 19 mutations. Epilepsia. VPA: Valproate 2011;52(7):1251–7. 9. Redies C, Vanhalst K, Fv R. delta-Protocadherins: unique structures and Acknowledgements functions. Cell Mol Life Sci. 2005;62(23):2840–52. This study was technically supported by Kangso Medical Inspection, Beijing, 10. Dibbens LM, Tarpey PS, Hynes K, et al. X-linked protocadherin 19 mutations China. The authors thank the patients and their parents. cause female-limited epilepsy and cognitive impairment. Nat Genet. 2008; 40(6):776–81. 11. Hynes K, Tarpey P, Dibbens LM, et al. Epilepsy and mental retardation Funding limited to females with PCDH19 mutations can present de novo or in single This study was financially supported by the Natural Science Fund of China generation families. J Med Genet. 2010;47(3):211–6. (grant number 31640047). 12. Dibbens LM, Kneen R, Bayly MA, et al. Recurrence risk of epilepsy and mental retardation in females due to parental mosaicism of PCDH19 Availability of data and materials The datasets used and/or analysed during the current study are available mutations. Neurology. 2011;76(17):1514–9. from the corresponding author upon reasonable request. 13. Marini C, Darra F, Specchio N, et al. Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy. Epilepsia. 2012;53(12): Authors’ contributions 2111–9. ZBC conceived the study. YXT wrote the manuscript. MH and SCM collected 14. Terracciano A, Trivisano M, Cusmai R, et al. PCDH19-related epilepsy in two patient data. PPL revised the manuscript. SGX, YW and LPC facilitated all mosaic male patients. Epilepsia. 2016;57(3):e51–5. project-related work. All authors have read and agreed to the manuscript. 15. Perez D, Hsieh DT, Rohena L. Somatic mosaicism of PCDH19 in a male with All authors declare responsibility for all aspects of this work. early infantile epileptic encephalopathy and review of the literature. Am J Med Genet A. 2017;173(6):1625–30. Ethics approval and consent to participate 16. Thiffault I, Farrow E, Smith L, et al. PCDH19-related epileptic encephalopathy This study was approved by the Ethics Committee of the Affiliated Hospital in a male mosaic for a truncating variant. Am J Med Genet A. 2016;170(6): of Qingdao University. Written informed consent for participating in the 1585–9. study was obtained from all the patients’ parents. 17. de Lange IM, Rump P, Neuteboom RF, et al. Male patients affected by mosaic PCDH19 mutations: five new cases. Neurogenetics. 2017;18(3): Consent for publication 147–53. Informed consent was obtained from all subjects’ parents in this study. All the 18. Scheffer IE, Turner SJ, Dibbens LM, et al. Epilepsy and mental retardation patients’ guardians agree to the publication. limited to females: an under-recognized disorder. Brain. 2008;131(Pt 4):918–27. 19. Tan C, Shard C, Ranieri E, et al. Mutations of protocadherin 19 in female Competing interests epilepsy (PCDH19-FE) lead to allopregnanolone deficiency. Hum Mol Genet. The authors declare that they have no competing interests. 2015;24(18):5250–9. Tan et al. BMC Medical Genetics (2018) 19:92 Page 8 of 8 20. Stosser MB, Lindy AS, Butler E, et al. High frequency of mosaic pathogenic variants in genes causing epilepsy-related neurodevelopmental disorders. Genet Med. 2018;20(4):403–10. 21. Carvill GL, Heavin SB, Yendle SC, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45(7):825–30.

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BMC Medical GeneticsSpringer Journals

Published: Jun 4, 2018

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