PCDH19-related epilepsy in mosaic males: The phenotypic implication of genotype and variant allele frequency
ObjectiveTo analyze the genotypes and phenotypes of mosaic male patients with PCDH19-related epilepsy (PCDH19-RE) and explore the correlation between genotype, variant allele frequency (VAF), and phenotypic severity.MethodsClinical data and peripheral blood samples of 11 male mosaic patients were co...
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| Format: | Article |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2022.1041509/full |
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| author | Yi Chen Xiaoxu Yang Jiaoyang Chen Xiaoling Yang Ying Yang Aijie Liu Xiaoli Zhang Wenjuan Wu Dan Sun Zhixian Yang Yuwu Jiang Yuehua Zhang |
| author_facet | Yi Chen Xiaoxu Yang Jiaoyang Chen Xiaoling Yang Ying Yang Aijie Liu Xiaoli Zhang Wenjuan Wu Dan Sun Zhixian Yang Yuwu Jiang Yuehua Zhang |
| author_sort | Yi Chen |
| collection | DOAJ |
| description | ObjectiveTo analyze the genotypes and phenotypes of mosaic male patients with PCDH19-related epilepsy (PCDH19-RE) and explore the correlation between genotype, variant allele frequency (VAF), and phenotypic severity.MethodsClinical data and peripheral blood samples of 11 male mosaic patients were collected and analyzed in our study. The VAF of the PCDH19 gene from peripheral blood was quantified using amplicon-based deep sequencing. Additional 20 mosaic male patients with PCDH19-RE were collected from the published literature, with 10 patients whose VAFs of the PCDH19 gene were available for analytic purposes.ResultsIn our cohort of 11 patients, 10 variants were identified, and four were novel. The VAF of the PCDH19 gene from peripheral blood ranged from 27 to 90%. The median seizure onset age was 6 months (range: 4–9 months). Clinical manifestations included cluster seizures (100%), fever sensitivity (73%), focal seizures (91%), developmental delay/intellectual disability (DD/ID, 82%), and autistic features (45%). Thirty-one mosaic male patients collected from our cohort and the literature developed seizures mostly (87%) within one year of age. Variant types included missense variants (42%), truncating variants (52%), splice variants (3%), and whole PCDH19 deletion (3%). Among 21 patients with a definite VAF from our cohort and the literature, nine had a low VAF ( ≤ 50%) and 12 had a high VAF (> 50%). Seventy-five percent of variants from the high VAF group were missense, whereas 89% of those from the low VAF group were truncations. The median seizure onset age was 6 months in the low VAF group and 9 months in the high VAF group (p = 0.018). Forty-four percent (4/9) of patients from the low VAF group achieved seizure-free for ≥1 year, whereas none of the 12 patients from the high VAF group did (p = 0.021). DD/ID was present in 83% (10/12) of the high VAF group and 56% (5/9) of the low VAF group (p = 0.331).ConclusionThe predominant variant types were truncating and missense variants. Missense variants tended to have higher VAFs. Patients with a high VAF were more likely to have a more severe epileptic phenotype. Our findings shed light on the phenotypic implications of VAF in mosaic males with PCDH19-RE. |
| first_indexed | 2024-04-12T00:03:26Z |
| format | Article |
| id | doaj.art-f89026c6f89b4d4797cfdd5d642dcf46 |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-04-12T00:03:26Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neurology |
| spelling | doaj.art-f89026c6f89b4d4797cfdd5d642dcf462022-12-22T03:56:11ZengFrontiers Media S.A.Frontiers in Neurology1664-22952022-11-011310.3389/fneur.2022.10415091041509PCDH19-related epilepsy in mosaic males: The phenotypic implication of genotype and variant allele frequencyYi Chen0Xiaoxu Yang1Jiaoyang Chen2Xiaoling Yang3Ying Yang4Aijie Liu5Xiaoli Zhang6Wenjuan Wu7Dan Sun8Zhixian Yang9Yuwu Jiang10Yuehua Zhang11Department of Pediatrics, Peking University First Hospital, Beijing, ChinaCenter for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, ChinaDepartment of Pediatrics, Peking University First Hospital, Beijing, ChinaDepartment of Pediatrics, Peking University First Hospital, Beijing, ChinaDepartment of Pediatrics, Peking University First Hospital, Beijing, ChinaDepartment of Pediatric Neurology, Capital Institute of Pediatrics, Beijing, ChinaDepartment of Pediatrics, The Third Affiliated Hospital of Zheng Zhou University, Zhengzhou, ChinaDepartment of Neurology, Hebei Children's Hospital, Shijiazhuang, ChinaDepartment of Neurology, Wuhan Children's Hospital, Wuhan, ChinaDepartment of Pediatrics, Peking University First Hospital, Beijing, ChinaDepartment of Pediatrics, Peking University First Hospital, Beijing, ChinaDepartment of Pediatrics, Peking University First Hospital, Beijing, ChinaObjectiveTo analyze the genotypes and phenotypes of mosaic male patients with PCDH19-related epilepsy (PCDH19-RE) and explore the correlation between genotype, variant allele frequency (VAF), and phenotypic severity.MethodsClinical data and peripheral blood samples of 11 male mosaic patients were collected and analyzed in our study. The VAF of the PCDH19 gene from peripheral blood was quantified using amplicon-based deep sequencing. Additional 20 mosaic male patients with PCDH19-RE were collected from the published literature, with 10 patients whose VAFs of the PCDH19 gene were available for analytic purposes.ResultsIn our cohort of 11 patients, 10 variants were identified, and four were novel. The VAF of the PCDH19 gene from peripheral blood ranged from 27 to 90%. The median seizure onset age was 6 months (range: 4–9 months). Clinical manifestations included cluster seizures (100%), fever sensitivity (73%), focal seizures (91%), developmental delay/intellectual disability (DD/ID, 82%), and autistic features (45%). Thirty-one mosaic male patients collected from our cohort and the literature developed seizures mostly (87%) within one year of age. Variant types included missense variants (42%), truncating variants (52%), splice variants (3%), and whole PCDH19 deletion (3%). Among 21 patients with a definite VAF from our cohort and the literature, nine had a low VAF ( ≤ 50%) and 12 had a high VAF (> 50%). Seventy-five percent of variants from the high VAF group were missense, whereas 89% of those from the low VAF group were truncations. The median seizure onset age was 6 months in the low VAF group and 9 months in the high VAF group (p = 0.018). Forty-four percent (4/9) of patients from the low VAF group achieved seizure-free for ≥1 year, whereas none of the 12 patients from the high VAF group did (p = 0.021). DD/ID was present in 83% (10/12) of the high VAF group and 56% (5/9) of the low VAF group (p = 0.331).ConclusionThe predominant variant types were truncating and missense variants. Missense variants tended to have higher VAFs. Patients with a high VAF were more likely to have a more severe epileptic phenotype. Our findings shed light on the phenotypic implications of VAF in mosaic males with PCDH19-RE.https://www.frontiersin.org/articles/10.3389/fneur.2022.1041509/fullPCDH19 genemalemosaicismepilepsyphenotypegenotype |
| spellingShingle | Yi Chen Xiaoxu Yang Jiaoyang Chen Xiaoling Yang Ying Yang Aijie Liu Xiaoli Zhang Wenjuan Wu Dan Sun Zhixian Yang Yuwu Jiang Yuehua Zhang PCDH19-related epilepsy in mosaic males: The phenotypic implication of genotype and variant allele frequency Frontiers in Neurology PCDH19 gene male mosaicism epilepsy phenotype genotype |
| title | PCDH19-related epilepsy in mosaic males: The phenotypic implication of genotype and variant allele frequency |
| title_full | PCDH19-related epilepsy in mosaic males: The phenotypic implication of genotype and variant allele frequency |
| title_fullStr | PCDH19-related epilepsy in mosaic males: The phenotypic implication of genotype and variant allele frequency |
| title_full_unstemmed | PCDH19-related epilepsy in mosaic males: The phenotypic implication of genotype and variant allele frequency |
| title_short | PCDH19-related epilepsy in mosaic males: The phenotypic implication of genotype and variant allele frequency |
| title_sort | pcdh19 related epilepsy in mosaic males the phenotypic implication of genotype and variant allele frequency |
| topic | PCDH19 gene male mosaicism epilepsy phenotype genotype |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2022.1041509/full |
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