X-chromosome inactivation and PCDH19-associated epileptic encephalopathy: A novel PCDH19 variant in a Chinese family

Hung, Ling-Yin; Subramaniam, Shreenidhi Ranganatha; Tong, Tsz-Yan Tammy; Chan, Wing-Ki; Yau, Eric; Ching, Chor Kwan

doi:10.1016/j.cca.2021.07.023

Cited by 8 publications

(7 citation statements)

References 14 publications

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“…The concomitant psychiatric symptoms were also diverse including hyperactive, autistic, and obsessive-compulsive features ( 7 ). In addition, epileptic encephalopathy was also reported in previous PCDH19 -FE pedigree ( 32 , 33 ).…”

Section: Discussionmentioning

confidence: 52%

“…In addition, the X chromosome inactivation was also a potential reason for phenotype heterogeneity. Previous publications revealed the association of X-inactivation and PCDH19 -related epileptic encephalopathy with skewed X-chromosome inactivation as a potential protective factor ( 32 ). Epigenetic modifications participated in the skewed X-inactivation, which preferentially inhibited the expression of wild-type or mutant proteins returning the heterozygous to the homozygous state.…”

Section: Discussionmentioning

confidence: 99%

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Genetic variants and phenotype analysis in a five-generation Chinese pedigree with PCDH19 female-limited epilepsy

Zhou

Ouyang²,

Ji³

et al. 2023

Front. Neurol.

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ObjectiveAlbeit the gene of PCDH19-FE was ascertained, the correlation of gene mutation, PCDH19 protein structure, and phenotype heterogeneity remained obscure. This study aimed to report a five-generation pedigree of seven female patients of PCDH19-FE and tried to explore whether two variants were correlated with PCDH19 protein structure and function alteration, and PCDH19-FE phenotype.MethodsWe analyzed the clinical data and genetic variants of a PCDH19-FE pedigree, to explore the phenotype heterogeneity of PCDH19-FE and underlying mechanisms. In addition to the clinical information of family members, next-generation sequencing was adopted to detect the variant sites of probands with validation by sanger sequencing. And the sanger sequencing was conducted in other patients in this pedigree. The biological conservation analysis and population polymorphism analysis of variants were also performed subsequently. The structure alteration of mutated PCDH19 protein was predicted by AlphaFold2.ResultsBased on a five-generation pedigree of PCDH19-FE, missense variants of c.695A>G and c.2760T>A in the PCDH19 gene were found in the heterozygous proband (V:1), which resulted in the change of amino acid 232 from Asn to Ser (p.Asn232Ser) and amino acid 920 from Asp to Glu (p.Asp920Glu) influencing PCDH19 function. The other six females in the pedigree (II:6, II:8, IV:3, IV:4, IV:5, IV:11) exhibited different clinical phenotypes but shared the same variant. Two males with the same variant have no clinical manifestations (III:3, III:10). The biological conservation analysis and population polymorphism analysis demonstrated the highly conservative characteristics of these two variants. AlphaFold2 predicted that the variant, p.Asp920Glu, led to the disappearance of the hydrogen bond between Asp at position 920 and His at position 919. Furthermore, the hydrogen bond between Asp920 and His919 also disappeared when the Asn amino acid mutated to Ser at position 232.ConclusionA strong genotype-phenotype heterogeneity was observed among female patients with the same genotype in our PCDH19-FE pedigree. And two missense variants, c.695A > G and c.2760T>A in the PCDH19 gene, have been identified in our pedigree. The c.2760T>A variant was a novel variant site probably related to the PCDH19-FE.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Genetic variants and phenotype analysis in a five-generation Chinese pedigree with PCDH19 female-limited epilepsy

Zhou

Ouyang²,

Ji³

et al. 2023

Front. Neurol.

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“…The authors concluded that extremely skewed XCI could affect phenotypic variability and patient outcomes. However, only five pedigrees have been reported with this condition so far (Hung et al., 2021; Zhao et al., 2021), which seems to indicate a low probability of occurrence. In our case study, we were unable to assess the XCI pattern of the fetuses due to a lack of expertise and resources for conducting an XCI assay, but we informed the woman of the corresponding risk during the genetic counseling.…”

Section: Discussionmentioning

confidence: 99%

Prenatal diagnosis of developmental and epileptic encephalopathy 9 with a 10.05‐Mb microdeletion at Xq21.31q22.1 inherited from mother: A case report and literature review

Zhu,

Liu,

Geng

et al. 2023

Molec Gen & Gen Med

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BackgroundDevelopmental and epileptic encephalopathy 9 (DEE9) is characterized by early infantile seizures and mild‐to‐severe neuropsychiatric symptoms. Despite being an X‐linked dominant disorder, DEE9 mainly affects heterozygous females or mosaic males, while hemizygous males are less affected. PCDH19 gene has been documented as the causative gene.MethodsKaryotyping analysis and copy number variation sequencing (CNV‐seq) were performed on a pregnant woman with epilepsy, together with her husband, son, and fetus.ResultsA disease‐causing microdeletion, seq[GRCh37] del(X)(q21.31q22.1) (90310001–100360000), was identified in the pregnant woman and her female fetus. The microdeletion includes the entire PCDH19 gene and is classified as “pathogenic” according to the American College of Medical Genetics and Genomics guidelines.ConclusionIn this case study, we have not only identified the epilepsy type of the woman as DEE9 but have also made an unfavorable prognosis for her fetus. Our findings from this prenatal case provide valuable clinical resources for prenatal diagnosis and genetic counseling, while also implying the potential of CNV‐seq as a viable method for uncovering PCDH19‐related epilepsy.

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“…[11,12] In females, skewed XCI can result in phenotypic heterogeneity of many X-linked disorders, disease severities were positive correlation with the activated ratio of mutated X chromosome. [13][14][15] Recently, some reports revealed that XCI might be a modifier of FVIII plasma levels, leading to the low expression of clotting factor levels and bleeding symptoms in HA carriers. [16][17][18] Correlation between XCI patterns and FVIII levels in HA female carriers with the same F8 variant contributed to further confirm this theory.…”

Section: Introductionmentioning

confidence: 99%

A novel F8 variant in a Chinese hemophilia A family and involvement of X-chromosome inactivation: A case report

Zhang

et al. 2023

Medicine

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Rationale: Hemophilia A (HA) is an X-linked recessive bleeding disorder, which shows factor VIII (FVIII) deficiency caused by genetic variant in F8 gene. Patient concerns: Males with F8 variants are affected, whereas female carriers with a wide range of FVIII levels are usually asymptomatic, it is possible that different X-chromosome inactivation (XCI) may effect the FVIII activity. Diagnoses: We identified a novel variant F8: c.6193T > G in a Chinese HA proband, it was inherited from the mother and grandmother with different FVIII levels. Interventions: We performed Androgen receptor gene (AR) assays and RT-PCR. Outcomes: AR assays revealed that the X chromosome with the F8 variant was severely skewed inactivated in the grandmother with higher FVIII levels, but not in the mother with lower FVIII levels. Further, RT-PCR of mRNA confirmed that only the wild allele of F8 was expressed in the grandmother, with lower expression in the wild allele of the mother. Lessons: Our findings suggest that F8: c.6193T > G could be the cause of HA and that XCI affected the FVIII plasma levels in female carriers.

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X-chromosome inactivation and PCDH19-associated epileptic encephalopathy: A novel PCDH19 variant in a Chinese family

Cited by 8 publications

References 14 publications

Genetic variants and phenotype analysis in a five-generation Chinese pedigree with PCDH19 female-limited epilepsy

Genetic variants and phenotype analysis in a five-generation Chinese pedigree with PCDH19 female-limited epilepsy

Prenatal diagnosis of developmental and epileptic encephalopathy 9 with a 10.05‐Mb microdeletion at Xq21.31q22.1 inherited from mother: A case report and literature review

A novel F8 variant in a Chinese hemophilia A family and involvement of X-chromosome inactivation: A case report

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