Somatic Mosaicism of <i>PCDH19</i> in a male with early infantile epileptic encephalopathy and review of the literature

Perez, Dorian; Hsieh, David T.; Rohena, Luis

doi:10.1002/ajmg.a.38233

Cited by 28 publications

(24 citation statements)

References 22 publications

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“…Thus, its original acronym EFMR seems not representative of all patients. Mosaic male patients have the same phenotype presented by female patients, as reported in literature, because they have the same hypothesized pathological mechanism of molecular interference …”

Section: Discussionsupporting

confidence: 61%

“…PCDH19‐related epilepsy was initially named “epilepsy and mental retardation limited to females” (EFMR), underlining ID and exclusive occurrence in females as the two main findings of this syndrome. Thereafter, additional clinical and genetic studies were published gathering hundreds of female patients and leading to phenotypic expansion and refinement . ID turned out to be an inconsistent finding, as approximately 30% of previously published patients and those in our cohort had normal cognitive development at last follow‐up.…”

Section: Discussionmentioning

confidence: 87%

“…The first association between PCDH19 gene mutations and epilepsy dates back to 2008 . Since then, the number of patients with PCDH19‐related epilepsy has grown and a more detailed phenotype has been delineated . PCDH19 is currently regarded as one of the most frequently mutated genes in epilepsy following SCN1A , but estimates of incidence and prevalence are lacking.…”

Section: Introductionmentioning

confidence: 99%

“…Although the PCDH19 gene is located on Xq22, this condition has an unusual X‐linked mode of inheritance sparing transmitting males, who are affected only when somatic mosaicism for the PCDH19 mutation occurs …”

Section: Introductionmentioning

confidence: 99%

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Defining the electroclinical phenotype and outcome of PCDH19‐related epilepsy: A multicenter study

et al. 2018

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Summary Objective PCDH19‐related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever‐induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19‐related epilepsy and better define the epileptic phenotype, genotype‐phenotype correlations, and related outcome‐predicting factors. Methods We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19‐related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. Results At last follow‐up (median = 12 years, range = 1.9‐42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure‐free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty‐six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). Significance We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long‐term follow‐up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Defining the electroclinical phenotype and outcome of PCDH19‐related epilepsy: A multicenter study

et al. 2018

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“…One splice donor site (1/108) variant was reported in the intron 1 splice site (c.2147+2T>C) in a mosaic male. Mosaicism was observed in blood, buccal cells, and fibroblasts in this individual who was presented with a severe phenotype (Perez, Hsieh, & Rohena, ).…”

Section: Variants and Polymorphisms Definedmentioning

confidence: 78%

A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern

et al. 2019

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The PCDH19 gene consists of six exons encoding a 1,148 amino acid transmembrane protein, Protocadherin 19, which is involved in brain development. Heterozygous pathogenic variants in this gene are inherited in an unusual X‐linked dominant pattern in which heterozygous females are affected, while hemizygous males are typically unaffected, although they pass on the pathogenic variant to each affected daughter. PCDH19‐related disorder is known to cause early‐onset epilepsy in females characterized by seizure clusters exacerbated by fever and in most cases, onset is within the first year of life. This condition was initially described in 1971 and in 2008 PCDH19 was identified as the underlying genetic etiology. This condition is the result of pathogenic loss‐of‐function variants that may be de novo or inherited from an affected mother or unaffected father and cellular interference has been hypothesized to be the culprit. Heterozygous females are symptomatic because of the presence of both wild‐type and mutant cells that interfere with one another due to the production of different surface proteins, whereas nonmosaic hemizygous males produce a homogenous population of cells. Here, we review novel pathogenic variants in the PCDH19 gene since 2012 to date, and summarize any genotype‐phenotype correlations.

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The odyssey of complex neurogenetic disorders: From undetermined to positive

Salinas

Vega

Marsili

et al. 2020

American J of Med Genetics Pt C

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The genetic and phenotypic heterogeneity of neurogenetic diseases forces patients and their families into a "diagnostic odyssey." An increase in the variability of genetic disorders and the corresponding gene-disease associations suggest the need to periodically re-evaluate the significance of variants of undetermined pathogenicity. Here, we report the diagnostic and clinical utility of Targeted Gene Panel Sequencing (TGPS) and Whole Exome Sequencing (WES) in 341 patients with suspected neurogenetic disorders from centers in Buenos Aires and Cincinnati over the last 4 years, focusing on the usefulness of reinterpreting variants previously classified as of uncertain significance. After a mean of ±2years (IC 95:0.73-3.27), approximately 30% of the variants of uncertain significance were reclassified as pathogenic. The use of next generation sequencing methods has facilitated the identification of both germline and mosaic pathogenic variants, expanding the diagnostic yield. These results demonstrate the high clinical impact of periodic reanalysis of undetermined variants in clinical neurology. K E Y W O R D S diagnostic odyssey, mosaicism, targeted gene panel sequencing, variants of unknown significance, whole exome sequencing 1 | INTRODUCTION Neurogenetic diseases encompass a vast group of entities with marked genetic and phenotypic heterogeneity. Nowadays, the process of establishing a diagnosis for this subset of neurological conditions requires extensive clinical, radiological, and genetic evaluations, often becoming a "diagnostic odyssey" for the patient and the family (Carmichael, Tsipis, Windmueller, Mandel, & Estrella, 2015). Next Generation Sequencing (NGS) has become a widely used tool for obtaining genetic diagnosis in clinical medicine (Might &

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Somatic Mosaicism of PCDH19 in a male with early infantile epileptic encephalopathy and review of the literature

Cited by 28 publications

References 22 publications

Defining the electroclinical phenotype and outcome of PCDH19‐related epilepsy: A multicenter study

Defining the electroclinical phenotype and outcome of PCDH19‐related epilepsy: A multicenter study

A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern

The odyssey of complex neurogenetic disorders: From undetermined to positive

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