<i>PCDH19</i>‐related epileptic encephalopathy in a male mosaic for a truncating variant

Thiffault, Isabelle; Farrow, Emily; Smith, Laurie D.; Lowry, Jennifer A.; Zellmer, Lee; Black, Benjamin; Abdelmoity, Ahmed; Miller, Neil; Soden, Sarah E; Saunders, Carol J.

doi:10.1002/ajmg.a.37617

Cited by 43 publications

(47 citation statements)

References 31 publications

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“…Four of the currently described male patients are the oldest reported so far (ages 10, 13 twice and 14 years old), which gives the opportunity to investigate whether PCDH19 -related phenotypes evolve the same way in male and female patients. Our current findings confirm previously reported observations of similar clinical features in male and female patients, also for older children [2, 13, 14]. Focal seizures with affective symptoms (fearful screaming) are very common in female patients and become more prevalent with an increasing age [26].…”

Section: Discussionsupporting

confidence: 92%

“…We here report five male patients with mosaic PCDH19 likely pathogenic variants, which raises the total number of described male patients to nine [2, 13, 14]. Four of the currently described male patients are the oldest reported so far (ages 10, 13 twice and 14 years old), which gives the opportunity to investigate whether PCDH19 -related phenotypes evolve the same way in male and female patients.…”

Section: Discussionmentioning

confidence: 98%

“…Only four affected mosaic male patients have been described in literature until now, the oldest being 7 years old [2, 13, 14]. Here, we report five additional male patients with mosaic PCDH19 mutations, of ages 2, 10, 13, 13 and 14 years old.…”

Section: Introductionmentioning

confidence: 84%

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Male patients affected by mosaic PCDH19 mutations: five new cases

et al. 2017

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Pathogenic variants in the PCDH19 gene are associated with epilepsy, intellectual disability (ID) and behavioural disturbances. Only heterozygous females and mosaic males are affected, likely due to a disease mechanism named cellular interference. Until now, only four affected mosaic male patients have been described in literature. Here, we report five additional male patients, of which four are older than the oldest patient reported so far. All reported patients were selected for genetic testing because of developmental delay and/or epilepsy. Custom-targeted next generation sequencing gene panels for epilepsy genes were used. Clinical data were collected from medical records. All patients were mosaic in blood for likely pathogenic variants in the PCDH19 gene. In most, clinical features were very similar to the female phenotype, with normal development before seizure onset, which occurred between 5 and 10 months of age, clustering of seizures and sensitivity to fever. Four out of five patients had mild to severe ID and behavioural problems. We reaffirm the similarity between male and female PCDH19-related phenotypes, now also in a later phase of the disorder (ages 10–14 years).Electronic supplementary materialThe online version of this article (doi:10.1007/s10048-017-0517-5) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 98%

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Male patients affected by mosaic PCDH19 mutations: five new cases

et al. 2017

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“…In particular, mutations in PCDH19 cause a female-limited form of infant-onset epilepsy (Dibbens et al, 2008; Scheffer et al, 2008; Depienne and LeGuern, 2012; van Harssel et al, 2013; Leonardi et al, 2014; Thiffault et al, 2016; Terracciano et al, 2016). Therefore, it is imperative to understand the developmental roles of PCDH19 and other non-clustered δ-protocadherins, the structural basis of homophilic adhesion by these molecules, and the functional impact of pathogenic missense mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in PCDH19 cause an X-linked, female-limited form of infant-onset epilepsy (PCDH19 female epilepsy, PCDH19-FE; OMIM 300088) that is associated with intellectual disability, as well as compulsive or aggressive behavior and autistic features (Dibbens et al, 2008; Scheffer et al, 2008; Depienne and LeGuern, 2012; van Harssel et al, 2013; Leonardi et al, 2014; Thiffault et al, 2016; Terracciano et al, 2016; Walters et al, 2014). To date, well over 100 distinct mutations in PCDH19 have been identified in epilepsy patients, making it the second most clinically relevant gene in epilepsy.…”

Section: Introductionmentioning

confidence: 99%

Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy

Cooper

Jontes

Sotomayor

2016

eLife

116

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Non-clustered δ-protocadherins are homophilic cell adhesion molecules essential for the development of the vertebrate nervous system, as several are closely linked to neurodevelopmental disorders. Mutations in protocadherin-19 (PCDH19) result in a female-limited, infant-onset form of epilepsy (PCDH19-FE). Over 100 mutations in PCDH19 have been identified in patients with PCDH19-FE, about half of which are missense mutations in the adhesive extracellular domain. Neither the mechanism of homophilic adhesion by PCDH19, nor the biochemical effects of missense mutations are understood. Here we present a crystallographic structure of the minimal adhesive fragment of the zebrafish Pcdh19 extracellular domain. This structure reveals the adhesive interface for Pcdh19, which is broadly relevant to both non-clustered δ and clustered protocadherin subfamilies. In addition, we show that several PCDH19-FE missense mutations localize to the adhesive interface and abolish Pcdh19 adhesion in in vitro assays, thus revealing the biochemical basis of their pathogenic effects during brain development.DOI: http://dx.doi.org/10.7554/eLife.18529.001

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

Perez

Hsieh²,

Rohena

2017

American J of Med Genetics Pt A

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Early infantile epileptic encephalopathy-9 (EIEE9) linked to mutations of the PCDH19 gene on the X chromosome was once thought to only affect females. Clinical features of the mutation include early onset of variable types and frequency of recurrent cluster of seizures, mild to profound intellectual disability, autistic traits, psychiatric features, and behavioral disturbances. PCDH19 pathogenic variants usually occur via an unusual X-linked pattern where heterozygous females are affected, but hemizygous males are asymptomatic. Somatic mosaic males for PCDH19 mutations are affected with EIEE9; since this discovery, four somatic mosaic males have been reported. We report the fifth confirmed male with somatic mosaicism of a novel pathogenic variant c.2147+2 T>C located in the splice site of Intron 1 of the PCDH19 gene, which continues to support that cellular interference is responsible for the pathogenic mechanism. The importance of our report is to provide significant knowledge about this rare cause of epilepsy in males, guide subsequent functional studies on males portraying an EIEE9 phenotype that have been potentially misdiagnosed, targeted therapeutic approaches, and further elucidation of this complex and interesting genetic disorder.

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PCDH19‐related epileptic encephalopathy in a male mosaic for a truncating variant

Cited by 43 publications

References 31 publications

Male patients affected by mosaic PCDH19 mutations: five new cases

Male patients affected by mosaic PCDH19 mutations: five new cases

Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy

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

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