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Epilepsy Res. 2018 Sep;145:89-92. doi: 10.1016/j.eplepsyres.2018.06.008. Epub 2018 Jun 18.

PCDH19-related epilepsy in a male with Klinefelter syndrome: Additional evidence supporting PCDH19 cellular interference disease mechanism.

Author information

1
Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
2
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, United States.
3
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
4
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, United States; Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
5
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, United States; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
6
Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
7
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, United States. Electronic address: MASSEYSL@EMAIL.CHOP.EDU.
8
Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Pathology & Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, United States. Electronic address: Ahmad.Tayoun@ajch.ae.

Abstract

Heterozygous de novo or inherited pathogenic variants in the PCDH19 gene cause a spectrum of neurodevelopmental features including developmental delay and seizures. PCDH19 epilepsy was previously known as "epilepsy and mental retardation limited to females", since the condition almost exclusively affects females. It is hypothesized that the co-existence of two populations of neurons, some with and some without PCDH19 protein expression, results in pathologically abnormal interactions between these neurons, a mechanism also referred to as cellular interference. Consequently, PCDH19-related epilepsies are inherited in an atypical X-linked pattern, such that hemizygous, non-mosaic, 46,XY males are typically unaffected, while individuals with a disease-causing PCDH19 variant, mainly heterozygous females and mosaic males, are affected. As a corollary to this hypothesis, an individual with Klinefelter syndrome (KS) (47,XXY) who has a heterozygous disease-causing PCDH19 variant should develop PCDH19-related epilepsy. Here, we report such evidence: - a male child with KS and PCDH19-related epilepsy - supporting the PCDH19 cellular interference disease hypothesis.

KEYWORDS:

Epilepsy; Klinefelter syndrome; Molecular diagnostics; PCDH19

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