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Hum Mutat. 2018 Dec 24. doi: 10.1002/humu.23701. [Epub ahead of print]

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

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Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris, 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, Paris, France.
IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France.
The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Al Jalila Children's Specialty Hospital, Dubai, United Arab Emirates.


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.


PCDH19; X-linked; cellular interference; epilepsy


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