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

Developmental and epileptic encephalopathy 9 (DEE9, MIM #300088) is an early onset seizure disorder associated with cognitive impairment and behavioral disturbances. It is caused by mutation in protocadherin 19 with an unusual X-linked inheritance selectively involving heterozygous females or mosaic...

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Bibliographic Details
Published in:Clinica chimica acta 2021-10, Vol.521, p.285-288
Main Authors: Hung, Ling-Yin, Subramaniam, Shreenidhi Ranganatha, Tong, Tsz-Yan Tammy, Chan, Wing-Ki, Yau, Eric Kin-Cheong, Ching, Chor-Kwan
Format: Article
Language:English
Subjects:
Cadherins - genetics
Cellular interference
China
Chromosomes
Developmental and epileptic encephalopathy
Epilepsy - genetics
Female
Genes, X-Linked
Humans
Male
Mutation
PCDH19
Protocadherin 19
Protocadherins
X-chromosome inactivation
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Summary:Developmental and epileptic encephalopathy 9 (DEE9, MIM #300088) is an early onset seizure disorder associated with cognitive impairment and behavioral disturbances. It is caused by mutation in protocadherin 19 with an unusual X-linked inheritance selectively involving heterozygous females or mosaic hemizygous males, while hemizygous males are unaffected. Cellular interference was the postulated mechanism underlying the unusual inheritance pattern. We report a Chinese girl who presented with severe treatment refractory seizures at 26 months of age and was found heterozygous for a novel likely pathogenic missense variant NM_001184880.2:c.488T>A p.(Val163Glu) in PCDH19. Her younger sister, who was also heterozygous for the variant, was asymptomatic with normal development at the time of reporting at 37 months of age. X-chromosome inactivation study by androgen receptor gene methylation assay in DNA from peripheral leukocytes was performed which demonstrated somewhat skewed X-chromosome inactivation in the proband and extremely skewed X-chromosome inactivation in the asymptomatic younger sibling. PCDH19-related seizure disorder has incomplete penetrance and variable expressivity. Further studies are required to determine the potential role of X-chromosome inactivation on the phenotypic variability and patient outcomes. Liberal referral for PCDH19 testing among female patients with early-onset seizures should be considered to enhance case detection.
ISSN:0009-8981
1873-3492
DOI:10.1016/j.cca.2021.07.023