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Case Reports
. 2019 Feb;56(2):81-88.
doi: 10.1136/jmedgenet-2017-105235. Epub 2018 Oct 4.

Mosaicism and incomplete penetrance of PCDH19 mutations

Aijie Liu #  1   2 , Xiaoxu Yang #  3 , Xiaoling Yang #  1 , Qixi Wu  4   5 , Jing Zhang  1 , Dan Sun  6 , Zhixian Yang  1 , Yuwu Jiang  1 , Xiru Wu  1 , Liping Wei  3 , Yuehua Zhang  1
Affiliations
Case Reports

Mosaicism and incomplete penetrance of PCDH19 mutations

Aijie Liu et al. J Med Genet. 2019 Feb.

Abstract

Background: Mutations in the PCDH19 gene have mainly been reported in female patients with epilepsy. To date, PCDH19 mutations have been reported in hundreds of females and only in 10 mosaic male epileptic patients with mosaicism.

Objective: We aimed to investigate the occurrence of mosaic PCDH19 mutations in 42 families comprising at least one patient with PCDH19-related epilepsy.

Methods: Two male patients with mosaic PCDH19 variants were identified using targeted next-generation sequencing. Forty female patients with PCDH19 variants were identified by Sanger sequencing and Multiple Ligation Probe Amplification (MLPA). Microdroplet digital PCR was used to quantify the mutant allelic fractions (MAFs) in 20 families with PCDH19 variants.

Results: Five mosaic individuals, four males and one female, were identified in total. Mosaic variant was confirmed in multiple somatic tissues from one male patient and in blood from the other male patient. Among 22 female patients harbouring a newly occurred PCDH19 variant identified by Sanger sequencing and MLPA, Sanger sequencing revealed two mosaic fathers (9%, 2/22), one with two affected daughters and the other with an affected child. Two asymptomatic mosaic fathers were confirmed as gonosomal mosaicism, with MAFs ranging from 4.16% to 37.38% and from 1.27% to 19.13%, respectively. In 11 families with apparent de novo variants, 1 female patient was identified as a mosaic with a blood MAF of 26.72%.

Conclusion: Our study provides new insights into phenotype-genotype correlations in PCDH19 related epilepsy and the finding of high-frequency mosaicism has important implications for genetic counselling.

Keywords: epilepsy; mddpcr; mosaicism; pcdh19; sequencing.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Sanger sequencing chromatograms of three mosaic probands families. (A) Sanger sequencing shows that the proband is mosaic for the PCDH19 variant (c.317T>A) in blood, buccal epithelium, saliva and urine. The variant appears to be hemizygous in his hair follicles. The variant is absent in his parents’ blood. (B) Sanger sequencing shows that the proband is mosaic for the PCDH19 variant (c.158dupT) in blood. The variant is absent in his parents’ blood. (C) Sanger sequencing shows that the proband is mosaic for the PCDH19 variant (c.2341delA) in blood. The variant is absent in her parents’ blood.
Figure 2
Figure 2
The mDDPCR results of Family 25. Detection of PCDH19 c.317T>A mutation in Proband 25’s multiple tissues (blood, buccal epithelium, saliva and urine). The wild-type and mutant population are circled in the top panels and bottom panels, respectively, with the % MUT indicated in the top right corner (MUT drops/total of WT+MUT droplets). MAF, mutant allelic fraction; mDDPCR, microdroplet digital PCR; WT, wild type.
Figure 3
Figure 3
Sanger sequencing chromatograms of two parental mosaic families. (A) Sanger sequencing shows that the proband is heterozygous for the PCDH19 variant (c.488T>G) and her father is mosaic for the same variant in blood, hair, buccal epithelium, finger nails, saliva, urine and purified sperm. The variant is absent in her mother’s blood. (B) Sanger sequencing shows that the proband is heterozygous for the PCDH19 variant (c.370G>A) and her father is mosaic for the same variant in blood, buccal epithelium, finger nails, saliva, urine and purified sperms. The variant is absent in her mother’s blood.
Figure 4
Figure 4
The mDDPCR results of Family 1. Detection of PCDH19 c.488T>G mutation in Proband 1’s blood and her father’s multiple tissues (blood, hair follicles, buccal epithelium, finger nails, saliva, urine and purified sperms). The wild-type (‘WT’) and mutant (‘MUT’ or ‘MU’) population are circled in the top panels and bottom panels, respectively, with the % MUT indicated in the top right corner (MUT drops/total of WT+MUT droplets). MAF, mutant allelic fraction; mDDPCR, microdroplet digital PCR; WT, wild type.
Figure 5
Figure 5
The mDDPCR results of Family 13. Detection of PCDH19 c.370G>A mutation in Proband 13’s blood, her sister’s blood and their father’s multiple tissues (blood, buccal epithelium, finger nails, saliva, urine and purified sperms). The wild-type and mutant population are circled in the top panels and bottom panels, respectively, with the % MUT indicated in the top right corner (MUT drops/total of WT+MUT droplets). MAF, mutant allelic fraction; mDDPCR, microdroplet digital PCR; WT, wild type.
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