Dataset Information

Case report: A novel mosaic nonsense mutation of PCDH19 in a Chinese male with febrile epilepsy.

ABSTRACT: The clinical features of the PCDH19 gene mutation include febrile epilepsy ranging from mild to severe, with or without intellectual disability, cognitive impairment, and psych-behavioral disorders, but there has been little research on males with the mosaic mutation of PCDH19. This study reported a novel, de novo, and mosaic PCDH19 nonsense mutation (NM_001184880: c.840C > A, p. Tyr280^*) from a Chinese male in early middle childhood by trio whole-exome sequence (Trio-WES) and confirmed by Sanger sequence. The proportion of the mosaic mutation (c.840C > A, p. Tyr280^*) in PCDH19 was 27.9% in, buccal mucosal cells, 48.3% in exfoliated cells in the urine, and 50.6% in peripheral blood of proband. He had the first onset of seizures in toddlerhood with febrile epilepsy, mild impaired cognitive psychological, and behavioral abnormalities. The electroencephalography (EEG) exhibited sharp waves and sharp slow complex waves in the bilateral parietal, occipital, and posterior temporal regions during the interictal period. Pinpoint white matter lesions in the periventricular white matter and slightly bulging bilateral ventricles appeared on cranial magnetic resonance imaging (MRI). With Depakine and Keppra he gained good control over his epilepsy. This study might expand the genotypes and broaden the spectrums.

SUBMITTER: Chen G

PROVIDER: S-EPMC9556843 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Case report: A novel mosaic nonsense mutation of PCDH19 in a Chinese male with febrile epilepsy.

Chen Guilan G Zhou Hang H Lu Yan Y Wang You Y Li Yingsi Y Xue Jiaxin J Cheng Ken K Huang Ruibin R Han Jin J

Frontiers in neurology 20220929

The clinical features of the PCDH19 gene mutation include febrile epilepsy ranging from mild to severe, with or without intellectual disability, cognitive impairment, and psych-behavioral disorders, but there has been little research on males with the mosaic mutation of PCDH19. This study reported a novel, de novo, and mosaic PCDH19 nonsense mutation (NM_001184880: c.840C > A, p. Tyr280*) from a Chinese male in early middle childhood by trio whole-exome seq ...[more]

PMID: 36247776

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Project description:BackgroundThe link between the protocadherin-19 (PCDH19) gene and epilepsy suggests that an unusual form of X-linked inheritance affects females but is transmitted through asymptomatic males. Individuals with epilepsy associated with mutations in the PCDH19 gene display generalized or focal seizures with or without fever sensitivity. The clinical manifestation of the condition ranges from mild to severe, resulting in intellectual disability and behavioural disturbance. In the present study, we assessed mutations in the PCDH19 gene and the clinical features of a group of Chinese patients with early infantile epileptic encephalopathy and aimed to provide further insight into the understanding of epilepsy and mental retardation limited to females (EFMR; MIM 300088).Case presentationWe described three variations in the PCDH19 gene in Chinese patients with epilepsy who developed generalized seizures occurring in clusters with or without triggering by fever. Candidate genes were screened for mutations that cause epilepsy and related paroxysmal or nervous system diseases in the coding exons and intron-exon boundaries using polymerase chain reaction (PCR) of genomic deoxyribonucleic acid (DNA) followed by sequencing. The variations were sequenced using next-generation sequencing technology and verified with first-generation sequencing. Exome sequencing of a multigene epilepsy panel revealed three mutations in the PCDH19 gene in a mosaic male and two unrelated females. These included a frameshift mutation c.1508_1509insT (p.Thr504HisfsTer19), a missense mutation c.1681C > T (p.Pro561Ser) and a nonsense mutation c.918C > G (p.Tyr306Ter). Of the three mutations in the PCDH19 gene associated with early infantile epileptic encephalopathy, the frameshift variation in a mosaic male is novel and de novo, the missense variation is de novo and is the second ever reported in females, and the nonsense variation was inherited from the paternal line and is the first example discovered in a female.ConclusionsThe results from our current study provide new insight into and perspectives for the molecular genetic link between epilepsy and PCDH19 alterations. Moreover, our new findings of the male mosaic variant broaden the spectrum of PCDH19-related epilepsy and provide a new understanding of this complex genetic disorder.

Project description:RationaleEpilepsy with mental retardation limited to females (EFMR) is a rare type of X-linked epilepsy disorder, affecting heterozygous females disproportionately. The pathogenesis of EFMR has been identified as mutations in the protocadherin 19 (PCDH19) gene. To data, more than 60 different mutations in PCDH19 have been identified. Most of them are located at exon 1, but we describe a novel deletion mutation c.2468delT at exon 3 of PCDH19.Patient concernsThe patient was an 11-year-old girl with onset of seizures at the age of 18 months and followed by progressive intellectual disability (ID) later.DiagnosisThe girl was diagnosed as EFMR when a novel deletion mutation c.2468delT at exon 3 of PCDH19 was found. The deletion mutation c.2468delT was predicted to have caused a frameshift mutation of amino acid at position 823 (p.L823fs). There was no family history of seizures or ID. Her father was asymptomatic, but the mutation screening shows that he had a hemizygous mutation c.2468delT at the same site of PCDH19. The secondary structure of PCDH19 (wide type) showed that the sequences undergoing frameshift mutations were located in the cytoplasm and contain 9 phosphorylation sites. The p.L823fs mutation caused a totally different amino sequence after position of 823, thereby resulting in the disappearance of phosphorylation sites. The frameshift mutation of amino acid at position 823 might affect its binding capability with GABAA receptor and results in migration and morphological maturation of hippocampal neurons.InterventionsThe patient has received antiepileptic treatments, including sodium valproate, carbamazepine, levetiracetam, topiramate and clonazepam et al. OUTCOMES:: The antiepileptic treatment effects were limited.LessonsThis case report describes a novel PCDH19 gene mutation (c.2468delT) at exon 3 in a girl suffering from EFMR. The deletion mutation was predicted to cause a frameshift mutation-p.L823fs, which is highly conserved across different species.

Project description:This study aimed to report a rare case of intermittent azoospermia and ring-like small supernumerary marker chromosomes (sSMCs). An infertile man was diagnosed with azoospermia presenting a normal male phenotype with complete masculinization. Karyotyping and polymerase chain reaction (PCR) were used to detect 16 sequence-tagged sites on the AZF subregions of the Y chromosome, and 115 candidate genes were screened for mutations. Mutations included single nucleotide variations, insertions, and deletions. Metaphase chromosomes were studied by standard trypsin-Giemsa banding; fluorescent in situ hybridization and PCR were performed to analyze specific Y chromosome regions; gene mutations were detected. Chromosomal analysis detected 117 metaphase cells; a mosaicism with marker 1 and marker 2 sSMCs in 2 metaphase cells (47, X, +mar1x2 karyotype), a mosaicism with marker 2 sSMCs in 14 metaphase cells (46, X, +mar2 karyotype), and a mosaicism with marker 1 sSMCs in 76 metaphase cells (46, X, +mar1 karyotype), coexisting with a 45,X cell line in the remaining 25 metaphase cells. PCR analysis showed the sY160 heterochromosome on the AZFc subregion was absent. Next-generation sequencing identified an asthenozoospermia-specific mutation in GAPDHS (rs2293681), and Sanger sequencing verified this mutation. This gene encodes a protein belonging to the glyceraldehyde-3-phosphate dehydrogenase family of enzymes that play an important role in carbohydrate metabolism. Like its somatic cell counterpart, this sperm-specific enzyme functions in a nicotinamide adenine dinucleotide-dependent manner to remove hydrogen and add phosphate to glyceraldehyde 3-phosphate to form 1,3-diphosphoglycerate. During spermiogenesis, this enzyme may play an important role in regulating the switch between different energy-producing pathways, and it is required for sperm motility and male fertility. A mosaic 46, X, +mar1[76]/45, X[25]/46, X, +mar2[14]/47, X, +mar1x2[2] karyotype could be the main explanation for the azoospermia/severe oligospermia, while the likely pathogenic GAPDHS intron mutation may contribute to the symptom of immotile sperms detected in the semen analysis.

Dataset Information

Case report: A novel mosaic nonsense mutation of PCDH19 in a Chinese male with febrile epilepsy.

Publications

Case report: A novel mosaic nonsense mutation of <i>PCDH19</i> in a Chinese male with febrile epilepsy.

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