Somatic mosaicism of a CDKL5 mutation identified by next-generation sequencing

Kato, Takeshi; Morisada, Naoya; Nagase, Hiroaki; Nishiyama, Masahiro; Toyoshima, Daisaku; Nagao, Taku; Maruyama, Azusa; Fu, Xue Jun; Nozu, Kandai; Wada, Hiroyoshi; Takada, Satoshi; Iijima, Kazumoto

doi:10.1016/j.braindev.2015.03.002

Cited by 16 publications

(12 citation statements)

References 10 publications

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“…The observation of an additional affected male mosaic for PCDH19 further supports cellular interference as the pathogenic mechanism for this condition. Mosaicism is well described in early infantile epileptic encephalopathy resulting from channelopathies ( SCN1A , KCNQ2 , SCN2A , and SCN8A) but in most cases, the de novo variant originated from germline mosaicism in a parent [Zerem et al, ; Kato et al, ; Larsen et al, ; Milh et al, ]. Indeed, parental mosaicism is found in at least 7% of the families with SCN1A variants [Depienne et al, ].…”

Section: Discussionmentioning

confidence: 99%

PCDH19‐related epileptic encephalopathy in a male mosaic for a truncating variant

Thiffault

Farrow

Smith

et al. 2016

American J of Med Genetics Pt A

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Variants in the X-linked gene PCDH19 are associated with early infantile epileptic encephalopathy-9. This unusual condition spares hemizygous males except for psychiatric and behavioral abnormalities, and for this reason is also known as female limited epilepsy. Some cases are due to de novo PCDH19 variants, but may also be paternally inherited. Our patient is a 6-year-old male with epileptic encephalopathy. Exome sequencing revealed apparent heterozygosity in PCDH19 for a novel nonsense variant, c.605C>A (p.Ser202*), inconsistent with expectations for a male. Testing of other tissues revealed a mixture of mutant and normal alleles. These results are consistent with somatic mosaicism for p.Ser202*. This is the second male with somatic mosaicism for PCDH19 deficiency, providing further support for cellular interference as the pathogenic mechanism for this condition, which leads to this unusual mode of inheritance in which females are more severely affected than males. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

PCDH19‐related epileptic encephalopathy in a male mosaic for a truncating variant

Thiffault

Farrow

Smith

et al. 2016

American J of Med Genetics Pt A

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“…A high SB score indicates that the variant call may be caused by an artifact of the alignment process rather than a true mutation 8 . Certain targeting methodologies, including those using Illumina TruSight capture techniques selectively amplify one target strand 9 ; for these assays, SB is not a meaningful measure of quality.…”

Section: Strand Bias (Sb)mentioning

confidence: 99%

Current practices and guidelines for clinical next-generation sequencing oncology testing

Strom¹

2016

Cancer Biology &Amp; Medicine

137

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Next-generation sequencing (NGS) has been rapidly integrated into molecular pathology, dramatically increasing the breadth genomic of information available to oncologists and their patients. This review will explore the ways in which this new technology is currently applied to bolster care for patients with solid tumors and hematological malignancies, focusing on practices and guidelines for assessing the technical validity and clinical utility of DNA variants identified during clinical NGS oncology testing.

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“…Whole-exome sequence has also been used to recently identify a variation in the CDKL5 gene in a 5-year-old Japanese boy with intractable epilepsy, severe developmental delay, and RTT-like features (Kato et al, 2015 ). Variations in CDKL 5 are associated with epileptic encephalopathy (Bahi-Buisson et al, 2008 ).…”

Section: Recent Studies Using Ngs In “Rtt” Patientsmentioning

confidence: 99%

The Utility of Next-Generation Sequencing in Gene Discovery for Mutation-Negative Patients with Rett Syndrome

Gold

Christodoulou

2015

Front. Cell. Neurosci.

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Rett syndrome (RTT) is a rare, severe disorder of neuronal plasticity that predominantly affects girls. Girls with RTT usually appear asymptomatic in the first 6–18 months of life, but gradually develop severe motor, cognitive, and behavioral abnormalities that persist for life. A predominance of neuronal and synaptic dysfunction, with altered excitatory–inhibitory neuronal synaptic transmission and synaptic plasticity, are overarching features of RTT in children and in mouse models. Over 90% of patients with classical RTT have mutations in the X-linked methyl-CpG-binding (MECP2) gene, while other genes, including cyclin-dependent kinase-like 5 (CDKL5), Forkhead box protein G1 (FOXG1), myocyte-specific enhancer factor 2C (MEF2C), and transcription factor 4 (TCF4), have been associated with phenotypes overlapping with RTT. However, there remain a proportion of patients who carry a clinical diagnosis of RTT, but who are mutation negative. In recent years, next-generation sequencing technologies have revolutionized approaches to genetic studies, making whole-exome and even whole-genome sequencing possible strategies for the detection of rare and de novo mutations, aiding the discovery of novel disease genes. Here, we review the recent progress that is emerging in identifying pathogenic variations, specifically from exome sequencing in RTT patients, and emphasize the need for the use of this technology to identify known and new disease genes in RTT patients.

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Somatic mosaicism of a CDKL5 mutation identified by next-generation sequencing

Cited by 16 publications

References 10 publications

PCDH19‐related epileptic encephalopathy in a male mosaic for a truncating variant

PCDH19‐related epileptic encephalopathy in a male mosaic for a truncating variant

Current practices and guidelines for clinical next-generation sequencing oncology testing

The Utility of Next-Generation Sequencing in Gene Discovery for Mutation-Negative Patients with Rett Syndrome

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