Parental Mosaicism in “De Novo” Epileptic Encephalopathies

Myers, Candace T.; Hollingsworth, Georgina; Muir, Alison M.; Schneider, Amy; Thuesmunn, Zoe; Knupp, Allison; King, Chontelle; LaCroix, Amy J.; Mehaffey, Michele G.; Berkovic, Samuel F.; Carvill, Gemma L.; Sadleir, Lynette G.; Scheffer, Ingrid E.; Mefford, Heather C

doi:10.1056/nejmc1714579

Cited by 113 publications

(106 citation statements)

References 5 publications

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“…Together with our series, there are now three affected sibling pairs as well as an individual whose brother had previously passed away with the same phenotype. 27 At present, we do not have evidence to conclude that GNAO1 is more likely to be associated with parental mosaicism than other genes. However, their recurrence in siblings leads to the hypothesis of parental mosaicism, either in the germline with low allele frequency undetectable by standard clinical sequencing or restricted to the gametes.…”

Section: Discussionmentioning

confidence: 65%

Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate–binding region

et al. 2019

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Summary Objective To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype‐protein structure‐phenotype relationships. Methods We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three‐dimensional structural protein model. Results The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)‐binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207‐221 had only movement disorder and hypotonia. Patients with variants affecting the C‐terminal region had the mildest phenotypes. Significance GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP‐binding domain of GNAO1, highlighting the importance of this region for G‐protein signaling and neurodevelopment.

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Section: Discussionmentioning

confidence: 65%

Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate–binding region

et al. 2019

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“…Our detection rate is slightly lower than recently published studies reporting parental mosaicism in 8.3% of families with developmental and epileptic encephalopathy, and in 8.6%-17% of families with Dravet syndrome due to de novo SCN1A variants, respectively. [4][5][6] However, parents without detectable mosaicism in blood could still have an increased recurrence risk, as the variant might be present in other tissues. To minimize ascertainment bias we did not restrict recruitment to solely the presence of a de novo variant in the genes of interest but also aimed for a recruitment of all consecutive cases of de novo variants in the study genes from the respective contributor and included those where samples of both parents were available.…”

Section: Discussionmentioning

confidence: 99%

“…Some previous studies based on a collection of random cases with de novo variants from various sources which may give advantage to recruitment of familial cases. [4][5][6] The individual recurrence risk in the mosaic parents is hypothetically up to 50%; however, the precise recurrence risk is almost impossible to predict. By performing smMIPS we used a very sensitive and cost-efficient method for detecting low-grade variants.…”

Section: Discussionmentioning

confidence: 99%

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Parental mosaicism in epilepsies due to alleged de novo variants

Møller

Liebmann

Larsen³

et al. 2019

Epilepsia

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Summary Severe early onset epilepsies are often caused by de novo pathogenic variants. Few studies have reported the frequency of somatic mosaicism in parents of children with severe epileptic encephalopathies. Here we aim to investigate the frequency of mosaicism in the parents of children with epilepsy caused by alleged de novo variants. We tested parental genomic DNA derived from different tissues for 75 cases using targeted next‐generation sequencing. Five parents (6.6%) showed mosaicism at minor allele frequencies of 0.8%‐29% for the pathogenic variant detected in their offspring. Parental mosaicism was observed in the following genes: SCN1A, SCN2A, SCN8A, and STXBP1. One of the identified parents had epilepsy himself. Our results show that de novo events can occur already in parental tissue and in some cases can be detected in peripheral blood. Consequently, parents affected by low‐grade mosaicism are faced with an increased recurrence risk for transmitting the pathogenic variant, compared to the overall recurrence risk for a second affected child estimated at approximately 1%. However, testing for parental somatic mosaicism will help identifying those parents who truly are at higher risk and will significantly improve genetic counseling in the respective families.

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“…A recent study detected parental mosaicism in 3 out of 40 families with apparent de novo pathogenic SCN1A variants by using smMIPs 35. No validation studies were performed, which may have led to false positive results; however, as the reported percentages of mosaicism were relatively high (16.7%–30.6%), this risk may be low.…”

Section: Discussionmentioning

confidence: 99%

Assessment of parental mosaicism in SCN1A-related epilepsy by single-molecule molecular inversion probes and next-generation sequencing

et al. 2018

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BackgroundDravet syndrome is a severe genetic encephalopathy, caused by pathogenic variants in SCN1A. Low-grade parental mosaicism occurs in a substantial proportion of families (7%–13%) and has important implications for recurrence risks. However, parental mosaicism can remain undetected by methods regularly used in diagnostics. In this study, we use single-molecule molecular inversion probes (smMIP), a technique with high sensitivity for detecting low-grade mosaic variants and high cost-effectiveness, to investigate the incidence of parental mosaicism of SCN1A variants in a cohort of 90 families and assess the feasibility of this technique.MethodsDeep sequencing of SCN1A was performed using smMIPs. False positive rates for each of the proband’s pathogenic variants were determined in 145 unrelated samples. If parents showed corresponding variant alleles at a significantly higher rate than the established noise ratio, mosaicism was confirmed by droplet digital PCR (ddPCR).ResultsSequence coverage of at least 100× at the location of the corresponding pathogenic variant was reached for 80 parent couples. The variant ratio was significantly higher than the established noise ratio in eight parent couples, of which four (5%) were regarded as true mosaics, based on ddPCR results. The false positive rate of smMIP analysis without ddPCR was therefore 50%. Three of these variants had previously been considered de novo in the proband by Sanger sequencing.ConclusionsmMIP technology combined withnext generation sequencing (NGS) performs better than Sanger sequencing in the detection of parental mosaicism. Because parental mosaicism has important implications for genetic counselling and recurrence risks, we stress the importance of implementing high-sensitivity NGS-based assays in standard diagnostics.

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Parental Mosaicism in “De Novo” Epileptic Encephalopathies

Cited by 113 publications

References 5 publications

Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate–binding region

Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate–binding region

Parental mosaicism in epilepsies due to alleged de novo variants

Assessment of parental mosaicism in SCN1A-related epilepsy by single-molecule molecular inversion probes and next-generation sequencing

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