Somatic mosaicism for a <i><scp>SLC2A1</scp></i> mutation: implications for genetic counseling for <scp>GLUT1</scp> deficiency syndrome

Takahashi, Satoru; Matsufuji, Mayumi; Yonee, Chihiro; Tsuru, Hisashi; Sano, Nozomi; Oguni, Hirokazu

doi:10.1111/cge.12902

Cited by 6 publications

(3 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Trio test identified cases with parental mosaicism. Parental mosaicism of SLC2A1 has been reported (20,21), and the level of mosaicism appears to be related to symptoms, which is consistent with the results of this study. Parental mosaicisms of SPTAN1 and RORA have not been reported yet to the best of our knowledge.…”

Section: Discussionsupporting

confidence: 92%

Analysis of trio test in neurodevelopmental disorders

Kim

Kwon²,

Lee³

et al. 2022

Front. Pediatr.

View full text Add to dashboard Cite

BackgroundTrio test has been widely used for diagnosis of various hereditary disorders. We aimed to investigate the contribution of trio test in genetically diagnosing neurodevelopmental disorders (NDD).MethodsWe retrospectively reviewed 2,059 NDD cases with genetic test results. The trio test was conducted in 563 cases. Clinical usefulness, optimal timing, and methods for the trio test were reviewed.ResultsPathogenic or likely pathogenic variants were detected in 112 of 563 (19.9%) patients who underwent the trio test. With trio test results, the overall diagnostic yield increased by 5.4% (112/2,059). Of 165 de novo variants detected, 149 were pathogenic and we detected 85 novel pathogenic variants. Pathogenic, de novo variants were frequently detected in CDKL5, ATP1A3, and STXBP1.ConclusionThe trio test is an efficient method for genetically diagnosing NDD. We identified specific situations where a certain trio test is more appropriate, thereby providing a guide for clinicians when confronted with variants of unknown significance of specific genes.

show abstract

Section: Discussionsupporting

confidence: 92%

Analysis of trio test in neurodevelopmental disorders

Kim

Kwon²,

Lee³

et al. 2022

Front. Pediatr.

View full text Add to dashboard Cite

show abstract

“…Postzygotic mosaicism describes individuals who developed from a single zygote but consist of multiple cell populations with different genotypes (Strachan and Read 1999). The mosaicism arises due to postzygotic errors in DNA replication (De 2011;Lupski 2013) and can lead to disease states in the mosaic carriers (Poduri et al 2013;Priest et al 2016;Terracciano et al 2016), or in the heterozygous offspring inheriting the mutant allele (Dal et al 2014;Huang et al 2014;Acuna-Hidalgo et al 2015;Dou et al 2017), and contribute to the recurrent risk of genetic disorders in children (Depienne et al 2010;Xu et al 2015;Takahashi et al 2017). With the recent development of deep sequencing technology, a small number of studies reported the genomic pattern of postzygotic single-nucleotide mosaicisms (pSNMs) in noncancerous human samples (Huang et al 2014(Huang et al , 2018Dou et al 2017;Ju et al 2017), and this has enabled the quantitative analysis of pSNMs during the normal developmental process.…”

mentioning

confidence: 99%

A model for postzygotic mosaicisms quantifies the allele fraction drift, mutation rate, and contribution to de novo mutations

Dou

Yang

et al. 2018

Genome Res.

View full text Add to dashboard Cite

The allele fraction (AF) distribution, occurrence rate, and evolutionary contribution of postzygotic single-nucleotide mosaicisms (pSNMs) remain largely unknown. In this study, we developed a mathematical model to describe the accumulation and AF drift of pSNMs during the development of multicellular organisms. By applying the model, we quantitatively analyzed two large-scale data sets of pSNMs identified from human genomes. We found that the postzygotic mutation rate per cell division during early embryogenesis, especially during the first cell division, was higher than the average mutation rate in either male or female gametes. We estimated that the stochastic cell death rate per cell cleavage during human embryogenesis was ∼5%, and parental pSNMs occurring during the first three cell divisions contributed to ∼10% of the de novo mutations observed in children. We further demonstrated that the genomic profiles of pSNMs could be used to measure the divergence distance between tissues. Our results highlight the importance of pSNMs in estimating recurrence risk and clarified the quantitative relationship between postzygotic and de novo mutations.

show abstract

“…The first group of mechanisms that comes to mind that may underlie phenotypic variability in IEM is a difference in the expression of the abnormal protein, often determined by genetic factors. Likewise, phenotypic severity and age of onset are expected to be modulated by differences in residual protein activity driven by (i) random X inactivation such as in ornithine transcarbamylase (OTC) deficiency, pyruvate dehydrogenase (PDH) deficiency, adrenomyeloneuropathy (AMN) or Fabry disease; (ii) genetic imprinting like in Niemann-Pick type A/B disease (Simonaro et al 2006) or citrullinemia (Verma et al 2017); (iii) somatic mosaicism like in OTC deficiency (Giorgi et al 2000), PDH deficiency (Ridout et al (Takahashi et al 2017); (iv) composite heterozygosity between a pathogenic mutation and a modifier variant either in the same gene, as in maple syrup urine disease (MSUD) (Frézal et al 1985), or in a different gene, as in fatty acid oxidation defect (Vockley et al 2000)o rO T Cd e f i c i e n c y (Mira and Boles 2012)-the so-called synergistic heterozygosity; (v) mutational load (i.e., heteroplasmy) in mitochondrial DNA diseases like NARP/Leigh or MELAS syndromes; and (vi) functional consequences of the mutation that may lead to a conformational versus a metabolic defect like in triose phosphate isomerase deficiency (Orosz et al 2009).…”

mentioning

confidence: 99%

The phenotype of adult versus pediatric patients with inborn errors of metabolism

Saudubray

Mochel

2018

J of Inher Metab Disea

View full text Add to dashboard Cite

Until recently, inborn errors of metabolism (IEM) were considered a pediatric specialty, as emphasized by the term "inborn," and the concept of adult onset IEM has only very recently reached the adult medical community. Still, an increasing number of adult onset IEM have now been recognized, as new metabolomics and molecular diagnostic techniques have become available. Here, we discuss possible mechanisms underlying phenotypic variability in adult versus children with IEM. Specifically, phenotypic severity and age of onset are expected to be modulated by differences in residual protein activity possibly driven by various genetic factors. Phenotypic variability may also occur in the context of similar protein expression, which suggests the intervention of environmental, ontogenic, and aging factors.

show abstract

Somatic mosaicism for a SLC2A1 mutation: implications for genetic counseling for GLUT1 deficiency syndrome

Abstract: A heterozygous SLC2A1 mutation in the severely affected child was inherited from his less severely affected mother who was mosaic for the mutation.

Cited by 6 publications

References 4 publications

Analysis of trio test in neurodevelopmental disorders

Analysis of trio test in neurodevelopmental disorders

A model for postzygotic mosaicisms quantifies the allele fraction drift, mutation rate, and contribution to de novo mutations

The phenotype of adult versus pediatric patients with inborn errors of metabolism

Contact Info

Product

Resources

About