Case Report: A Synonymous Mutation in NF1 Located at the Non-canonical Splicing Site Leading to Exon 45 Skipping

Jin, Pengzhen; Yan, Kai; Ye, Shaofen; Qian, Yeqing; Wu, Zaigui; Wang, Miaomiao; Xu, Yuqing; Xu, Yanfei; Dong, Minyue

doi:10.3389/fgene.2021.772958

Cited by 6 publications

(4 citation statements)

References 37 publications

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“…EMC1 is a core subunit for the assembly and function of the EMC complex. Mutations in EMC1 have been associated with GDD in several studies (Harel et al, 2016;Geetha et al, 2018;Gao et al, 2019;Sun et al, 2019;Jin et al, 2021;Dhindsa et al, 2022) (Figure 2), where the affected individuals showed variable clinical presentation with major findings such as global developmental delay, cerebellar atrophy, psychomotor retardation, hypotonia, and visual impairment (Supplementary Table 1). The clinical features of the proband in current report are highly similar to the phenotypes described in previous individuals, supporting a diagnosis of EMC1-related disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Depletion of EMC1 is related to retinal degeneration, neural crest development defect, and glial abnormality in experimental animal models (Cabet et al, 2020;Chung et al, 2022;Dhindsa et al, 2022). To date, about a dozen of EMC1 variants, including missense, splice site, nonsense, and frameshift variants have been identified and associated with highly variable clinical presentation, ranging from isolated retinitis pigmentosa or congenital heart disease to severe global development delay (Harel et al, 2016;Geetha et al, 2018;Gao et al, 2019;Jin et al, 2021;Dhindsa et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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Novel compound heterozygous variants in EMC1 associated with global developmental delay: a lesson from a non-silent synonymous exonic mutation

Wang¹,

Wang²,

Gao³

et al. 2023

Front. Mol. Neurosci.

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BackgroundThe endoplasmic reticulum-membrane protein complex (EMC) as a molecular chaperone is required for the proper synthesis, folding and traffic of several transmembrane proteins. Variants in the subunit 1 of EMC (EMC1) have been implicated in neurodevelopmental disorders.MethodsWhole exome sequencing (WES) with Sanger sequencing validation was performed for a Chinese family, including the proband (a 4-year-old girl who displayed global developmental delay, severe hypotonia and visual impairment), her affected younger sister and her non-consanguineous parents. RT-PCR assay and Sanger sequencing were used to detect abnormal RNA splicing.ResultsNovel compound heterozygous variants in EMC1, including the maternally inherited chr1: 19566812_1956800delinsATTCTACTT[hg19];NM_015047.3:c.765_777delins ATTCTACTT;p.(Leu256fsTer10) and the paternally inherited chr1:19549890G> A[hg19];NM_015047.3:c.2376G>A;p.(Val792=) are identified in the proband and her affected sister. RT-PCR assay followed by Sanger sequencing reveals that the c.2376G>A variant leads to aberrant splicing, with retention of intron 19 (561bp) in the mature mRNA, which is presumed to introduce a premature translational termination codon (p.(Val792fsTer31)).ConclusionNovel compound heterozygous variants in EMC1 have been identified in individuals with global developmental delay. Non-silent synonymous mutations should be kept in mind in genetic analysis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel compound heterozygous variants in EMC1 associated with global developmental delay: a lesson from a non-silent synonymous exonic mutation

Wang¹,

Wang²,

Gao³

et al. 2023

Front. Mol. Neurosci.

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“…However, as an absolute quantitative method with greater precision and sensitivity, ddPCR could be a promising technique for detection of mosaicism, especially for asymptomatic carriers who suffer from recurrent occurrence (Jin et al, 2021). Jin et al (2020) reported a case of tuberous sclerosis (TSC) with atypical clinical symptoms. They found a mosaic candidate mutation (c.1096G>T) by WES.…”

Section: Discussionmentioning

confidence: 99%

Detection of gonosomal mosaicism by ultra‐deep sequencing and droplet digital PCR in patients with Emery–Dreifuss muscular dystrophy

Xie

Luo

Zhong

et al. 2023

Molec Gen & Gen Med

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Background Emery–Dreifuss muscular dystrophy (EDMD2) is a rare form of muscular dystrophy that is inherited as an autosomal dominant trait. In some patients, it is inherited from parental mosaicism, and this increases the recurrence risk significantly. The presence of mosaicism is underestimated due to the limitations of genetic testing and the difficulty in obtaining samples. Methods A peripheral blood sample from a 9‐year‐old girl with EDMD2 was analyzed by enhanced whole exome sequencing (WES). Sanger sequencing in her unaffected parents and younger sister was performed for validation. In the mother, ultra‐deep sequencing and droplet digital PCR (ddPCR) in multiple samples (blood, urine, saliva, oral epithelium, and nail clippings) were performed in order to identify the suspected mosaicism of the variant. Results WES revealed a heterozygous mutation (LMNA, c.1622G>A) in the proband. Sanger sequencing of the mother suggested the presence of mosaicism. The ratio of mosaic mutation was confirmed in different samples by ultra‐deep sequencing and ddPCR (19.98%–28.61% and 17.94%–28.33%, respectively). This inferred that the mosaic mutation may have occurred early during embryonic development and that the mother had gonosomal mosaicism. Conclusion We described a case of EDMD2 caused by maternal gonosomal mosaicism which was confirmed by using ultra‐deep sequencing and ddPCR. This study illustrates the importance of a systematic and comprehensive screening of parental mosaicism with more sensitive approaches and the use of multiple tissue samples.

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“…Synonymous mutations are often considered non-pathogenic because they do not alter the amino acid of the encoded protein; however, synonymous mutations at non-canonical splicing sites can lead to abnormal splicing, and reports about the relationship between synonymous mutations and abnormal splicing have increased recently ( 40 ). In our study, we found that the child has the synonymous variance c.3453C>T (p.Gly1151=) from the mother, and the location is near the splicing site at the 5’ end of the intron starts with the GT called donor, and the mutation creates a new donor site.…”

Section: Discussionmentioning

confidence: 99%

A synonymous mutation in PI4KA impacts the transcription and translation process of gene expression

Zhang

Kang²,

Zhang³

et al. 2022

Front. Immunol.

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Phosphatidylinositol-4-kinase alpha (PI4KIIIα), encoded by the PI4KA gene, can synthesize phosphatidylinositol-4-phosphate (PI-4-P), which serves as a specific membrane marker and is instrumental in signal transduction. PI4KA mutations can cause autosomal recessive diseases involving neurological, intestinal, and immunological conditions (OMIM:619621, 616531, 619708). We detected sepsis, severe diarrhea, and decreased immunoglobulin levels in one neonate. Two novel compound heterozygous mutations, c.5846T>C (p.Leu1949Pro) and c.3453C>T (p.Gly1151=), were identified in the neonate from the father and the mother, respectively. Sanger sequencing and reverse transcription polymerase chain reaction (RT-PCR) for peripheral blood and minigene splicing assays showed a deletion of five bases (GTGAG) with the c.3453C>T variant at the mRNA level, which could result in a truncated protein (p.Gly1151GlyfsTer17). The missense mutation c.5846T>C (p.Leu1949Pro) kinase activity was measured, and little or no catalytic activity was detected. According to the clinical characteristics and gene mutations with functional verification, our pediatricians diagnosed the child with a combined immunodeficiency and intestinal disorder close to gastrointestinal defects and immunodeficiency syndrome 2 (GIDID2; OMIM: 619708). Medicines such as immunomodulators are prescribed to balance immune dysregulation. This study is the first report of a synonymous mutation in the PI4KA gene that influences alternative splicing. Our findings expand the mutation spectrum leading to PI4KIIIa deficiency-related diseases and provide exact information for genetic counseling.

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Case Report: A Synonymous Mutation in NF1 Located at the Non-canonical Splicing Site Leading to Exon 45 Skipping

Cited by 6 publications

References 37 publications

Novel compound heterozygous variants in EMC1 associated with global developmental delay: a lesson from a non-silent synonymous exonic mutation

Novel compound heterozygous variants in EMC1 associated with global developmental delay: a lesson from a non-silent synonymous exonic mutation

Detection of gonosomal mosaicism by ultra‐deep sequencing and droplet digital PCR in patients with Emery–Dreifuss muscular dystrophy

A synonymous mutation in PI4KA impacts the transcription and translation process of gene expression

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