Intragenic multi-exon deletion in the FBN1 gene in a child with mildly dilated aortic sinus: a retrotransposal event

Brett, Maggie; Korovesis, George; Lai, Angeline; Lim, Eileen C.P.; Tan, Eng Leong

doi:10.1038/jhg.2017.32

Cited by 9 publications

(6 citation statements)

References 38 publications

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“…44 The spectrum of diseases that have been reported in relation to SVA transposition, including Marfan syndrome, hemophilia B, neurofibromatosis types 1 and 2, leukemia, and congenital muscular dystrophy, has been increasing progressively. [45][46][47][48][49][50] In this study, we report a homozygous CNV that is generated by an SVA transposition event and causes MMAF, leading to male infertility.…”

Section: Efficiency Of Wes To Detect Pathological Cnvs and Importancementioning

confidence: 87%

A Homozygous Ancestral SVA-Insertion-Mediated Deletion in WDR66 Induces Multiple Morphological Abnormalities of the Sperm Flagellum and Male Infertility

Kherraf

Amiri-Yekta

Dacheux

et al. 2018

The American Journal of Human Genetics

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Multiple morphological abnormalities of the sperm flagellum (MMAF) is a severe form of male infertility defined by the presence of a mosaic of anomalies, including short, bent, curled, thick, or absent flagella, resulting from a severe disorganization of the axoneme and of the peri-axonemal structures. Mutations in DNAH1, CFAP43, and CFAP44, three genes encoding axoneme-related proteins, have been described to account for approximately 30% of the MMAF cases reported so far. Here, we searched for pathological copy-number variants in whole-exome sequencing data from a cohort of 78 MMAF-affected subjects to identify additional genes associated with MMAF. In 7 of 78 affected individuals, we identified a homozygous deletion that removes the two penultimate exons of WDR66 (also named CFAP251), a gene coding for an axonemal protein preferentially localized in the testis and described to localize to the calmodulin- and spoke-associated complex at the base of radial spoke 3. Sequence analysis of the breakpoint region revealed in all deleted subjects the presence of a single chimeric SVA (SINE-VNTR-Alu) at the breakpoint site, suggesting that the initial deletion event was potentially mediated by an SVA insertion-recombination mechanism. Study of Trypanosoma WDR66's ortholog (TbWDR66) highlighted high sequence and structural analogy with the human protein and confirmed axonemal localization of the protein. Reproduction of the human deletion in TbWDR66 impaired flagellar movement, thus confirming WDR66 as a gene associated with the MMAF phenotype and highlighting the importance of the WDR66 C-terminal region.

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Section: Efficiency Of Wes To Detect Pathological Cnvs and Importancementioning

confidence: 87%

A Homozygous Ancestral SVA-Insertion-Mediated Deletion in WDR66 Induces Multiple Morphological Abnormalities of the Sperm Flagellum and Male Infertility

Kherraf

Amiri-Yekta

Dacheux

et al. 2018

The American Journal of Human Genetics

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“…MAST2, as a microtubule associated kinase, plays important roles in a wide range of life activities. Previous studies have reported the role of MAST2 in evolution 12 , marfan syndrome 13 , neurodegeneration 14 , rabies virus infection 15 , nonobstructive azoospermia 16 , experimental autoimmune encephalomyelitis 17 , chronic myeloid leukemia 18 and breast cancer 4 . Our studies showed the abnormal expression and prognostic effects of MAST2 in liver cancer, which broadened the field of scientific research on MAST2.…”

Section: Discussionmentioning

confidence: 99%

High MAST2 mRNA expression and its role in diagnosis and prognosis of liver cancer

Jiao

Jiang

et al. 2019

Sci Rep

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Liver cancer is a high morbidity and low survival disease all over the world. Chromosomal instability is hallmark of liver cancer. Microtubule-associated serine and threonine kinase 2 (MAST2), as a microtubule associated protein, may involve in tumorous chromosomal instability and plays important roles in cell proliferation and survival. The role of MAST2 in liver cancer has not been well elucidated, which is the aim of our study. In this study, The Cancer Genome Atlas database was used to study the MAST2 mRNA expression in liver cancer, and Chi-squared tests were performed to test the correlation between clinical features and MAST2 expression. ROC curve was performed to examined the diagnostic capacity. The prognostic value of MAST2 in liver cancer was assessed through Kaplan–Meier curves as well as Cox analysis. Our results showed MAST2 was upregulated in liver cancer, and the area under the curve (AUC) was 0.925 and indicated powerful diagnostic capability. High MAST2 expression was associated with advanced clinical status such as histological type (p = 0.0059), histologic grade (p = 0.0142), stage (p = 0.0008), T classification (p = 0.0028), N classification (p = 0.0107), survival status (p = 0.0062), and poor prognosis of patients. Importantly, MAST2 was an independent risk factor for patients’ prognosis after adjusting for other risk factors including stage, T classification, and residual tumor. In total, MAST2 is a potential diagnostic and prognostic biomarker of liver cancer.

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“…A deletion of three FBN1 exons (7–9) from intron 6 to intron 9, spanning approximately 38.6 kb at 15q21.1 with a concomitant SVA F1 insertion, was identified in a study of a child with mildly dilated aortic sinus (Figure 1(c)). 44 Mutations in the FBN1 gene typically result in an autosomal dominant connective tissue disorder termed Marfan syndrome (MFS), which affects the skeletal, cardiovascular, and ocular systems. 62 In this case, the child displayed no other features indicative of an MFS diagnosis.…”

Section: Sva Insertions Associated With Large Genomic Deletionsmentioning

confidence: 99%

Mechanisms of disease-associated SINE-VNTR-Alus

Pfaff

Singleton

Kõks

2022

Exp Biol Med (Maywood)

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SINE-VNTR-Alus (SVAs) are the youngest retrotransposon family in the human genome. Their ongoing mobilization has generated genetic variation within the human population. At least 24 insertions to date, detailed in this review, have been associated with disease. The predominant mechanisms through which this occurs are alterations to normal splicing patterns, exonic insertions causing loss-of-function mutations, and large genomic deletions. Dissecting the functional impact of these SVAs and the mechanism through which they cause disease provides insight into the consequences of their presence in the genome and how these elements could influence phenotypes. Many of these disease-associated SVAs have been difficult to characterize and would not have been identified through routine analyses. However, the number identified has increased in recent years as DNA and RNA sequencing data became more widely available. Therefore, as the search for complex structural variation in disease continues, it is likely to yield further disease-causing SVA insertions.

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Intragenic multi-exon deletion in the FBN1 gene in a child with mildly dilated aortic sinus: a retrotransposal event

Cited by 9 publications

References 38 publications

A Homozygous Ancestral SVA-Insertion-Mediated Deletion in WDR66 Induces Multiple Morphological Abnormalities of the Sperm Flagellum and Male Infertility

A Homozygous Ancestral SVA-Insertion-Mediated Deletion in WDR66 Induces Multiple Morphological Abnormalities of the Sperm Flagellum and Male Infertility

High MAST2 mRNA expression and its role in diagnosis and prognosis of liver cancer

Mechanisms of disease-associated SINE-VNTR-Alus

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