An <i>FBN1</i> deep intronic variant is associated with pseudoexon formation and a variable Marfan phenotype in a five generation family

Guo, Dongchuan; Duan, Xueyan; Mimnagh, Kathleen; Cecchi, Alana C.; Marin, Isabella; Yu, Yang; Torres, Walter V; Lee, Kwanghyuk; Xue, Zhaohui; Murdock, David R.; Leal, Suzanne M.; Wheeler, Marsha M.; Smith, Josh; Bamshad, Michael J.; Milewicz, Dianna M.

doi:10.1111/cge.14322

Cited by 3 publications

(3 citation statements)

References 12 publications

(19 reference statements)

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“…Among the 32 cases individually clinically described, the core features of Variants in deep intronic are either missed by exome sequencing or were classified as unknown significance by regular variants interpretation pipeline at first met. Variants at >100 and even >1000 bp far away from exons are proved to be pathogenic through combining of genome sequencing and RNA study [16][17][18][19]. Such variants usually exert a pathogenic effect by causing pseudoexon inclusion into the tran-script, further being translated into damaged protein or experience NMD.…”

Section: Discussionmentioning

confidence: 99%

COG6-CDG: Two Novel Variants and Milder Phenotype in a Chinese Patient

Zhang,

2024

Human Mutation

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Here, we present a Han Chinese pediatric girl highly suspected of congenial disorder of glycosylation type IIL (CDG2L; OMIM#614576). Her clinical symptoms include transferase abnormal, liver cirrhosis, hemogram, coagulopathy, growth retardation, intellectual disability, frequent infections, and enamel hypoplasia. Trio-genome sequencing identified in COG6 a paternal variant c.1672C>T (p.Gln558Ter) and a maternal variant c.153+392A>G (p.?). Reverse transcription-polymerase chain reaction (RT-PCR) using mRNA isolated from peripheral blood confirmed the pathogenicity of both variants. The paternal variant resulted in nonsense-mediated mRNA decay. The maternal variant generated two aberrant COG6 transcripts with 154 bp overlap and was predicted to result in a frameshift at the same position, leading to generation of a premature termination codon. They might result in synthesis of a truncated form of COG6. Thus, the patient was genetically diagnosed.

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Section: Discussionmentioning

confidence: 99%

COG6-CDG: Two Novel Variants and Milder Phenotype in a Chinese Patient

Zhang,

2024

Human Mutation

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“…Nowadays, whole‐genome sequencing (WGS) is increasingly recognized as a vital technique in diagnostic genetic screening of rare genetic diseases. Compared to whole exome sequencing and panel‐based next‐generation sequencing (NGS), WGS showed improved diagnostic yield by enabling identification of pathogenic variants in deep intronic regions, 10 , 11 structural variants, 12 and variants located in regulatory region.…”

Section: Introductionmentioning

confidence: 99%

Overcoming challenges associated with identifying FBN1 deep intronic variants through whole‐genome sequencing

Kim,

Jang,

Jang

et al. 2024

Clinical Laboratory Analysis

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BackgroundMarfan syndrome (MFS), caused by pathogenic variants of FBN1 (fibrillin‐1), is a systemic connective tissue disorder with variable phenotypes and treatment responsiveness depending on the variant. However, a significant number of individuals with MFS remain genetically unexplained. In this study, we report novel pathogenic intronic variants in FBN1 in two unrelated families with MFS.MethodsWe evaluated subjects with suspected MFS from two unrelated families using Sanger sequencing or multiplex ligation‐dependent probe amplification of FBN1 and/or panel‐based next‐generation sequencing. As no pathogenic variants were identified, whole‐genome sequencing was performed. Identified variants were analyzed by reverse transcription‐PCR and targeted sequencing of FBN1 mRNA harvested from peripheral blood or skin fibroblasts obtained from affected probands.ResultsWe found causative deep intronic variants, c.6163+1484A>T and c.5788+36C>A, in FBN1. The splicing analysis revealed an insertion of in‐frame or out‐of‐frame intronic sequences of the FBN1 transcript predicted to alter function of calcium‐binding epidermal growth factor protein domain. Family members carrying c.6163+1484A>T had high systemic scores including prominent skeletal features and aortic dissection with lesser aortic dilatation. Family members carrying c.5788+36C>A had more severe aortic root dilatation without aortic dissection. Both families had ectopia lentis.ConclusionVariable penetrance of the phenotype and negative genetic testing in MFS families should raise the possibility of deep intronic FBN1 variants and the need for additional molecular studies. This study expands the mutation spectrum of FBN1 and points out the importance of intronic sequence analysis and the need for integrative functional studies in MFS diagnosis.

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“…Confirmation of FBN1 alterations, mainly missense and loss of function (Lof) variants or rare chromosomal rearrangements ( Colovati et al, 2012 ; Dordoni et al, 2017 ; Schnause et al, 2021 ), is achieved in approximately 90% of cases meeting the Ghent II nosology criteria applied for the clinical diagnosis of MFS ( Loeys et al, 2010 ; Zeigler et al, 2021 ). Alterations of FBN1 linked to MFS have also been identified outside the FBN1 coding region and were proven to be causal through functional analysis ( Guo et al, 2023 ). However, in approximately 10% of patients with distinctive clinical signs of MFS, including positivity to GHENT II criteria, no alteration of FBN1 is detectable by routine DNA investigation.…”

Section: Introductionmentioning

confidence: 99%

Case Report: Decrypting an interchromosomal insertion associated with Marfan’s syndrome: how optical genome mapping emphasizes the morbid burden of copy-neutral variants

Bonaglia,

Salvo,

Sironi

et al. 2023

Front. Genet.

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Optical genome mapping (OGM), which allows analysis of ultra-high molecular weight (UHMW) DNA molecules, represents a response to the restriction created by short-read next-generation-sequencing, even in cases where the causative variant is a neutral copy-number-variant insensitive to quantitative investigations. This study aimed to provide a molecular diagnosis to a boy with Marfan syndrome (MFS) and intellectual disability (ID) carrying a de novo translocation involving chromosomes 3, 4, and 13 and a 1.7 Mb deletion at the breakpoint of chromosome 3. No FBN1 alteration explaining his Marfan phenotype was highlighted. UHMW gDNA was isolated from both the patient and his parents and processed using OGM. Genome assembly was followed by variant calling and annotation. Multiple strategies confirmed the results. The 3p deletion, which disrupted ROBO2, (MIM*602431) included three copy-neutral insertions. Two came from chromosome 13; the third contained 15q21.1, including the FBN1 from intron-45 onwards, thus explaining the MFS phenotype. We could not attribute the ID to a specific gene variant nor to the reshuffling of topologically associating domains (TADs). Our patient did not have vesicular reflux-2, as reported by missense alterations of ROBO2 (VUR2, MIM#610878), implying that reduced expression of all or some isoforms has a different effect than some of the point mutations. Indeed, the ROBO2 expression pattern and its role as an axon-guide suggests that its partial deletion is responsible for the patient’s neurological phenotype. Conclusion: OGM testing 1) highlights copy-neutral variants that could remain invisible if no loss of heterozygosity is observed and 2) is mandatory before other molecular studies in the presence of any chromosomal rearrangement for an accurate genotype-phenotype relationship.

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An FBN1 deep intronic variant is associated with pseudoexon formation and a variable Marfan phenotype in a five generation family

Cited by 3 publications

References 12 publications

COG6-CDG: Two Novel Variants and Milder Phenotype in a Chinese Patient

COG6-CDG: Two Novel Variants and Milder Phenotype in a Chinese Patient

Overcoming challenges associated with identifying FBN1 deep intronic variants through whole‐genome sequencing

Case Report: Decrypting an interchromosomal insertion associated with Marfan’s syndrome: how optical genome mapping emphasizes the morbid burden of copy-neutral variants

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