Three Novel Mutations in &lt;i&gt;FBN1&lt;/i&gt; and &lt;i&gt;TGFBR2&lt;/i&gt; in Patients with the Syndromic Form of Thoracic Aortic Aneurysms and Dissections

Cao, Jingli; Hu, Ting; Li, Zhuo; Linpeng, Siyuan; Long, Xigui; Wu, Lingqian

doi:10.1536/ihj.18-046

Cited by 9 publications

(18 citation statements)

References 32 publications

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“…Three other FBN1 -associated diseases were placed in ranks 2–4. Clinical and molecular data were simulated according to patient 1 in Cao et al 33 . The HPO terms are shown in panel (b).…”

Section: Resultsmentioning

confidence: 99%

Interpretable Clinical Genomics with a Likelihood Ratio Paradigm

Robinson

Ravanmehr

Jacobsen

et al. 2020

Preprint

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Human Phenotype Ontology (HPO)-based analysis has become standard for genomic diagnostics of rare diseases. Current algorithms use a variety of semantic and statistical approaches to prioritize the typically long lists of genes with candidate pathogenic variants. These algorithms do not provide robust estimates of the strength of the predictions beyond the placement in a ranked list, nor do they provide measures of how much any individual phenotypic observation has contributed to the prioritization result. However, given that the overall success rate of genomic diagnostics is only around 25-50% or less in many cohorts, a good ranking cannot be taken to imply that the gene or disease at rank one is necessarily a good candidate. Likelihood ratios (LR) are statistics for summarizing diagnostic accuracy, providing a measure of how much more (or less) a patient with a disease has a particular test result compared to patients without the disease. Here, we present an approach to genomic diagnostics that exploits the LR framework to provide an estimate of (1) the posttest probability of candidate diagnoses; (2) the LR for each observed HPO phenotype, and (3) the predicted pathogenicity of observed genotypes. LIkelihood Ratio Interpretation of Clinical AbnormaLities (LIRICAL) placed the correct diagnosis within the first three ranks in 92.9% of 384 cases reports comprising 262 Mendelian diseases, with the correct diagnosis having a mean posttest probability of 67.3%. Simulations show that LIRICAL is robust to many typically encountered forms of genomic and phenomic noise. In summary, LIRICAL provides accurate, clinically interpretable results for phenotype-driven genomic diagnostics.

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“…Three other FBN1 -associated diseases were placed in ranks 2–4. Clinical and molecular data were simulated according to patient 1 in Cao et al 33 . The HPO terms are shown in panel (b).…”

Section: Resultsmentioning

confidence: 99%

Interpretable Clinical Genomics with a Likelihood Ratio Paradigm

Robinson

Ravanmehr

Jacobsen

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Whether the incidence of gene mutation associated with Marfan syndrome or AD is higher in Chinese patients than in patients from western countries deserves further study. However, a recent study by Cao, et al 13) shed some light on this issue, who identified three novel heterozygous mutations in four Chinese patients with suspected Marfan syndrome, which indicated that some mutations associated with Marfan syndrome or AD might be ethnicspecific. Another distinct feature in our study was the relatively higher proportion of male patients.…”

Section: Discussionmentioning

confidence: 99%

Influence of Age on Clinical Presentation, Therapeutic Options, and Outcome in Chinese Patients with Acute Aortic Dissection

Huang

Chen

et al. 2019

Int. Heart J.

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It has been shown in previous studies that Chinese patients with acute aortic dissection (AD) were approximately 10 years younger than patients from western countries. However, there is a lack of studies concerning the age-related differences in clinical characteristics and outcomes in Chinese patients with acute AD. A total of 1,061 patients with AD (570 type A and 491 type B AD) were enrolled between 2006 and 2008. The clinical characteristics were compared between the patients in our study and those in the International Registry of Acute Aortic Dissection (IRAD). Compared with patients in the IRAD, those in our study were relatively younger, comprised more males, and had a higher proportion of Marfan syndrome but received fewer surgical interventions. When stratified by 10-year age, younger patients were more likely to have type A AD, familial AD, and Marfan syndrome, whereas older patients tended to comprise more females and type B AD. As age increased, the proportion of surgical intervention gradually decreased regardless of the type of AD. During a median follow-up of 2.2 years, 147 patients died, of whom 94 (63.9%) had type A AD and 53 (36.1%) had type B AD. Long-term mortality increased with increasing age, especially in patients above 70 years old. Furthermore, the recurrence rate of AD was higher in both the young and the older patients. In conclusion, compared with western patients with AD, Chinese patients have distinct characteristics and more attention should be paid to the young and older patients because of their high long-term mortality and recurrence rate.

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“…Previous studies report somatogonadal mosaicism in other HCTD, for example in Loeys–Dietz syndromes [ 17 , 18 ] and vEDS [ 14 ]. We report here, to our knowledge, the first patient with a somatogonadal mosaicism in COL5A1 responsible for the cEDS diagnosed in his son.…”

Section: Discussionmentioning

confidence: 99%

“…Mosaicism has been reported in other genes of HCTD, in particular in Loeys–Dietz syndrome with mosaic variants in TGFBR1 and TGFBR2 [ 17 , 18 ]. We therefore, reviewed all affected individuals for other HCTD genes but also familial thoracic aortic aneurysm/dissection (FTAAD) genes studied in our center.…”

Section: Introductionmentioning

confidence: 99%

Parental mosaicism in Marfan and Ehlers–Danlos syndromes and related disorders

et al. 2021

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Marfan syndrome (MFS) is a heritable connective tissue disorder (HCTD) caused by pathogenic variants in FBN1 that frequently occur de novo. Although individuals with somatogonadal mosaicisms have been reported with respect to MFS and other HCTD, the overall frequency of parental mosaicism in this pathology is unknown. In an attempt to estimate this frequency, we reviewed all the 333 patients with a disease-causing variant in FBN1. We then used direct sequencing, combined with High Resolution Melting Analysis, to detect mosaicism in their parents, complemented by NGS when a mosaicism was objectivized. We found that (1) the number of apparently de novo events is much higher than the classically admitted number (around 50% of patients and not 25% as expected for FBN1) and (2) around 5% of the FBN1 disease-causing variants were not actually de novo as anticipated, but inherited in a context of somatogonadal mosaicisms revealed in parents from three families. High Resolution Melting Analysis and NGS were more efficient at detecting and evaluating the level of mosaicism compared to direct Sanger sequencing. We also investigated individuals with a causal variant in another gene identified through our “aortic diseases genes” NGS panel and report, for the first time, on an individual with a somatogonadal mosaicism in COL5A1. Our study shows that parental mosaicism is not that rare in Marfan syndrome and should be investigated with appropriate methods given its implications in patient’s management.

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Three Novel Mutations in <i>FBN1</i> and <i>TGFBR2</i> in Patients with the Syndromic Form of Thoracic Aortic Aneurysms and Dissections

Cited by 9 publications

References 32 publications

Interpretable Clinical Genomics with a Likelihood Ratio Paradigm

Interpretable Clinical Genomics with a Likelihood Ratio Paradigm

Influence of Age on Clinical Presentation, Therapeutic Options, and Outcome in Chinese Patients with Acute Aortic Dissection

Parental mosaicism in Marfan and Ehlers–Danlos syndromes and related disorders

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