Further Evidence for the Implication of LZTR1, a Gene not Associated with the Ras-Mapk Pathway, in the Pathogenesis of Noonan Syndrome

Ghedira, Nehla; Kraoua, Lilia; Lagarde, Arnaud; Abdelaziz, Rim Ben; Olschwang, Sylviane; Desvignes, Jean-Pierre; Abdelhak, Sonia; Monastiri, K.; Lévy, Nicolas; Sandre-Giovannoli, Annachiara De; Mrad, Ridha

doi:10.4172/0974-8369.1000414

Cited by 7 publications

(8 citation statements)

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“…TGF-beta signaling plays a critical role in cardiac development and cardiovascular physiology, leading to pulmonary arterial hypertension and cardiac abnormalities in mice when dysregulated {Drake 2015; Soubrier 2013}. LZTR1 encodes a member of the BTB-Kelch superfamily that is highly expressed in the heart during development and has been associated with Noonan {Yamamoto 2015; Ghedira 2017} and DiGeorge Syndromes {Kurahashi 1995}, both of which are characterized by CHD. KCTD10 binds to and represses the transcriptional activity of TBX5 (T-box transcription factor), which plays a dose-dependent role in the formation of cardiac chambers {Tong 2014}.…”

Section: Discussionmentioning

confidence: 99%

Early post-zygotic mutations contribute to congenital heart disease

Hsieh

et al. 2019

Preprint

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53Background 54The contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital 55 heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and 56 cardiovascular tissue has not been determined. 58Results 59We developed a computational method, Expectation-Maximization-based detection of Mosaicism (EM-60 mosaic), to analyze mosaicism in exome sequences of 2530 CHD proband-parent trios. EM-mosaic 61 detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 62 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac 63 tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 64 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic 65 variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were 66 confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, 67 suggesting a role in CHD. The frequency of mosaic variants above 10% mosaicism was 0.13/person in 68 blood and 0.14/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available 69 revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele 70 fraction. 72 Conclusions 73We estimate that ~1% of CHD probands have a mosaic variant detectable in blood that could contribute 74 to cardiac malformations, particularly those damaging variants expressed at higher allele fraction 75 compared to benign variants. Although blood is a readily-available DNA source, cardiac tissues analyzed 76 contributed ~5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses. 77 78 Keywords 79 Mosaic, Somatic, Congenital Heart Disease, Exome Sequencing 80 2 Background 81 Mosaicism results from somatic mutations that arise post-zygotically in an early embryonic cell, 82 resulting in two or more cell populations with distinct genotypes in the developing embryo {Biesecker 83 2013}. The developmental status of the early embryonic cell at the time of mutagenesis determines the 84 proportion of variant-carrying cells and the tissue distribution of these cells in the post-natal child {Acuna-85 Hidalgo 2015}. While germline variants have a variant allele frequency (VAF) of 0.5, somatic mosaic 86 variants have a significantly lower VAF. 87 Post-zygotic mosaic mutations have been implicated in several diseases including non-malignant 88 developmental disorders such as overgrowth syndromes {Poduri 2013; Lindhurst 2012; Kurek 2016}, 89 structural brain malformations {Poduri 2012; Jamuar 2014; Riviere 2012; Lee 2012}, epilepsy {Stosser 90 2018}, and autism spectrum disorder {Lim 2017; Krupp 2017; Freed 2016; Dou 2017}. Recent analyses 91 also identified mosaic variants in a cohort of patients with congenital heart disease (CHD) {Manheimer 92 2018}, but the prev...

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Section: Discussionmentioning

confidence: 99%

Early post-zygotic mutations contribute to congenital heart disease

Hsieh

et al. 2019

Preprint

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“…In the present cohort, the single LZTR1 ‐associated NS patient showed MVD and pulmonary valve dysplasia, without stenosis. According to previous published reports, LZTR1 clinical phenotype is similar to that of PTPN11 ‐positive‐affected individuals; however, there are contrasting results about prevalence of cardiac involvement, ranging from 50% to 100%, with a relatively high incidence of HCM (Chinton et al, 2020; Ghedira et al, 2017; Johnston et al, 2018; Li et al, 2019; Umeki et al, 2019; Yamamoto et al, 2015).…”

Section: Discussionmentioning

confidence: 92%

“… f Chinton et al, 2020; Ghedira et al, 2017; Johnston et al, 2018; Li et al, 2019; Umeki et al, 2019; Yamamoto et al, 2015. …”

Section: Resultsmentioning

confidence: 99%

“…Lee et al, 2020;Li et al, 2019;Yaoita et al, 2016. dCroonen et al, 2013;Digilio et al, 2011;Ko et al, 2008;Kobayashi et al, 2010;Kouz et al, 2016;Lee et al, 2011;Li et al, 2019;Pandit et al, 2007;Razzaque et al, 2007. eBaldassarre et al, 2014;Capalbo et al, 2012;Cordeddu et al, 2009;Croonen et al, 2013;Digilio et al, 2011;Gripp et al, 2013;Hoban et al, 2012;Komatsuzaki et al, 2010;B. H. Lee et al, 2011;Li et al, 2019. fChinton et al, 2020;Ghedira et al, 2017;…”

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Genotype‐cardiac phenotype correlations in a large single‐center cohort of patients affected by RASopathies: Clinical implications and literature review

Leoni

Blandino

Delogu

et al. 2021

American J of Med Genetics Pt A

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Congenital heart disease (CHD) and hypertrophic cardiomyopathy (HCM) are common features in patients affected by RASopathies. The aim of this study was to assess genotype‐ phenotype correlations, focusing on the cardiac features and outcomes of interventions for cardiac conditions, in a single‐center cohort of 116 patients with molecularly confirmed diagnosis of RASopathy, and compare these findings with previously published data. All enrolled patients underwent a comprehensive echocardiographic examination. Relevant information was also retrospectively collected through the analysis of clinical records. As expected, significant associations were found between PTPN11 mutations and pulmonary stenosis (both valvular and supravalvular) and pulmonary valve dysplasia, and between SOS1 mutations and valvular defects. Similarly, HRAS mutations were significantly associated with HCM. Potential associations between less prevalent mutations and cardiac defects were also observed, including RIT1 mutations and HCM, SOS2 mutations and septal defects, and SHOC2 mutations and septal and valve abnormalities. Patients with PTPN11 mutations were the most likely to require both a primary treatment (transcatheter or surgical) and surgical reintervention. Other cardiac anomalies less reported until recently in this population, such as isolated functional and structural mitral valve diseases, as well as a sigmoid‐shaped interventricular septum in the absence of HCM, were also reported. In conclusion, our study confirms previous data but also provides new insights on cardiac involvement in RASopathies. Further research concerning genotype/phenotype associations in RASopathies could lead to a more rational approach to surgery and the consideration of drug therapy in patients at higher risk due to age, severity, anatomy, and comorbidities.

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“…TGF-beta signaling plays a critical role in cardiac development and cardiovascular physiology, leading to pulmonary arterial hypertension and cardiac abnormalities in mice when dysregulated [17,74]. LZTR1 encodes a member of the BTB-Kelch superfamily that is highly expressed in the heart during development and has been associated with Noonan [26,85] and DiGeorge Syndromes [46], both of which are characterized by CHD. The individual with the LZTR1 damaging mosaic variant did have pulmonary lymphangiectasias that are a less common feature of Noonan syndrome, but did not have other clinical findings common to Noonan syndrome.…”

Section: Discussionmentioning

confidence: 99%

EM-mosaic detects mosaic point mutations that contribute to congenital heart disease

et al. 2020

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Background: The contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined. Methods: We developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD probandparent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available. Results: EM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.

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Further Evidence for the Implication of LZTR1, a Gene not Associated with the Ras-Mapk Pathway, in the Pathogenesis of Noonan Syndrome

Cited by 7 publications

References 20 publications

Early post-zygotic mutations contribute to congenital heart disease

Early post-zygotic mutations contribute to congenital heart disease

Genotype‐cardiac phenotype correlations in a large single‐center cohort of patients affected by RASopathies: Clinical implications and literature review

EM-mosaic detects mosaic point mutations that contribute to congenital heart disease

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