Clinical and genetic description of patients with prenatally identified cardiac tumors

Mariscal‐Mendizábal, Luisa F.; Sevilla‐Montoya, Rosalba; Martínez‐García, Alfonso J.; Aláez-Verson, Carmen; Monroy-Muñoz, Irma Eloísa; Pérez‐Durán, Javier; Cerón‐Albarrán, Jorge A.; Carrillo‐Sánchez, Karol; Molina-Garay, Carolina; Flores-Lagunes, Luis Leonardo; Jiménez-Olivares, M.; Aguinaga‐Ríos, Mónica

doi:10.1002/pd.5521

Cited by 9 publications

(12 citation statements)

References 19 publications

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“…Rhabdomyomas are the most common type of prenatal cardiac tumors, when isolated, 50% to 70% are related to the tuberous sclerosis complex (TSC). 26 A recent study on 10 prenatally detected cardiac tumors, which were postnatally confirmed as rhabdomyomas, revealed three TSC2 mutations in four patients by NGS. 26 Together with our data, it is important to take consideration of conventional mutation screening in TSC2 gene for prenatal identified cardiac rhabdomyoma.…”

Section: Discussionmentioning

confidence: 97%

“…Clinical data of the study cohort Age of pregnant women (median) y (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41) Gestational weeks (median) wk Sex of fetuses (M/ Data analysis and filtering were documented detailed in our previous publications. 12 The raw image files were processed using bcl2fastq software (Illumina) for base calling and raw data generation.…”

Section: T a B L Ementioning

confidence: 99%

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Prenatal exome sequencing in fetuses with congenital heart defects

et al. 2020

Clinical Genetics

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The genetic diagnosis of congenital heart defects (CHDs) is challenging because of genetic and phenotypic heterogeneity. The aim of our study was to evaluate the clinical value of whole exome sequencing (WES) in the prenatal diagnosis of CHDs in a large cohort. Trio‐based WES was performed in 260 fetuses with CHDs negative for karyotype and chromosome microarray analysis results. WES produced a diagnostic yield of 10% (26/260) in the entire cohort. Relative high diagnostic rate was observed in cases with cardiac rhabdomyoma (60%), complex CHDs (16.7%), septal defect (14.0%), and conotruncal defect (9.9%). There was no significant difference between the diagnostic yields in simple and complex CHDs groups (9.9% vs 16.7%), and in non‐isolated and isolated CHDs groups (15.7% vs 7.9%). The diagnostic yields in cases with CHDs with soft markers, CHDs with fetal growth restriction, and CHDs with other structural anomalies (syndromic CHDs) were 0 (0/13), 50% (1/2) and 18.2% (10/55), respectively. Variants of unknown significance were detected in 16 (6.2%) fetuses, and secondary findings in 7 (2.7%) cases. Variants in 14 candidate genes were identified. Our study demonstrates an incremental diagnostic yield by trio‐based WES in the prenatal diagnosis of CHDs after routine tests, not as high as expected.

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Section: Discussionmentioning

confidence: 97%

Section: T a B L Ementioning

confidence: 99%

Prenatal exome sequencing in fetuses with congenital heart defects

et al. 2020

Clinical Genetics

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“…The first detected alteration in TSC fetus is cardiac rhabdomyoma, a benign fetal cardiac tumor commonly associated with TSC (Bader et al, 2003;Saada et al, 2009), and this was the case for the majority of the cases investigated here. With the development of high-resolution ultrasound echocardiography and magnetic resonance, the prenatal diagnosis in the second and third trimesters of pregnancy increased considerably (Bejiqi et al, 2017;Mariscal-Mendizábal et al, 2019). Prenatal diagnosis has gained interest with recent data suggesting that maternal treatment with inhibitors of the mTOR pathway (everolimus and sirolimus) may be beneficial for rhabdomyomas without any serious adverse events reported (Barnes et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Progression of Fetal Brain Lesions in Tuberous Sclerosis Complex

Gelot

Represa

2020

Front. Neurosci.

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Tuberous sclerosis (TSC) is a multisystem autosomal dominant genetic disorder due to loss of function of TSC1/TSC2 resulting in increased mTOR (mammalian target of rapamycin) signaling. In the brain, TSC is characterized by the formation of specific lesions that include subependymal and white matter nodules and cortical tubers. Cells that constitute TSC lesions are mainly Giant cells and dysmorphic neurons and astrocytes, but normal cells also populate the tubers. Although considered as a developmental disorder, the histopathological features of brain lesions have been described in only a limited number of fetal cases, providing little information on how these lesions develop. In this report we characterized the development of TSC lesions in 14 fetal brains ranging from 19 gestational weeks (GW) to term and 2 postnatal cases. The study focused on the telencephalon at the level of the caudothalamic notch. Our data indicate that subcortical lesions, forming within and at the vicinity of germinative zones, are the first alterations (already detected in 19GW brains), characterized by the presence of numerous dysmorphic astrocytes and Giant, balloon-like, cells. Our data show that cortical tuber formation is a long process that initiates with the presence of dysmorphic astrocytes (by 19-21GW), progress with the apparition of Giant cells (by 24GW) and mature with the appearance of dysmorphic neurons by the end of gestation (by 36GW). Furthermore, the typical tuberal aspect of cortical lesions is only reached when bundles of neurofilament positive extensions delineate the bottom of the cortical lesion (by 36GW). In addition, our study reveals the presence of Giant cells and dysmorphic neurons immunopositive for interneuron markers such as calbindin and parvalbumin, suggesting that TSC lesions would be mosaic lesions generated from different classes of progenitors.

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“…Most of the studies on TSC have been implemented in populations of Europe, USA, Canada and Brazil; hence, it is relevant to include more cases from other Latin American countries in order to investigate and expand the responsible TSC genotype, better delineate the clinical features and contribute to possibly identifying genotype-phenotype correlations. To our knowledge, there are only two previous published molecular studies of TSC patients in Mexico: one involving three patients with early-stage polycystic kidney disease that were molecularly confirmed to represent TSC2/PKD1 contiguous gene syndrome cases 17 and one involving three TSC2-cases with prenatally documented cardiac rhabdomyomas 18 . Therefore, in order to improve our knowledge of this disease and to spread the use of innovative and highly sensitive molecular techniques such as MLPA and NGS for the diagnosis of TSC in countries where the disease has been under-studied, we used a combined molecular strategy to analyze the mutational spectrum of TSC1 and TSC2 and the principal clinical features of 66 Mexican-descent unrelated cases of TSC.…”

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confidence: 99%

First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants

Reyna-Fabián

Hernández‐Martínez

Alcántara-Ortigoza

et al. 2020

Sci Rep

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echavarría 4 , carlos G. todd-Quiñones 5,6 & Ariadna González-del Angel 1* the aim of this study was to improve knowledge of the mutational spectrum causing tuberous sclerosis complex (tSc) in a sample of Mexican patients, given the limited information available regarding this disease in Mexico and Latin America. Four different molecular techniques were implemented to identify from single nucleotide variants to large rearrangements in the TSC1 and TSC2 genes of 66 unrelated Mexican-descent patients that clinically fulfilled the criteria for a definitive TSC diagnosis. The mutation detection rate was 94%, TSC2 pathogenic variants (pV) prevailed over TSC1 PV (77% vs. 23%) and a recurrent mutation site (hotspot) was observed in TSC1 exon 15. Interestingly, 40% of the identified mutations had not been previously reported. The wide range of novels PV made it difficult to establish any genotype-phenotype correlation, but most of the pV conditioned neurological involvement (intellectual disability and epilepsy). Our 3D protein modeling of two variants classified as likely pathogenic demonstrated that they could alter the structure and function of the hamartin (TSC1) or tuberin (TSC2) proteins. Molecular analyses of parents and first-degree affected family members of the index cases enabled us to distinguish familial (18%) from sporadic (82%) cases and to identify one case of apparent gonadal mosaicism. Tuberous sclerosis complex (TSC; MIM #191100, MIM #613254) is an autosomal dominant syndrome characterized by the presence of multiple hamartomas in different organs and systems. The incidence is about 0.1-1/10,000 births and the prevalence varies from 1/6,000 to 1/10,000 among different populations 1-3. The manifestations of TSC are highly variable among individuals and even within the same family 4 , but the most common clinical features are localized in skin and central nervous system 5-7. TSC is caused by pathogenic variants (PV) in the tumor suppressor-genes, TSC1 (tuberous sclerosis complex 1, MIM *605284, 9q34.13) and TSC2 (tuberous sclerosis complex 2, MIM *191092, 16p13.3). These PV can be detected by various molecular techniques, such as single-strand conformational polymorphism (SSCP), direct Sanger sequencing (SS), multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS). There are currently more than 2,000 pathogenic TSC1/TSC2 variants described in the Leiden Open Variation Database (www.lovd.nl/TSC1 and www.lovd.nl/TSC2) 8 ; of them, 21-26% are located in TSC1 and 69-79% in TSC2 9,10. In approximately 5-25% of the analyzed TSC cases, a PV could not be identified in either gene 9,11,12. The emergence of new techniques, such as NGS, has significantly increased the mutation detection rate

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Clinical and genetic description of patients with prenatally identified cardiac tumors

Cited by 9 publications

References 19 publications

Prenatal exome sequencing in fetuses with congenital heart defects

Prenatal exome sequencing in fetuses with congenital heart defects

Progression of Fetal Brain Lesions in Tuberous Sclerosis Complex

First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants

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