Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management

Mattassi, Raul; Manara, Elena; Colombo, Piergiuseppe; Manara, Sofia; Porcella, Antonella; Bruno, Giulia; Bruson, Alice; Bertelli, Matteo

doi:10.1016/j.jvs.2017.02.034

Cited by 21 publications

(19 citation statements)

References 43 publications

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“…Here, we again confirmed that most venous malformations are caused by somatic mutations in PIK3CA and TEK [ 22 ], although a genotype–phenotype correlation is difficult to establish, since patients with the same mutation can manifest different kinds of malformations. For instance, since most venous malformations affecting limbs are painful [ 23 ], we found such features in 8/10 patients with mutations in TEK , but in only 3/20 of patients with mutations in PIK3CA .…”

Section: Discussionsupporting

confidence: 73%

Somatic Variant Analysis Identifies Targets for Tailored Therapies in Patients with Vascular Malformations

Paolacci

Mattassi

Marceddu³

et al. 2020

JCM

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Vascular malformations include various disorders characterized by morphological, structural and/or functional alterations of blood and lymph vessels. Most are sporadic, due to somatic mutations. Here, we report a cohort of patients with sporadic and/or unifocal vascular malformations, in whom we carried out next generation sequencing analysis of a panel of genes associated with vascular malformations. The 115 patients analyzed were from different clinical centres. In 37 patients (32%), we found pathogenic mutations: most of these were gain–of–function mutations in PIK3CA (18%, 21/115) and TEK (13/115, 11%). We also found mutations in GNAQ, CCM2 and PTEN. Identifying pathogenic variants in patients with vascular malformations can help improve management, particularly in cases with activating mutations that cause an increase in cell proliferation. Personalized pharmacological treatment, if possible, is now considered preferable to surgery and can help prevent recurrences, i.e., long–term complications of residual malformation or regrowth of tumors. For instance, rapamycin is currently being investigated for the treatment of various vascular malformations associated with hyperactivation of the phosphoinositide 3–kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway.

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Section: Discussionsupporting

confidence: 73%

Somatic Variant Analysis Identifies Targets for Tailored Therapies in Patients with Vascular Malformations

Paolacci

Mattassi

Marceddu³

et al. 2020

JCM

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“…Targeted NGS is also particularly indicated for the identification of germline and somatic variants. In this regard, a depth coverage of 100× is sufficient to detect at least a 6% imbalance between unaffected and affected tissues 81. If somatic mutations are involved in the aetiology of lymphatic malformations more than was previously thought, improvement in the detection rate of somatic mutations and the capacity to distinguish mutant tissues from non-mutant tissues will help in the planning of targeted intervention for the affected regions.…”

Section: Discussionmentioning

confidence: 99%

Genetic tests in lymphatic vascular malformations and lymphedema

Michelini

Paolacci²,

Manara³

et al. 2018

J Med Genet

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Syndromes with lymphatic malformations show phenotypic variability within the same entity, clinical features that overlap between different conditions and allelic as well as heterogeneity. The aim of this review is to provide a comprehensive clinical genetic description of lymphatic malformations and the techniques used for their diagnosis, and to propose a flowchart for genetic testing. Literature and database searches were performed to find conditions characterised by lymphatic malformations or the predisposition to lymphedema after surgery, to identify the associated genes and to find the guidelines and genetic tests currently used for the molecular diagnosis of these disorders. This search allowed us to identify several syndromes with lymphatic malformations that are characterised by a great heterogeneity of phenotypes, alleles and, and a high frequency of sporadic cases, which may be associated with somatic mutations. For these disorders, we found many diagnostic tests, an absence of harmonic guidelines for molecular diagnosis and well-established clinical guidelines. Targeted sequencing is the preferred method for the molecular diagnosis of lymphatic malformations. These techniques are easy to implement and have a good diagnostic success rates. In addition, they are relatively inexpensive and permit parallel analysis of all known disease-associated genes. The targeted sequencing approach has improved the diagnostic process, giving patients access to better treatment and, potentially, to therapy personalised to their genetic profiles. These new techniques will also facilitate the prenatal and early postnatal diagnosis of congenital lymphatic conditions and the possibility of early intervention.

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“…DNA samples were processed for library preparation targeted capture and sequencing as previous reported [ 57 , 58 ]. In particular, 150 bp paired-end reads sequencing was performed on MiSeq personal sequencer (Illumina, San Diego, CA) according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Clinical Evaluation of a Custom Gene Panel as a Tool for Precision Male Infertility Diagnosis by Next-Generation Sequencing

Cannarella

Precone²,

Busetto

et al. 2020

Life

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Background: Up to 15% of couples are infertile and male factor infertility accounts for approximately 50% of these cases. Male infertility is a multifactorial pathological condition. The genetic of male infertility is very complex and at least 2000 genes are involved in its etiology. Genetic testing by next-generation sequencing (NGS) technologies can be relevant for its diagnostic value in male infertile patients. Therefore, the aim of this study was to implement the diagnostic offer with the use of an NGS panel for the identification of genetic variants. Methods: We developed an NGS gene panel that we used in 22 male infertile patients. The panel consisted of 110 genes exploring the genetic causes of male infertility; namely spermatogenesis failure due to single-gene mutations, central hypogonadism, androgen insensitivity syndrome, congenital hypopituitarism, and primary ciliary dyskinesia. Results: NGS and a subsequent sequencing of the positive pathogenic or likely pathogenic variants, 5 patients (23%) were found to have a molecular defect. In particular, pathogenic variants were identified in TEX11, CCDC39, CHD7, and NR5A1 genes. Moreover, 14 variants of unknown significance and 7 novel variants were found that require further functional studies and family segregation. Conclusion: This extended NGS-based diagnostic approach may represent a useful tool for the diagnosis of male infertility. The development of a custom-made gene panel by NGS seems capable of reducing the proportion of male idiopathic infertility.

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Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management

Cited by 21 publications

References 43 publications

Somatic Variant Analysis Identifies Targets for Tailored Therapies in Patients with Vascular Malformations

Somatic Variant Analysis Identifies Targets for Tailored Therapies in Patients with Vascular Malformations

Genetic tests in lymphatic vascular malformations and lymphedema

Clinical Evaluation of a Custom Gene Panel as a Tool for Precision Male Infertility Diagnosis by Next-Generation Sequencing

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