Juvenile myelomonocytic leukemia-associated variants are associated with neo-natal lethal Noonan syndrome

Mason‐Suares, Heather; Toledo, Diana M; Gekas, Jean; Lafferty, Katherine; Meeks, Naomi; Pacheco, M. Cristina; Sharpe, David; Mullen, Thomas E.; Lebo, Matthew S.

doi:10.1038/ejhg.2016.202

Cited by 17 publications

(14 citation statements)

References 23 publications

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“…Fourth, with SNP-array analysis and massive parallel sequencing other major genetic causes of NIHF were excluded. This included hematological disease, chromosomal aneuploidies, and variants in genes known to cause lymphatic dysplasia including RASopathies, (generalized) lymphedema, or inborn errors of metabolism (Bellini et al, 2015;Hakami, Dillon, Lebo, & Mason-Suares, 2016;Houweling et al, 2010;Johnston et al, 2018;Joyce et al, 2016;Mardy et al, 2019;Martin-Almedina et al, 2016;Mason-Suares et al, 2017;Meng et al, 2019;Moreno et al, 2013;Pagnamenta et al, 2019;Quinlan-Jones et al, 2019;Stuurman et al, 2019;Sudrie-Arnaud et al, 2018;Weissbach et al, 2019;Yates et al, 2017). Finally, no other causes for the NIHF, such as intra-uterine infections and cardiac abnormalities, were present.…”

Section: The Lymphatic Dysplasia and Hydrops Phenotypementioning

confidence: 99%

A homozygous variant in growth and differentiation factor 2 (GDF2) may cause lymphatic dysplasia with hydrothorax and nonimmune hydrops fetalis

Aukema

Brinke

Timens

et al. 2020

American J of Med Genetics Pt A

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Section: The Lymphatic Dysplasia and Hydrops Phenotypementioning

confidence: 99%

A homozygous variant in growth and differentiation factor 2 (GDF2) may cause lymphatic dysplasia with hydrothorax and nonimmune hydrops fetalis

Aukema

Brinke

Timens

et al. 2020

American J of Med Genetics Pt A

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“…It was thus suggested that JMML variants can be embryonic lethal as a result of a strong increase in RAS pathway activity. This concept was recently illustrated by the description of four cases of a prenatally or neonatally lethal form of NS associated with PTPN11 or NRAS variants that had previously been described in JMML . It is not clear whether this lethality results from changes in apoptosis pathways during embryonic development; further research on possible connections between apoptosis and RAS pathway activation is warranted.…”

Section: Defects In Acad Associated With Activating Mutations Of the mentioning

confidence: 99%

FAS and RAS related Apoptosis defects: From autoimmunity to leukemia

Meynier

Rieux-Laucat

2018

Immunological Reviews

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Summary The human adaptive immune system recognizes almost all the pathogens that we encounter and all the tumor antigens that may arise during our lifetime. Primary immunodeficiencies affecting lymphocyte development or function therefore lead to severe infections and tumor susceptibility. Furthermore, the fact that autoimmunity is a frequent feature of primary immunodeficiencies reveals a third function of the adaptive immune system: its self‐regulation. Indeed, the generation of a broad repertoire of antigen receptors (via a unique strategy of random somatic rearrangements of gene segments in T cell and B cell receptor loci) inevitably creates receptors with specificity for self‐antigens and thus leads to the presence of autoreactive lymphocytes. There are many different mechanisms for controlling the emergence or action of autoreactive lymphocytes, including clonal deletion in the primary lymphoid organs, receptor editing, anergy, suppression of effector lymphocytes by regulatory lymphocytes, and programmed cell death. Here, we review the genetic defects affecting lymphocyte apoptosis and that are associated with lymphoproliferation and autoimmunity, together with the role of somatic mutations and their potential involvement in more common autoimmune diseases.

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“…Therefore, it was hypothesized that if a cancer-associated variant is inherited in the germline, it would cause severe fetus malformations that would not be compatible with long-term survival [ 16 ]. Since 2005, there have been only a handful of reports available describing such cases [ 17 ]. Variant p.Glu76Gln has previously been reported only in association with leukemia and other cancers, but it has not been reported to be inherited in the germline [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

The Fetal Phenotype of Noonan Syndrome Caused by Severe, Cancer-Related PTPN11 Variants

et al. 2020

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Case series Patients: Female, 37-year-old • Female, 31-year-old Final Diagnosis: Noonan syndrome Symptoms: Fetal nuchal fold thickening Medication: — Clinical Procedure: Chorionic villi sampling Specialty: Genetics • Obstetrics and Gynecology Objective: Rare disease Background: The nuchal translucency measurement is the major focus of an early fetal ultrasound scan, with the goal to identify various inherited conditions, such as chromosomal aberrations and others. The diagnostic strategy for fetuses with increased nuchal translucency and normal karyotype is not clearly defined and may vary between countries. Case Reports: We describe 2 cases of Noonan syndrome diagnosed prenatally by ultrasound scanning and genetic testing. The prenatal ultrasound scans showed abnormal nuchal translucencies, cystic lymphangioma/cystic hygroma, and other findings. Both fetuses had normal karyotype; however, after additional analysis, pathogenic variants of the PTPN11 gene (encoding SH2 domain-containing protein tyrosine phosphatase) were found, previously frequently described as somatic variants in hematological malignancies in postnatal life, but not previously described with severe prenatal phenotype of Noonan syndrome. Conclusions: Our case reports confirm the hypothesis that severe, cancer related PTPN11 variants cause severe Noonan syndrome prenatal phenotype, when inherited in the germline. Analysis of pathogenic variants associated with Noonan syndrome should be included in the prenatal diagnostics for fetuses with increased nuchal translucency and normal karyotype.

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Juvenile myelomonocytic leukemia-associated variants are associated with neo-natal lethal Noonan syndrome

Cited by 17 publications

References 23 publications

A homozygous variant in growth and differentiation factor 2 (GDF2) may cause lymphatic dysplasia with hydrothorax and nonimmune hydrops fetalis

A homozygous variant in growth and differentiation factor 2 (GDF2) may cause lymphatic dysplasia with hydrothorax and nonimmune hydrops fetalis

FAS and RAS related Apoptosis defects: From autoimmunity to leukemia

The Fetal Phenotype of Noonan Syndrome Caused by Severe, Cancer-Related PTPN11 Variants

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