Investigation into the genetics of fetal congenital lymphatic anomalies

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Abstract

Objective:

Congenital lymphatic anomalies (LAs) arise due to defects in lymphatic development and often present in utero as pleural effusion, chylothorax, nuchal and soft tissue edema, ascites, or hydrops. Many LAs are caused by single nucleotide variants, which are not detected on routine prenatal testing.

Methods:

Demographic data were compared between two subcohorts, those with clinically significant fetal edema (CSFE) and isolated fetal edema. A targeted variant analysis of LA genes was performed using American College of Medical Genetics criteria on whole exome sequencing (WES) data generated for 71 fetal edema cases who remained undiagnosed after standard workup.

Results:

CSFE cases had poor outcomes, including preterm delivery, demise, and maternal preeclampsia. Pathogenic and likely pathogenic variants were identified in 7% (5/71) of cases, including variants in RASopathy genes, RASA1, SOS1, PTPN11, and a novel PIEZO1 variant. Variants of uncertain significance (VOUS) were identified in 45% (32/71) of cases. In CSFEs, VOUS were found in CELSR1, EPHB4, TIE1, PIEZO1, ITGA9, RASopathy genes, SOS1, SOS2, and RAF1.

Conclusions:

WES identified pathogenic and likely pathogenic variants and VOUS in LA genes in 51% of fetal edema cases, supporting WES and expanded hydrops panels in cases of idiopathic fetal hydrops and fluid collections.

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Most cited references 57

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Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Sue Richards, Nazneen Aziz, Sherri Bale … (2015)

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.

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The RASopathies.

Katherine Rauen (2013)

The RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. These disorders include neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. Because of the common underlying Ras/MAPK pathway dysregulation, the RASopathies exhibit numerous overlapping phenotypic features. The Ras/MAPK pathway plays an essential role in regulating the cell cycle and cellular growth, differentiation, and senescence, all of which are critical to normal development. Therefore, it is not surprising that Ras/MAPK pathway dysregulation has profound deleterious effects on both embryonic and later stages of development. The Ras/MAPK pathway has been well studied in cancer and is an attractive target for small-molecule inhibition to treat various malignancies. The use of these molecules to ameliorate developmental defects in the RASopathies is under consideration.

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Clinical application of exome sequencing in undiagnosed genetic conditions

Anna C Need, Vandana Shashi, Yuki Hitomi … (2012)

Background There is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinical setting that includes patients with a broad range of phenotypic presentations. Methods The authors present a pilot programme of whole-exome sequencing on 12 patients with unexplained and apparent genetic conditions, along with their unaffected parents. Unlike many previous studies, the authors did not seek patients with similar phenotypes, but rather enrolled any undiagnosed proband with an apparent genetic condition when predetermined criteria were met. Results This undertaking resulted in a likely genetic diagnosis in 6 of the 12 probands, including the identification of apparently causal mutations in four genes known to cause Mendelian disease (TCF4, EFTUD2, SCN2A and SMAD4) and one gene related to known Mendelian disease genes (NGLY1). Of particular interest is that at the time of this study, EFTUD2 was not yet known as a Mendelian disease gene but was nominated as a likely cause based on the observation of de novo mutations in two unrelated probands. In a seventh case with multiple disparate clinical features, the authors were able to identify homozygous mutations in EFEMP1 as a likely cause for macular degeneration (though likely not for other features). Conclusions This study provides evidence that next-generation sequencing can have high success rates in a clinical setting, but also highlights key challenges. It further suggests that the presentation of known Mendelian conditions may be considerably broader than currently recognised.

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Author and article information

Journal

Journal ID (nlm-journal-id): 8106540

Journal ID (pubmed-jr-id): 6583

Journal ID (nlm-ta): Prenat Diagn

Journal ID (iso-abbrev): Prenat Diagn

Title: Prenatal diagnosis

ISSN (Print): 0197-3851

ISSN (Electronic): 1097-0223

Publication date Nihms-submitted: 21 April 2023

Publication date (Print): June 2023

Publication date (Electronic): 03 April 2023

Publication date PMC-release: 10 July 2023

Volume: 43

Issue: 6

Pages: 703-716

Affiliations

[1 ]Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA

[2 ]Department of Obstetrics and Gynecology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA

[3 ]Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, USA

[4 ]Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA

[5 ]Department of Pediatrics, Columbia University Vagelos College of Physicians andSurgeons, New York, New York, USA

[6 ]Department of Surgery, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA

Author notes

Correspondence Carrie J. Shawber, 630 W. 168th Street, New York, NY 10032, USA. cjs2002@ 123456cumc.columbia.edu

Author information

Jessica Giordano http://orcid.org/0000-0002-2265-0691

Madhulatha Pantrangi http://orcid.org/0009-0003-1013-1717

Joshua E. Motelow http://orcid.org/0000-0002-4367-4182

Ron Wapner http://orcid.org/0000-0003-0727-1244

Carrie J. Shawber http://orcid.org/0000-0003-2654-3559

Article

Manuscript ID: NIHMS1889580

DOI: 10.1002/pd.6345

PMC ID: 10330091

PubMed ID: 36959127

SO-VID: ff3db087-7d07-4995-8226-2cce02de6bc6

License:

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and in any medium, provided the original work is properly cited and is not used for commercial purposes.

Investigation into the genetics of fetal congenital lymphatic anomalies

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Abstract

Objective:

Methods:

Results:

Conclusions:

Related collections

Advocacy for Maternal and Women’s Health

Most cited references 57

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

The RASopathies.

Clinical application of exome sequencing in undiagnosed genetic conditions

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