Publications by authors named "Molly C Schroeder"

5 Publications

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Systematic evidence-based review: outcomes from exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability.

Genet Med 2020 Jun 23;22(6):986-1004. Epub 2020 Mar 23.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Purpose: Exome and genome sequencing (ES/GS) are performed frequently in patients with congenital anomalies, developmental delay, or intellectual disability (CA/DD/ID), but the impact of results from ES/GS on clinical management and patient outcomes is not well characterized. A systematic evidence review (SER) can support future evidence-based guideline development for use of ES/GS in this patient population.

Methods: We undertook an SER to identify primary literature from January 2007 to March 2019 describing health, clinical, reproductive, and psychosocial outcomes resulting from ES/GS in patients with CA/DD/ID. A narrative synthesis of results was performed.

Results: We retrieved 2654 publications for full-text review from 7178 articles. Only 167 articles met our inclusion criteria, and these were primarily case reports or small case series of fewer than 20 patients. The most frequently reported outcomes from ES/GS were changes to clinical management or reproductive decision-making. Two studies reported on the reduction of mortality or morbidity or impact on quality of life following ES/GS.

Conclusion: There is evidence that ES/GS for patients with CA/DD/ID informs clinical and reproductive decision-making, which could lead to improved outcomes for patients and their family members. Further research is needed to generate evidence regarding health outcomes to inform robust guidelines regarding ES/GS in the care of patients with CA/DD/ID.
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http://dx.doi.org/10.1038/s41436-020-0771-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222126PMC
June 2020

Diagnostic Utility of Next-Generation Sequencing for Disorders of Somatic Mosaicism: A Five-Year Cumulative Cohort.

Am J Hum Genet 2019 10;105(4):734-746

Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address:

Disorders of somatic mosaicism (DoSM) are a diverse group of syndromic and non-syndromic conditions caused by mosaic variants in genes that regulate cell survival and proliferation. Despite overlap in gene space and technical requirements, few clinical labs specialize in DoSM compared to oncology. We adapted a high-sensitivity next-generation sequencing cancer assay for DoSM in 2014. Some 343 individuals have been tested over the past 5 years, 58% of which had pathogenic and likely pathogenic (P/LP) findings, for a total of 206 P/LP variants in 22 genes. Parameters associated with the high diagnostic yield were: (1) deep sequencing (∼2,000× coverage), (2) a broad gene set, and (3) testing affected tissues. Fresh and formalin-fixed paraffin embedded tissues performed equivalently for identification of P/LP variants (62% and 71% of individuals, respectively). Comparing cultured fibroblasts to skin biopsies suggested that culturing might boost the allelic fraction of variants that confer a growth advantage, specifically gain-of-function variants in PIK3CA. Buccal swabs showed high diagnostic sensitivity in case subjects where disease phenotypes manifested in the head or brain. Peripheral blood was useful as an unaffected comparator tissue to determine somatic versus constitutional origin but had poor diagnostic sensitivity. Descriptions of all tested individuals, specimens, and P/LP variants included in this cohort are available to further the study of the DoSM population.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817554PMC
October 2019

Somatic mosaicism for a novel mutation in a male with severe pyruvate dehydrogenase complex deficiency.

Mol Genet Metab Rep 2014 28;1:362-367. Epub 2014 Aug 28.

Center for Human Genetics Laboratory University Hospitals Case Medical Center, Cleveland, OH, USA.

Pyruvate dehydrogenase complex (PDC) deficiencies are mostly due to mutations in the X-linked gene. Males with hemizygous mutations are clinically more severely affected, while those with mosaic mutations may manifest milder phenotypes. We report a patient harboring a novel, mosaic missense mutation, c.523G > A (p.A175T), with a severe clinical presentation of congenital microcephaly, significant brain abnormalities, persistent seizures, profound developmental delay, and failure to thrive. We review published cases of mosaicism.
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http://dx.doi.org/10.1016/j.ymgmr.2014.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121365PMC
August 2014

Regulation of the Hippo pathway by cell architecture and mechanical signals.

Semin Cell Dev Biol 2012 Sep 26;23(7):803-11. Epub 2012 Jun 26.

Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.

The Hippo signaling pathway is an evolutionarily conserved mediator of growth control, cell fate decisions and stem cell identity. At the heart of the pathway is a kinase cascade that is reminiscent of other signaling pathways, but recent studies indicate that the Hippo pathway is unique in that it is regulated by cellular architecture and the mechanical properties of the environment. The Hippo pathway may thus serve as a sensor of tissue structure and mechanical tension, integrating information regarding the size and shape of an organ into cellular behavior, such as whether or not to proliferate. In this review we summarize recent discoveries regarding the regulation of the Hippo pathway by cellular polarity, cell junctions, and the cytoskeleton and discuss how these data inform the study of development and disease.
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http://dx.doi.org/10.1016/j.semcdb.2012.06.001DOI Listing
September 2012

Tumor suppression by cell competition through regulation of the Hippo pathway.

Proc Natl Acad Sci U S A 2012 Jan 21;109(2):484-9. Epub 2011 Dec 21.

Department of Biochemistry and Molecular Biology and Program in Genes and Development, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Homeostatic mechanisms can eliminate abnormal cells to prevent diseases such as cancer. However, the underlying mechanisms of this surveillance are poorly understood. Here we investigated how clones of cells mutant for the neoplastic tumor suppressor gene scribble (scrib) are eliminated from Drosophila imaginal discs. When all cells in imaginal discs are mutant for scrib, they hyperactivate the Hippo pathway effector Yorkie (Yki), which drives growth of the discs into large neoplastic masses. Strikingly, when discs also contain normal cells, the scrib(-) cells do not overproliferate and eventually undergo apoptosis through JNK-dependent mechanisms. However, induction of apoptosis does not explain how scrib(-) cells are prevented from overproliferating. We report that cell competition between scrib(-) and wild-type cells prevents hyperproliferation by suppressing Yki activity in scrib(-) cells. Suppressing Yki activation is critical for scrib(-) clone elimination by cell competition, and experimental elevation of Yki activity in scrib(-) cells is sufficient to fuel their neoplastic growth. Thus, cell competition acts as a tumor-suppressing mechanism by regulating the Hippo pathway in scrib(-) cells.
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http://dx.doi.org/10.1073/pnas.1113882109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258595PMC
January 2012