Publications by authors named "Sarah K Savage"

13 Publications

  • Page 1 of 1

Turner syndrome in diverse populations.

Am J Med Genet A 2020 02 19;182(2):303-313. Epub 2019 Dec 19.

Department of Paediatrics, Hong Kong Children's Hospital, Hong Kong, China.

Turner syndrome (TS) is a common multiple congenital anomaly syndrome resulting from complete or partial absence of the second X chromosome. In this study, we explore the phenotype of TS in diverse populations using clinical examination and facial analysis technology. Clinical data from 78 individuals and images from 108 individuals with TS from 19 different countries were analyzed. Individuals were grouped into categories of African descent (African), Asian, Latin American, Caucasian (European descent), and Middle Eastern. The most common phenotype features across all population groups were short stature (86%), cubitus valgus (76%), and low posterior hairline 70%. Two facial analysis technology experiments were conducted: TS versus general population and TS versus Noonan syndrome. Across all ethnicities, facial analysis was accurate in diagnosing TS from frontal facial images as measured by the area under the curve (AUC). An AUC of 0.903 (p < .001) was found for TS versus general population controls and 0.925 (p < .001) for TS versus individuals with Noonan syndrome. In summary, we present consistent clinical findings from global populations with TS and additionally demonstrate that facial analysis technology can accurately distinguish TS from the general population and Noonan syndrome.
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http://dx.doi.org/10.1002/ajmg.a.61461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141514PMC
February 2020

Phenotype delineation of ZNF462 related syndrome.

Am J Med Genet A 2019 10 30;179(10):2075-2082. Epub 2019 Jul 30.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.

Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.
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http://dx.doi.org/10.1002/ajmg.a.61306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935050PMC
October 2019

Enhancing Autonomy in Biobank Decisions: Too Much of a Good Thing?

J Empir Res Hum Res Ethics 2018 04 23;13(2):125-138. Epub 2018 Feb 23.

6 Harvard University, Boston, MA, USA.

The opportunity to receive individual research results (IRRs) in accordance with personal preferences may incentivize biobank participation and maximize perceived benefit. This trial investigated the relationship between parents' preferences and intent to participate (ITP) in biobank research utilizing their child's genetic information. We randomized parents of pediatric patients to four hypothetical biobanks, one of which employed a preference-setting model for return of results regarding their child. ITP was highest among those desiring all types of IRRs (93.3%) and decreased as participants became increasingly selective with their preferences ( p < .0001). We demonstrated that most parents would participate in a biobank that allows for preference setting; however, those who set preferences to receive a narrower set of IRRs are less likely to participate.
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http://dx.doi.org/10.1177/1556264617753483DOI Listing
April 2018

Preferences for the Return of Individual Results From Research on Pediatric Biobank Samples.

J Empir Res Hum Res Ethics 2017 04;12(2):97-106

2 Harvard Medical School, Boston, MA, USA.

Discussions about disclosing individual genetic research results include calls to consider participants' preferences. In this study, parents of Boston Children's Hospital patients set preferences for disclosure based on disease preventability and severity, and could exclude mental health, developmental, childhood degenerative, and adult-onset disorders. Participants reviewed hypothetical reports and reset preferences, if desired. Among 661 participants who initially wanted all results (64%), 1% reset preferences. Among 336 participants who initially excluded at least one category (36%), 38% reset preferences. Participants who reset preferences added 0.9 categories, on average; and their mean satisfaction on 0 to 10 scales increased from 4.7 to 7.2 ( p < .001). Only 2% reduced the number of categories they wanted disclosed. Findings demonstrate the benefits of providing examples of preference options and the tendency of participants to want results disclosed. Findings also suggest that preference-setting models that do not provide specific examples of results could underestimate participants' desires for information.
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http://dx.doi.org/10.1177/1556264617697839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407299PMC
April 2017

Family health history reporting is sensitive to small changes in wording.

Genet Med 2016 12 5;18(12):1308-1311. Epub 2016 May 5.

Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.

Purpose: Family health history is often collected through single-item queries that ask patients whether their family members are affected by certain conditions. The specific wording of these queries may influence what individuals report.

Methods: Parents of Boston Children's Hospital patients were invited to participate in a Web-based survey about the return of individual genomic research results regarding their children. Participants reported whether 11 types of medical conditions affected them or their family. Randomization determined whether participants were specifically instructed to consider their extended family.

Results: Family health history was reported by 2,901 participants. Those asked to consider their extended family were more likely to report a positive family history for 8 of 11 medical conditions. The largest differences were observed for cancer (65.1 vs. 45.7%; P < 0.001), cardiovascular conditions (72.5 vs. 56.0%; P < 0.001), and endocrine/hormonal conditions (50.9 vs. 36.7%; P < 0.001).

Conclusions: Small alterations to the way family health history queries are worded can substantially change patient responses. Clinicians and researchers need to be sensitive about patients' tendencies to omit extended family from health history reporting unless specifically asked to consider them.Genet Med 18 12, 1308-1311.
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http://dx.doi.org/10.1038/gim.2016.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097687PMC
December 2016

Participant Satisfaction With a Preference-Setting Tool for the Return of Individual Research Results in Pediatric Genomic Research.

J Empir Res Hum Res Ethics 2015 Oct;10(4):414-26

Boston Children's Hospital, MA, USA Harvard Medical School, Boston, MA, USA.

The perceived benefit of return of individual research results (IRRs) in accordance to participants' preferences in genomic biobank research is unclear. We developed an online preference-setting tool for return of IRRs based on the preventability and severity of a condition, which included an opt-out option for IRRs for mental illness, developmental disorders, childhood-onset degenerative conditions, and adult-onset conditions. Parents of patients <18 years of age at Boston Children's Hospital were randomized to the hypothetical scenario that their child was enrolled in one of four biobanks with different policies for IRRs to receive (a) "None," (b) "All," (c) "Binary"--choice to receive all or none, and (d) "Granular"--use the preference-setting tool to choose categories of IRRs. Parents were given a hypothetical IRRs report for their child. The survey was sent to 11,391 parents and completed by 2,718. The Granular group was the most satisfied with the process, biobank, and hypothetical IRRs received. The None group was least satisfied and least likely to agree that the biobank was beneficial (p < .001). The response to the statement that the biobank was harmful was not different between groups. Our data suggest that the ability to designate preferences leads to greater satisfaction and may increase biobank participation.
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http://dx.doi.org/10.1177/1556264615599620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686662PMC
October 2015

The development of a preference-setting model for the return of individual genomic research results.

J Empir Res Hum Res Ethics 2015 Apr 20;10(2):107-20. Epub 2015 Feb 20.

Harvard Medical School, Boston, MA, USA Boston Children's Hospital, MA, USA

Understanding participants' preferences for the return of individual research results (IRR) in genomic research may allow for the implementation of more beneficial result disclosure methods. We tested four preference-setting models through cognitive interviews of parents to explore how parents conceptualize the process of setting preferences and which disease characteristics they believe to be most important when deciding what results to receive on their child. Severity and preventability of a condition were highly influential in decision making and certain groups of research results were anticipated by participants to have negative psychological effects. These findings informed the development of an educational tool and preference-setting model that can be scaled for use in the return of IRR from large biobank studies.
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http://dx.doi.org/10.1177/1556264615572092DOI Listing
April 2015

An assessment of clinician and researcher needs for support in the era of genomic medicine.

Per Med 2014 Aug;11(6):569-579

Division of Genetics & Genomics, Boston Children's Hospital, Boston, MA 02115, USA.

Aim: To assess clinicians' and researchers' past, current and anticipated future use of next-generation sequencing (NGS) and anticipated needs for support. Materials & methods: A web-based survey was conducted at Boston Children's Hospital.

Results: Many clinicians anticipate that they will use exome/genome sequencing (44.8%) and/or candidate gene panels (50%) within the next year. Researcher respondents anticipate the need for exome/genome sequencing (48.0%) and candidate gene panels (31.8%). Few respondents (13.6%) said that they felt 'Completely Ready' or 'Pretty Much Ready' to incorporate NGS into their clinical practice or research.

Conclusion: Researchers and clinicians anticipate increased utilization of NGS. Respondents indicated varying degrees of need for a diverse list of support services, ranking interpretation and clinical correlation support as the most needed services.
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http://dx.doi.org/10.2217/pme.14.48DOI Listing
August 2014

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge.

Genome Biol 2014 Mar 25;15(3):R53. Epub 2014 Mar 25.

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance.

Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization.

Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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http://dx.doi.org/10.1186/gb-2014-15-3-r53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073084PMC
March 2014

Guidelines for return of research results from pediatric genomic studies: deliberations of the Boston Children's Hospital Gene Partnership Informed Cohort Oversight Board.

Genet Med 2014 Jul 9;16(7):547-52. Epub 2014 Jan 9.

1] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA [2] Children's Hospital Informatics Program, Boston Children's Hospital, Boston, Massachusetts, USA.

Purpose: Approaches to return individual results to participants in genomic research variably focus on actionability, duty to share, or participants' preferences. Our group at Boston Children's Hospital has prioritized participants' preferences by implementing the Gene Partnership, a genomic research repository, based on the "Informed Cohort" model that offers return of results in accordance with participant preferences. Recognizing that ethical oversight is essential, the Gene Partnership Informed Cohort Oversight Board was convened in 2009.

Methods: Over 3 years, the Informed Cohort Oversight Board developed guidelines for the return of individual genomic research results.

Results: The Informed Cohort Oversight Board defined its guiding principles as follows: to respect the developing autonomy of pediatric participants and parental decision-making authority by returning results consistent with participants' preferences and to protect participants from harm. Potential harms and strategies to eliminate harm were identified. Guidelines were developed for participant preferences that consider the child's development and family dynamics. The Informed Cohort Oversight Board agreed that to prevent harm, including harms related to interfering with a child's future autonomy, there will be results that should not be returned regardless of participant preferences.

Conclusion: The Informed Cohort Oversight Board developed guidelines for the return of results that respect the preferences of parents, children, and adult participants while seeking to protect against harm.
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http://dx.doi.org/10.1038/gim.2013.190DOI Listing
July 2014

The beliefs, motivations, and expectations of parents who have enrolled their children in a genetic biorepository.

Genet Med 2012 Mar 26;14(3):330-7. Epub 2012 Jan 26.

Department of Medicine, Division of Genetics and Program in Genomics, Children's Hospital Boston, Boston, Massachusetts, USA.

Purpose: Little is known about parental attitudes toward return of individual research results (IRRs) in pediatric genomic research. The aim of this study was to understand the views of the parents who enrolled their children in a genomic repository in which IRRs will be returned.

Methods: We conducted focus groups with parents of children with developmental disorders enrolled in the Gene Partnership (GP), a genomic research repository that offers to return IRRs, to learn about their understanding of the GP, motivations for enrolling their children, and expectations regarding the return of IRRs.

Results: Parents hoped to receive IRRs that would help them better understand their children's condition(s). They understood that this outcome was unlikely, but hoped that their children's participation in the GP would contribute to scientific knowledge. Most parents wanted to receive all IRRs about their child, even for diseases that were severe and untreatable, citing reasons of personal utility. Parents preferred electronic delivery of the results and wanted to designate their preferences regarding what information they would receive.

Conclusions: It is important for researchers to understand participant expectations in enrolling in a research repository that offers to disclose children's IRRs in order to effectively communicate the implications to parents during the consenting process.
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http://dx.doi.org/10.1038/gim.2011.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763713PMC
March 2012

Disclosing pathogenic genetic variants to research participants: quantifying an emerging ethical responsibility.

Genome Res 2012 Mar 6;22(3):421-8. Epub 2012 Jan 6.

Children's Hospital Informatics Program, Children's Hospital Boston, Boston, Massachusetts 02115, USA.

There is an emerging consensus that when investigators obtain genomic data from research participants, they may incur an ethical responsibility to inform at-risk individuals about clinically significant variants discovered during the course of their research. With whole-exome sequencing becoming commonplace and the falling costs of full-genome sequencing, there will be an increasingly large number of variants identified in research participants that may be of sufficient clinical relevance to share. An explicit approach to triaging and communicating these results has yet to be developed, and even the magnitude of the task is uncertain. To develop an estimate of the number of variants that might qualify for disclosure, we apply recently published recommendations for the return of results to a defined and representative set of variants and then extrapolate these estimates to genome scale. We find that the total number of variants meeting the threshold for recommended disclosure ranges from 3955-12,579 (3.79%-12.06%, 95% CI) in the most conservative estimate to 6998-17,189 (6.69%-16.48%, 95% CI) in an estimate including variants with variable disease expressivity. Additionally, if the growth rate from the previous 4 yr continues, we estimate that the total number of disease-associated variants will grow 37% over the next 4 yr.
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http://dx.doi.org/10.1101/gr.127845.111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3290777PMC
March 2012

Increased LIS1 expression affects human and mouse brain development.

Nat Genet 2009 Feb 11;41(2):168-77. Epub 2009 Jan 11.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.

Deletions of the PAFAH1B1 gene (encoding LIS1) in 17p13.3 result in isolated lissencephaly sequence, and extended deletions including the YWHAE gene (encoding 14-3-3epsilon) cause Miller-Dieker syndrome. We identified seven unrelated individuals with submicroscopic duplication in 17p13.3 involving the PAFAH1B1 and/or YWHAE genes, and using a 'reverse genomics' approach, characterized the clinical consequences of these duplications. Increased PAFAH1B1 dosage causes mild brain structural abnormalities, moderate to severe developmental delay and failure to thrive. Duplication of YWHAE and surrounding genes increases the risk for macrosomia, mild developmental delay and pervasive developmental disorder, and results in shared facial dysmorphologies. Transgenic mice conditionally overexpressing LIS1 in the developing brain showed a decrease in brain size, an increase in apoptotic cells and a distorted cellular organization in the ventricular zone, including reduced cellular polarity but preserved cortical cell layer identity. Collectively, our results show that an increase in LIS1 expression in the developing brain results in brain abnormalities in mice and humans.
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http://dx.doi.org/10.1038/ng.302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396744PMC
February 2009
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