Publications by authors named "Ingrid A Holm"

108 Publications

The Unrecognized Mortality Burden of Genetic Disorders in Infancy.

Am J Public Health 2021 Jul;111(S2):S156-S162

Monica H. Wojcik and Pankaj B. Agrawal are with the Division of Newborn Medicine and Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA. Rachel Stadelmaier is with the Department of Pediatrics, Boston Children's Hospital and Harvard Medical School. Dominique Heinke is with the Center for Birth Defects Research and Prevention, Massachusetts Department of Public Health and Harvard T. H. Chan School of Public Health, Harvard University, Boston. Ingrid A. Holm and Wen-Hann Tan are with the Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School.

To determine how deaths of infants with genetic diagnoses are described in national mortality statistics. We present a retrospective cohort study of mortality data, obtained from the National Death Index (NDI), and clinical data for 517 infants born from 2011 to 2017 who died before 1 year of age in the United States. Although 115 of 517 deceased infants (22%) had a confirmed diagnosis of a genetic disorder, only 61 of 115 deaths (53%) were attributed to , codes representing congenital anomalies or genetic disorders (Q00-Q99) as the underlying cause of death because of inconsistencies in death reporting. Infants with genetic diagnoses whose underlying causes of death were coded as Q00-Q99 were more likely to have chromosomal disorders than monogenic conditions (43/61 [70%] vs 18/61 [30%];  < .001), which reflects the need for improved accounting for monogenic disorders in mortality statistics. Genetic disorders, although a leading cause of infant mortality, are not accurately captured by vital statistics. . Expanded access to genetic testing and further clarity in death reporting are needed to describe properly the contribution of genetic disorders to infant mortality.
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http://dx.doi.org/10.2105/AJPH.2021.306275DOI Listing
July 2021

Effects of participation in a U.S. trial of newborn genomic sequencing on parents at risk for depression.

J Genet Couns 2021 Jul 26. Epub 2021 Jul 26.

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

Much emphasis has been placed on participant's psychological safety within genomic research studies; however, few studies have addressed parental psychological health effects associated with their child's participation in genomic studies, particularly when parents meet the threshold for clinical concern for depression. We aimed to determine if parents' depressive symptoms were associated with their child's participation in a randomized-controlled trial of newborn exome sequencing. Parents completed the Edinburgh Postnatal Depression Scale (EPDS) at baseline, immediately post-disclosure, and 3 months post-disclosure. Mothers and fathers scoring at or above thresholds for clinical concern on the EPDS, 12 and 10, respectively, indicating possible Major Depressive Disorder with Peripartum Onset, were contacted by study staff for mental health screening. Parental concerns identified in follow-up conversations were coded for themes. Forty-five parents had EPDS scores above the clinical threshold at baseline, which decreased by an average of 2.9 points immediately post-disclosure and another 1.1 points 3 months post-disclosure (both p ≤ .014). For 28 parents, EPDS scores were below the threshold for clinical concern at baseline, increased by an average of 4.7 points into the elevated range immediately post-disclosure, and decreased by 3.8 points at 3 months post-disclosure (both p < .001). Nine parents scored above thresholds only at 3 months post-disclosure after increasing an average of 5.7 points from immediately post-disclosure (p < .001). Of the 82 parents who scored above the threshold at any time point, 43 (52.4%) were reached and 30 (69.7%) of these 43 parents attributed their elevated scores to parenting stress, balancing work and family responsibilities, and/or child health concerns. Only three parents (7.0%) raised concerns about their participation in the trial, particularly their randomization to the control arm. Elevated scores on the EPDS were typically transient and parents attributed their symptomatology to life stressors in the postpartum period rather than participation in a trial of newborn exome sequencing.
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http://dx.doi.org/10.1002/jgc4.1475DOI Listing
July 2021

Preferences for Updates on General Research Results: A Survey of Participants in Genomic Research from Two Institutions.

J Pers Med 2021 May 11;11(5). Epub 2021 May 11.

Johns Hopkins University Berman Institute of Bioethics, Baltimore, MD 21205, USA.

There is a need for multimodal strategies to keep research participants informed about study results. Our aim was to characterize preferences of genomic research participants from two institutions along four dimensions of general research result updates: content, timing, mechanism, and frequency.

Methods: We conducted a web-based cross-sectional survey that was administered from 25 June 2018 to 5 December 2018.

Results: 397 participants completed the survey, most of whom (96%) expressed a desire to receive research updates. Preferences with high endorsement included: update content (brief descriptions of major findings, descriptions of purpose and goals, and educational material); update timing (when the research is completed, when findings are reviewed, when findings are published, and when the study status changes); update mechanism (email with updates, and email newsletter); and update frequency (every three months). Hierarchical cluster analyses based on the four update preferences identified four profiles of participants with similar preference patterns. Very few participants in the largest profile were comfortable with budgeting less money for research activities so that researchers have money to set up services to send research result updates to study participants.

Conclusion: Future studies may benefit from exploring preferences for research result updates, as we have in our study. In addition, this work provides evidence of a need for funders to incentivize researchers to communicate results to participants.
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http://dx.doi.org/10.3390/jpm11050399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151672PMC
May 2021

Nicotinic Receptors in the Brainstem Ascending Arousal System in SIDS With Analysis of Pre-natal Exposures to Maternal Smoking and Alcohol in High-Risk Populations of the Safe Passage Study.

Front Neurol 2021 10;12:636668. Epub 2021 Mar 10.

Department of Pathology, Massachusetts General Hospital, Boston, MA, United States.

Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS ( = 12) and infants dying from known causes ( = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive ( = 0.0002-0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis ( = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS ( = 11) combined with post-KCOD controls ( = 8) on the raphe obscurus ( = 0.01), gigantocellularis ( = 0.02), and the paragigantocellularis ( = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla-a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla.
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http://dx.doi.org/10.3389/fneur.2021.636668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988476PMC
March 2021

Discordant results between conventional newborn screening and genomic sequencing in the BabySeq Project.

Genet Med 2021 Jul 26;23(7):1372-1375. Epub 2021 Mar 26.

Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.

Purpose: Newborn screening (NBS) is performed to identify neonates at risk for actionable, severe, early-onset disorders, many of which are genetic. The BabySeq Project randomized neonates to receive conventional NBS or NBS plus exome sequencing (ES) capable of detecting sequence variants that may also diagnose monogenic disease or indicate genetic disease risk. We therefore evaluated how ES and conventional NBS results differ in this population.

Methods: We compared results of NBS (including hearing screens) and ES for 159 infants in the BabySeq Project. Infants were considered "NBS positive" if any abnormal result was found indicating disease risk and "ES positive" if ES identified a monogenic disease risk or a genetic diagnosis.

Results: Most infants (132/159, 84%) were NBS and ES negative. Only one infant was positive for the same disorder by both modalities. Nine infants were NBS positive/ES negative, though seven of these were subsequently determined to be false positives. Fifteen infants were ES positive/NBS negative, all of which represented risk of genetic conditions that are not included in NBS programs. No genetic explanation was identified for eight infants referred on the hearing screen.

Conclusion: These differences highlight the complementarity of information that may be gleaned from NBS and ES in the newborn period.
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http://dx.doi.org/10.1038/s41436-021-01146-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263473PMC
July 2021

Underrepresentation of Phenotypic Variability of 16p13.11 Microduplication Syndrome Assessed With an Online Self-Phenotyping Tool (Phenotypr): Cohort Study.

J Med Internet Res 2021 Mar 16;23(3):e21023. Epub 2021 Mar 16.

Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States.

Background: 16p13.11 microduplication syndrome has a variable presentation and is characterized primarily by neurodevelopmental and physical phenotypes resulting from copy number variation at chromosome 16p13.11. Given its variability, there may be features that have not yet been reported. The goal of this study was to use a patient "self-phenotyping" survey to collect data directly from patients to further characterize the phenotypes of 16p13.11 microduplication syndrome.

Objective: This study aimed to (1) discover self-identified phenotypes in 16p13.11 microduplication syndrome that have been underrepresented in the scientific literature and (2) demonstrate that self-phenotyping tools are valuable sources of data for the medical and scientific communities.

Methods: As part of a large study to compare and evaluate patient self-phenotyping surveys, an online survey tool, Phenotypr, was developed for patients with rare disorders to self-report phenotypes. Participants with 16p13.11 microduplication syndrome were recruited through the Boston Children's Hospital 16p13.11 Registry. Either the caregiver, parent, or legal guardian of an affected child or the affected person (if aged 18 years or above) completed the survey. Results were securely transferred to a Research Electronic Data Capture database and aggregated for analysis.

Results: A total of 19 participants enrolled in the study. Notably, among the 19 participants, aggression and anxiety were mentioned by 3 (16%) and 4 (21%) participants, respectively, which is an increase over the numbers in previously published literature. Additionally, among the 19 participants, 3 (16%) had asthma and 2 (11%) had other immunological disorders, both of which have not been previously described in the syndrome.

Conclusions: Several phenotypes might be underrepresented in the previous 16p13.11 microduplication literature, and new possible phenotypes have been identified. Whenever possible, patients should continue to be referenced as a source of complete phenotyping data on their condition. Self-phenotyping may lead to a better understanding of the prevalence of phenotypes in genetic disorders and may identify previously unreported phenotypes.
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http://dx.doi.org/10.2196/21023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074853PMC
March 2021

Genetic Factors Underlying Sudden Infant Death Syndrome.

Appl Clin Genet 2021 15;14:61-76. Epub 2021 Feb 15.

Robert's Program for Sudden Unexpected Death in Pediatrics, Boston Children's Hospital, Boston, MA, USA.

Sudden Infant Death syndrome (SIDS) is a diagnosis of exclusion. Decades of research have made steady gains in understanding plausible mechanisms of terminal events. Current evidence suggests SIDS includes heterogeneous biological conditions, such as metabolic, cardiac, neurologic, respiratory, and infectious conditions. Here we review genetic studies that address each of these areas in SIDS cases and cohorts, providing a broad view of the genetic underpinnings of this devastating phenomenon. The current literature has established a role for monogenic genetic causes of SIDS mortality in a subset of cases. To expand upon our current knowledge of disease-causing genetic variants in SIDS cohorts and their mechanisms, future genetic studies may employ functional assessments of implicated variants, broader genetic tests, and the inclusion of parental genetic data and family history information.
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http://dx.doi.org/10.2147/TACG.S239478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894824PMC
February 2021

Current Trends in Genetics and Neonatal Care.

Adv Neonatal Care 2021 Feb 2. Epub 2021 Feb 2.

Boston College, Connell School of Nursing, Chestnut Hill, Massachusetts (Dr Uveges); Division of Genetics and Genomics, Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts (Dr Holm); and Harvard Medical School, Boston, Massachusetts (Dr Holm).

Background: Genetic and genomic health applications are rapidly changing. A clear and updated description of these applications for the neonatal population is needed to guide current nursing practice.

Purpose: To provide scientific evidence and guidance on the current genetic and genomic applications pertinent to neonatal care.

Methods: A search of CINAHL and PubMed was conducted using the search terms "newborn/neonatal" and "genetics," "genomics," "newborn screening," "pharmacogenomics," "ethical," and "legal." Google searches were also conducted to synthesize professional guidelines, position statements, and current genetic practices.

Findings/results: Components of the newborn genetic assessment, including details on the newborn physical examination, family history, and laboratory tests pertinent to the newborn, are reported. The history and process of newborn screening are described, in addition to the impact of advancements, such as whole exome and genome sequencing, on newborn screening. Pharmacogenomics, a genomic application that is currently utilized primarily in the research context for neonates, is described and future implications stated. Finally, the specific ethical and legal implications for these genetic and genomic applications are detailed, along with genetic/genomic resources for nurses.

Implications For Practice: Providing nurses with the most up-to-date evidence on genetic and genomic applications ensures their involvement and contributions to quality neonatal care.

Implications For Research: Ongoing genetic/genomic research is needed to understand the implications of genetic/genomic applications on the neonatal population and how these new applications will change neonatal care.
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http://dx.doi.org/10.1097/ANC.0000000000000834DOI Listing
February 2021

Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI).

Genet Med 2021 02 2;23(2):396-407. Epub 2020 Oct 2.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Purpose: Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion.

Methods: We performed deep phenotyping of 20 GACI survivors.

Results: Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies.

Conclusion: GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.
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http://dx.doi.org/10.1038/s41436-020-00983-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867608PMC
February 2021

Participant choices for return of genomic results in the eMERGE Network.

Genet Med 2020 11 16;22(11):1821-1829. Epub 2020 Jul 16.

Divisions of Human Genetics and Patient Services, Cincinnati Children's Hospital, Cincinnati, OH, USA.

Purpose: Secondary findings are typically offered in an all or none fashion when sequencing is used for clinical purposes. This study aims to describe the process of offering categorical and granular choices for results in a large research consortium.

Methods: Within the third phase of the electronic MEdical Records and GEnomics (eMERGE) Network, several sites implemented studies that allowed participants to choose the type of results they wanted to receive from a multigene sequencing panel. Sites were surveyed to capture the details of the implementation protocols and results of these choices.

Results: Across the ten eMERGE sites, 4664 participants including adolescents and adults were offered some type of choice. Categories of choices offered and methods for selecting categories varied. Most participants (94.5%) chose to learn all genetic results, while 5.5% chose subsets of results. Several sites allowed participants to change their choices at various time points, and 0.5% of participants made changes.

Conclusion: Offering choices that include learning some results is important and should be a dynamic process to allow for changes in scientific knowledge, participant age group, and individual preference.
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http://dx.doi.org/10.1038/s41436-020-0905-3DOI Listing
November 2020

Children's rare disease cohorts: an integrative research and clinical genomics initiative.

NPJ Genom Med 2020 6;5:29. Epub 2020 Jul 6.

Computational Health Informatics Program, Boston Children's Hospital, Boston, MA 02115 USA.

While genomic data is frequently collected under distinct research protocols and disparate clinical and research regimes, there is a benefit in streamlining sequencing strategies to create harmonized databases, particularly in the area of pediatric rare disease. Research hospitals seeking to implement unified genomics workflows for research and clinical practice face numerous challenges, as they need to address the unique requirements and goals of the distinct environments and many stakeholders, including clinicians, researchers and sequencing providers. Here, we present outcomes of the first phase of the Children's Rare Disease Cohorts initiative (CRDC) that was completed at Boston Children's Hospital (BCH). We have developed a broadly sharable database of 2441 exomes from 15 pediatric rare disease cohorts, with major contributions from early onset epilepsy and early onset inflammatory bowel disease. All sequencing data is integrated and combined with phenotypic and research data in a genomics learning system (GLS). Phenotypes were both manually annotated and pulled automatically from patient medical records. Deployment of a genomically-ordered relational database allowed us to provide a modular and robust platform for centralized storage and analysis of research and clinical data, currently totaling 8516 exomes and 112 genomes. The GLS integrates analytical systems, including machine learning algorithms for automated variant classification and prioritization, as well as phenotype extraction via natural language processing (NLP) of clinical notes. This GLS is extensible to additional analytic systems and growing research and clinical collections of genomic and other types of data.
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http://dx.doi.org/10.1038/s41525-020-0137-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338382PMC
July 2020

A de novo BRPF1 variant in a case of Sudden Unexplained Death in Childhood.

Eur J Med Genet 2020 Sep 8;63(9):104002. Epub 2020 Jul 8.

Robert's Program for Sudden Unexpected Death in Pediatrics, Boston Children's Hospital, USA; Department of Pediatrics, Harvard Medical School, USA; Division of General Pediatrics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA. Electronic address:

Sudden Unexplained Death in Childhood (SUDC), the death of a child that remains unexplained after a complete autopsy and investigation, is a rare and poorly understood entity. This case report describes a 3-year-old boy with history of language delay and ptosis, who died suddenly in his sleep without known cause. A pathogenic de novo frameshift mutation in BRPF1, a gene which has been associated with the syndrome of Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP), was identified during a post-mortem evaluation. The finding of a pathogenic variant in BRPF1, which has not previously been associated with sudden death, in an SUDC case has implications for this child's family and contributes to the broader field of SUDC research. This case demonstrates the utility of post-mortem genetic testing in SUDC.
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http://dx.doi.org/10.1016/j.ejmg.2020.104002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469702PMC
September 2020

The role of sodium channels in sudden unexpected death in pediatrics.

Mol Genet Genomic Med 2020 08 25;8(8):e1309. Epub 2020 May 25.

Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

Background: Sudden Unexpected Death in Pediatrics (SUDP) is a tragic event, likely caused by the complex interaction of multiple factors. The presence of hippocampal abnormalities in many children with SUDP suggests that epilepsy-related mechanisms may contribute to death, similar to Sudden Unexplained Death in Epilepsy. Because of known associations between the genes SCN1A and SCN5A and sudden death, and shared mechanisms and patterns of expression in genes encoding many voltage-gated sodium channels (VGSCs), we hypothesized that individuals dying from SUDP have pathogenic variants across the entire family of cardiac arrhythmia- and epilepsy-associated VGSC genes.

Methods: To address this hypothesis, we evaluated whole-exome sequencing data from infants and children with SUDP for variants in VGSC genes, reviewed the literature for all SUDP-associated variants in VGSCs, applied a novel paralog analysis to all variants, and evaluated all variants according to American College of Medical Genetics and Genomics (ACMG) guidelines.

Results: In our cohort of 73 cases of SUDP, we assessed 11 variants as pathogenic in SCN1A, SCN1B, and SCN10A, genes with long-standing disease associations, and in SCN3A, SCN4A, and SCN9A, VGSC gene paralogs with more recent disease associations. From the literature, we identified 82 VGSC variants in SUDP cases. Pathogenic variants clustered at conserved amino acid sites intolerant to variation across the VGSC genes, which is unlikely to occur in the general population (p < .0001). For 54% of variants previously reported in literature, we identified conflicting evidence regarding pathogenicity when applying ACMG criteria and modern population data.

Conclusion: We report variants in several VGSC genes in cases with SUDP, involving both arrhythmia- and epilepsy-associated genes. Accurate variant assessment as well as future studies are essential for an improved understanding of the contribution of sodium channel-related variants to SUDP.
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http://dx.doi.org/10.1002/mgg3.1309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434613PMC
August 2020

Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants.

Genet Med 2020 08 19;22(8):1338-1347. Epub 2020 May 19.

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Purpose: Genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized.

Methods: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum.

Results: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent.

Conclusion: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.
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http://dx.doi.org/10.1038/s41436-020-0811-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737399PMC
August 2020

Understanding the Return of Genomic Sequencing Results Process: Content Review of Participant Summary Letters in the eMERGE Research Network.

J Pers Med 2020 May 13;10(2). Epub 2020 May 13.

Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA.

A challenge in returning genomic test results to research participants is how best to communicate complex and clinically nuanced findings to participants in a manner that is scalable to the large numbers of participants enrolled. The purpose of this study was to examine the features of genetic results letters produced at each Electronic Medical Records and Genomics (eMERGE3) Network site to assess their readability and content. Letters were collected from each site, and a qualitative analysis of letter content and a quantitative analysis of readability statistics were performed. Because letters were produced independently at each eMERGE site, significant heterogeneity in readability and content was found. The content of letters varied widely from a baseline of notifying participants that results existed to more detailed information about positive or negative results, as well as materials for sharing with family members. Most letters were significantly above the Centers for Disease Control-suggested reading level for health communication. While continued effort should be applied to make letters easier to understand, the ongoing challenge of explaining complex genomic information, the implications of negative test results, and the uncertainty that comes with some types of test and result makes simplifying letter text challenging.
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http://dx.doi.org/10.3390/jpm10020038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354464PMC
May 2020

Returning Results in the Genomic Era: Initial Experiences of the eMERGE Network.

J Pers Med 2020 Apr 27;10(2). Epub 2020 Apr 27.

Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA.

A goal of the 3rd phase of the Electronic Medical Records and Genomics (eMERGE3) Network was to examine the return of results (RoR) of actionable variants in more than 100 genes to consenting participants and their healthcare providers. Each of the 10 eMERGE sites developed plans for three essential elements of the RoR process: Disclosure to the participant, notification of the health care provider, and integration of results into the electronic health record (EHR). Procedures and protocols around these three elements were adapted as appropriate to individual site requirements and limitations. Detailed information about the RoR procedures at each site was obtained through structured telephone interviews and follow-up surveys with the clinical investigator leading or participating in the RoR process at each eMERGE3 institution. Because RoR processes at each of the 10 sites allowed for taking into account differences in population, disease focus and institutional requirements, significant heterogeneity of process was identified, including variability in the order in which patients and clinicians were notified and results were placed in the EHR. This heterogeneity in the process flow for eMERGE3 RoR reflects the "real world" of genomic medicine in which RoR procedures must be shaped by the needs of the patients and institutional environments.
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http://dx.doi.org/10.3390/jpm10020030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354592PMC
April 2020

Concurrent prenatal drinking and smoking increases risk for SIDS: Safe Passage Study report.

EClinicalMedicine 2020 Feb 20;19:100247. Epub 2020 Jan 20.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6710B Rockledge Drive, Room 2305, Bethesda, MD 20892, United States.

Background: Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality. Although the rate has plateaued, any unexpected death of an infant is a family tragedy thus finding causes and contributors to risk remains a major public health concern. The primary objective of this investigation was to determine patterns of drinking and smoking during pregnancy that increase risk of SIDS.

Methods: The Safe Passage Study was a prospective, multi-center, observational study with 10,088 women, 11,892 pregnancies, and 12,029 fetuses, followed to 1-year post delivery. Subjects were from two sites in Cape Town, South Africa and five United States sites, including two American Indian Reservations. Group-based trajectory modeling was utilized to categorize patterns of drinking and smoking exposure during pregnancy.

Findings: One-year outcome was ascertained in 94·2% infants, with 28 SIDS (2·43/1000) and 38 known causes of death (3·30/1000). The increase in relative risk for SIDS, adjusted for key demographic and clinical characteristics, was 11·79 (98·3% CI: 2·59-53·7,  < 0·001) in infants whose mothers reported both prenatal drinking and smoking beyond the first trimester, 3.95 (98·3% CI: 0·44-35·83,  = 0·14), for drinking only beyond the first trimester and 4·86 (95% CI: 0·97-24·27,  = 0·02) for smoking only beyond the first trimester as compared to those unexposed or reported quitting early in pregnancy.

Interpretation: Infants prenatally exposed to both alcohol and cigarettes continuing beyond the first trimester have a substantially higher risk for SIDS compared to those unexposed, exposed to alcohol or cigarettes alone, or when mother reported quitting early in pregnancy. Given that prenatal drinking and smoking are modifiable risk factors, these results address a major global public health problem.

Funding: National Institute on Alcohol Abuse and Alcoholism, National Institute of Child Health and Human Development, and the National Institute on Deafness and Other Communication Disorders.
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http://dx.doi.org/10.1016/j.eclinm.2019.100247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046523PMC
February 2020

FDA oversight of NSIGHT genomic research: the need for an integrated systems approach to regulation.

NPJ Genom Med 2019 10;4:32. Epub 2019 Dec 10.

12Rady Children's Institute for Genomic Medicine, San Diego, CA 92123 USA.

The National Institutes of Health (NIH) funded the Newborn Sequencing In Genomic medicine and public HealTh (NSIGHT) Consortium to investigate the implications, challenges, and opportunities associated with the possible use of genomic sequence information in the newborn period. Following announcement of the NSIGHT awardees in 2013, the Food and Drug Administration (FDA) contacted investigators and requested that pre-submissions to investigational device exemptions (IDE) be submitted for the use of genomic sequencing under Title 21 of the Code of Federal Regulations (21 CFR) part 812. IDE regulation permits clinical investigation of medical devices that have not been approved by the FDA. To our knowledge, this marked the first time the FDA determined that NIH-funded clinical genomic research projects are subject to IDE regulation. Here, we review the history of and rationale behind FDA oversight of clinical research and the NSIGHT Consortium's experiences in navigating the IDE process. Overall, NSIGHT investigators found that FDA's application of existing IDE regulations and medical device definitions aligned imprecisely with the aims of publicly funded exploratory clinical research protocols. IDE risk assessments by the FDA were similar to, but distinct from, protocol risk assessments conducted by local Institutional Review Boards (IRBs), and had the potential to reflect novel oversight of emerging genomic technologies. However, the pre-IDE and IDE process delayed the start of NSIGHT research studies by an average of 10 months, and significantly limited the scope of investigation in two of the four NIH approved projects. Based on the experience of the NSIGHT Consortium, we conclude that policies and practices governing the development and use of novel genomic technologies in clinical research urgently need clarification in order to mitigate potentially conflicting or redundant oversight by IRBs, NIH, FDA, and state authorities.
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http://dx.doi.org/10.1038/s41525-019-0105-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904743PMC
December 2019

IgG Fc glycosylation as an axis of humoral immunity in childhood.

J Allergy Clin Immunol 2020 02 24;145(2):710-713.e9. Epub 2019 Oct 24.

Division of Immunology, Boston Children's Hospital, Boston, Mass; Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Boston, Mass. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010538PMC
February 2020

Rethinking the "open future" argument against predictive genetic testing of children.

Genet Med 2019 10 21;21(10):2190-2198. Epub 2019 Mar 21.

Department of Pediatrics, University of Louisville, Louisville, KY, USA.

Professional consensus has traditionally discouraged predictive genetic testing when no childhood interventions can reduce future morbidity or mortality. However, advances in genome sequencing and accumulating evidence that children and families cope adequately with predictive genetic information have weakened this consensus. The primary argument remaining against testing appeals to children's "right to an open future." It claims that the autonomy of the future adult is violated when others make an irreversible choice to obtain or disclose predictive genetic information during childhood. We evaluate this argument and conclude that children's interest in an open future should not be understood as a right. Rather an open future is one significant interest to weigh against other important interests when evaluating decisions. Thus, predictive genetic testing is ethically permissible in principle, as long as the interests promoted outweigh potential harms. We conclude by offering an expanded model of children's interests that might be considered in such circumstances, and present two case analyses to illustrate how this framework better guides decisions about predictive genetic testing in pediatrics.
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http://dx.doi.org/10.1038/s41436-019-0483-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754817PMC
October 2019

Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project.

Am J Hum Genet 2019 01;104(1):76-93

Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address:

Genomic sequencing provides many opportunities in newborn clinical care, but the challenges of interpreting and reporting newborn genomic sequencing (nGS) results need to be addressed for its broader and effective application. The BabySeq Project is a pilot randomized clinical trial that explores the medical, behavioral, and economic impacts of nGS in well newborns and those admitted to a neonatal intensive care unit (NICU). Here we present childhood-onset and actionable adult-onset disease risk, carrier status, and pharmacogenomics findings from nGS of 159 newborns in the BabySeq Project. nGS revealed a risk of childhood-onset disease in 15/159 (9.4%) newborns; none of the disease risks were anticipated based on the infants' known clinical or family histories. nGS also revealed actionable adult-onset disease risk in 3/85 (3.5%) newborns whose parents consented to receive this information. Carrier status for recessive diseases and pharmacogenomics variants were reported in 88% and 5% of newborns, respectively. Additional indication-based analyses were performed in 29/32 (91%) NICU newborns and 6/127 (5%) healthy newborns who later had presentations that prompted a diagnostic analysis. No variants that sufficiently explained the reason for the indications were identified; however, suspicious but uncertain results were reported in five newborns. Testing parental samples contributed to the interpretation and reporting of results in 13/159 (8%) newborns. Our results suggest that nGS can effectively detect risk and carrier status for a wide range of disorders that are not detectable by current newborn screening assays or predicted based on the infant's known clinical or family history, and the interpretation of results can substantially benefit from parental testing.
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http://dx.doi.org/10.1016/j.ajhg.2018.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323417PMC
January 2019

Returning a Genomic Result for an Adult-Onset Condition to the Parents of a Newborn: Insights From the BabySeq Project.

Pediatrics 2019 01;143(Suppl 1):S37-S43

Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts.

The return of information from genomic sequencing in children, especially in early life, brings up complex issues around parental autonomy, the child's future autonomy, the best interest standard, and the best interests of the family. These issues are particularly important in considering the return of genomic results for adult-onset-only conditions in children. The BabySeq Project is a randomized trial used to explore the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of newborns who are healthy or sick. We discuss a case in which a variant in a gene for an actionable, adult-onset-only condition was detected, highlighting the ethical issues surrounding the return of such finding in a newborn to the newborn's parents.
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http://dx.doi.org/10.1542/peds.2018-1099HDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433124PMC
January 2019

Challenging the Current Recommendations for Carrier Testing in Children.

Pediatrics 2019 01;143(Suppl 1):S27-S32

Division of Genetics and Genomics and The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts;

The authors of current professional guidelines generally do not support the return of information about genetic carrier status for infants and children because of a perceived lack of immediate benefit and an abundance of caution regarding potential harm and desire to protect the children's future autonomy. The advent of genomic sequencing, used either as a diagnostic or a screening tool, and the increasing use of this technology in childhood creates the potential for the identification of carrier status in the pediatric period. As part of the BabySeq Project, researchers are exploring the implications of genomic sequencing in both newborns who are healthy and newborns who are sick and developing policies and procedures for the return of carrier status information to the parents and physicians of newborns. In this commentary, we review the history of carrier testing in children and explore the potential benefits, risks, and challenges of returning such results both for the children, their parents, and potential future siblings.
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http://dx.doi.org/10.1542/peds.2018-1099FDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433123PMC
January 2019

Perceived Benefits, Risks, and Utility of Newborn Genomic Sequencing in the BabySeq Project.

Pediatrics 2019 01;143(Suppl 1):S6-S13

Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, Texas;

Background And Objectives: There is interest in applying genomic sequencing (GS) to newborns' clinical care. Here we explore parents' and clinicians' attitudes toward and perceptions of the risks, benefits, and utility of newborn GS compared with newborn screening (NBS) prior to receiving study results.

Methods: The BabySeq Project is a randomized controlled trial used to explore the impact of integrating GS into the clinical care of newborns. Parents ( = 493) of enrolled infants ( = 309) and clinicians ( = 144) completed a baseline survey at enrollment. We examined between-group differences in perceived utility and attitudes toward NBS and GS. Open-ended responses about risks and benefits of each technology were categorized by theme.

Results: The majority of parents (71%) and clinicians (51%) agreed that there are health benefits of GS, although parents and clinicians agreed more that there are risks associated with GS (35%, 70%) than with NBS (19%, 39%; all < .05). Parents perceived more benefit and less risk of GS than did clinicians. Clinicians endorsed concerns about privacy and discrimination related to genomic information more strongly than did parents, and parents anticipated benefits of GS that clinicians did not.

Conclusions: Parents and clinicians are less confident in GS than NBS, but parents perceive a more favorable risk/benefit ratio of GS than do clinicians. Clinicians should be aware that parents' optimism may stem from their perceived benefits beyond clinical utility.
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http://dx.doi.org/10.1542/peds.2018-1099CDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480393PMC
January 2019

Enrichment sampling for a multi-site patient survey using electronic health records and census data.

J Am Med Inform Assoc 2019 03;26(3):219-227

Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.

Objective: We describe a stratified sampling design that combines electronic health records (EHRs) and United States Census (USC) data to construct the sampling frame and an algorithm to enrich the sample with individuals belonging to rarer strata.

Materials And Methods: This design was developed for a multi-site survey that sought to examine patient concerns about and barriers to participating in research studies, especially among under-studied populations (eg, minorities, low educational attainment). We defined sampling strata by cross-tabulating several socio-demographic variables obtained from EHR and augmented with census-block-level USC data. We oversampled rarer and historically underrepresented subpopulations.

Results: The sampling strategy, which included USC-supplemented EHR data, led to a far more diverse sample than would have been expected under random sampling (eg, 3-, 8-, 7-, and 12-fold increase in African Americans, Asians, Hispanics and those with less than a high school degree, respectively). We observed that our EHR data tended to misclassify minority races more often than majority races, and that non-majority races, Latino ethnicity, younger adult age, lower education, and urban/suburban living were each associated with lower response rates to the mailed surveys.

Discussion: We observed substantial enrichment from rarer subpopulations. The magnitude of the enrichment depends on the accuracy of the variables that define the sampling strata and the overall response rate.

Conclusion: EHR and USC data may be used to define sampling strata that in turn may be used to enrich the final study sample. This design may be of particular interest for studies of rarer and understudied populations.
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http://dx.doi.org/10.1093/jamia/ocy164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351976PMC
March 2019

Parents' attitudes toward consent and data sharing in biobanks: A multisite experimental survey.

AJOB Empir Bioeth 2018 Jul-Sep;9(3):128-142. Epub 2018 Sep 21.

x Division of Genetics and Genomics and the Manton Center for Orphan Diseases Research , Boston Children's Hospital.

Background: The factors influencing parents' willingness to enroll their children in biobanks are poorly understood. This study sought to assess parents' willingness to enroll their children, and their perceived benefits, concerns, and information needs under different consent and data-sharing scenarios, and to identify factors associated with willingness.

Methods: This large, experimental survey of patients at the 11 eMERGE Network sites used a disproportionate stratified sampling scheme to enrich the sample with historically underrepresented groups. Participants were randomized to receive one of three consent and data-sharing scenarios.

Results: In total, 90,000 surveys were mailed and 13,000 individuals responded (15.8% response rate). 5737 respondents were parents of minor children. Overall, 55% (95% confidence interval 50-59%) of parents were willing to enroll their youngest minor child in a hypothetical biobank; willingness did not differ between consent and data-sharing scenarios. Lower educational attainment, higher religiosity, lower trust, worries about privacy, and attitudes about benefits, concerns, and information needs were independently associated with less willingness to allow their child to participate. Of parents who were willing to participate themselves, 25% were not willing to allow their child to participate. Being willing to participate but not willing to allow one's child to participate was independently associated with multiple factors, including race, lower educational attainment, lower annual household income, public health care insurance, and higher religiosity.

Conclusions: Fifty-five percent of parents were willing to allow their youngest minor child to participate in a hypothetical biobank. Building trust, protecting privacy, and addressing attitudes may increase enrollment and diversity in pediatric biobanks.
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http://dx.doi.org/10.1080/23294515.2018.1505783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354766PMC
November 2019

Parental interest in genomic sequencing of newborns: enrollment experience from the BabySeq Project.

Genet Med 2019 03 13;21(3):622-630. Epub 2018 Sep 13.

Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Purpose: Newborn genomic sequencing (nGS) has great potential to improve pediatric care. Parental interest and concerns about genomics are relatively unexplored. Understanding why parents decline research consent for nGS may reveal implementation barriers.

Methods: We evaluated parental interest in a randomized trial of nGS in well-baby and intensive care unit nursery settings. Interested families attended an informational enrollment session (ES) with a genetic counselor prior to consenting. Reason(s) for declining participation and sociodemographic associations were analyzed.

Results: Of 3860 eligible approached families, 10% attended ES, 67% of whom enrolled. Of 1760 families queried for decline reasons, 58% were uninterested in research. Among 499 families considering research, principal reasons for decline prior to ES included burdensome study logistics (48%), feeling overwhelmed postpartum (17%), and lack of interest/discomfort with genetic testing (17%). Decliners after ES more often cited concerns about privacy/insurability (41%) and uncertain/unfavorable results (23%).

Conclusion: Low interest in research and study logistics were major initial barriers to postpartum enrollment and are likely generic to many postpartum research efforts. Concerns over privacy and result implications were most commonly cited in decliners after ES. Understanding parental concerns around research nGS may inform future integration of nGS into newborn screening, predictive testing, and pediatric diagnostics.
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http://dx.doi.org/10.1038/s41436-018-0105-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420384PMC
March 2019

Using Newborn Sequencing to Advance Understanding of the Natural History of Disease.

Authors:
Ingrid A Holm

Hastings Cent Rep 2018 Jul;48 Suppl 2:S45-S46

A significant portion of newborns cared for in the neonatal intensive care unit or other ICUs, such as the cardiac ICU, have a medical condition with a genetic component, including congenital malformations, the leading cause of death in the NICU. In many cases, however, it is not clear which condition the child has or what can be done to help him or her. Genomic sequencing of sick newborns has the potential to bypass the prolonged journey to a diagnosis, improving the medical care of individual infants. Sequencing also has the potential to benefit others beyond the child whose genome is sequenced and his or her immediate family. Sequence data from sick newborns will expand medicine's understanding of genetic diseases, leading to improvements in clinicians' ability to counsel family and to provide even more targeted care. Not only will more frequent use of sequencing lead to discovery of new genes; it will also provide unique insights into the full spectrum of known Mendelian genetic diseases, so-called phenotypic expansion, when a gene previously recognized as associated with a phenotype is found to be associated with an expanded set of clinical features. Genetic and environmental changes that modify the expression of a genetic disease may also be elucidated.
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http://dx.doi.org/10.1002/hast.886DOI Listing
July 2018

Harmonizing Outcomes for Genomic Medicine: Comparison of eMERGE Outcomes to ClinGen Outcome/Intervention Pairs.

Healthcare (Basel) 2018 Jul 13;6(3). Epub 2018 Jul 13.

Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA.

Genomic medicine is moving from research to the clinic. There is a lack of evidence about the impact of genomic medicine interventions on health outcomes. This is due in part to a lack of standardized outcome measures that can be used across different programs to evaluate the impact of interventions targeted to specific genetic conditions. The eMERGE Outcomes working group (OWG) developed measures to collect information on outcomes following the return of genomic results to participants for several genetic disorders. These outcomes were compared to outcome intervention pairs for genetic disorders developed independently by the ClinGen Actionability working group (AWG). In general, there was concordance between the defined outcomes between the two groups. The ClinGen outcomes tended to be from a higher level and the AWG scored outcomes represented a subset of outcomes referenced in the accompanying AWG evidence review. eMERGE OWG outcomes were more detailed and discrete, facilitating a collection of relevant information from the health records. This paper demonstrates that common outcomes for genomic medicine interventions can be identified. Further work is needed to standardize outcomes across genomic medicine implementation projects and to make these publicly available to enhance dissemination and assist in making precision public health a reality.
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http://dx.doi.org/10.3390/healthcare6030083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164315PMC
July 2018
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