Theoretical Investigation of Linear Relationships between the Dihedral Torsion Angles and Diosmium Bond Distances in Diosmium Sawhorse Complexes.

Strong linear relationships between their Ceq-Os-Os-Ceq dihedral angles and their Os-Os bond distances in diosmium sawhorse complexes Os2(u-O2CR)2(CO)4L2 (L = CO and/or PR3) form two trendlines depending upon the presence or absence of terminal phosphines. These trends appear unrelated to the basicity of the bridging ligand or the number of phosphines. The mathematical derivation of the relationship between the O-Os-Os-O dihedral angle and the Os-Os bond distance shows how the other geometric parameters affect this relationship. Optimized density functional theory (DFT) structures reveal a similar strong linear correlation, where more electron-donating ligands render shorter Os-Os bond distances and larger dihedral angles, but these results form a single trendline. Computational scans of individual parameters show that the Os-Os bond responds strongly to changes in the dihedral angles, but the dihedral angles only respond weakly to changes in the Os-Os bond distance because the Os-Os-O bond angle links and modifies their direct coupling. Solid-state analysis of their structures, including DFT geometry optimizations, shows that phosphines protect the Os-Os bond distance from packing influences along the Os-Os axis, while in complexes without phosphines, packing compresses the Os-Os bond and the weak dihedral responses create the second trendline.

A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization.

The vast majority of severe (Type 0) spinal muscular atrophy (SMA) cases are caused by homozygous deletions of survival motor neuron 1 (SMN1). We report a case in which the patient has two copies of SMN1 but clinically presents as Type 0 SMA. The patient is an African American male carrying a homozygous maternally inherited missense variant (c.796T>C) in a cis-oriented SMN1 duplication on one chromosome and an SMN1 deletion on the other chromosome (genotype: 2*+0). Initial extensive genetic workups including exome sequencing were negative. Deletion analysis used in the initial testing for SMA also failed to detect SMA as the patient has two copies of SMN1. Because of high clinical suspicion, SMA diagnosis was finally confirmed based on full-length SMN1 sequencing. The patient was initially treated with risdiplam and later gene therapy with onasemnogene abeparvovec at 5 months without complications. The patient's muscular weakness has stabilized with mild improvement. The patient is now 28 months old and remains stable and diffusely weak, with stable respiratory ventilatory support. This case highlights challenges in the diagnosis of SMA with a non-deletion genotype and provides a clinical example demonstrating that disruption of functional SMN protein polymerization through an amino acid change in the YG-box domain represents a little known but important pathogenic mechanism for SMA. Clinicians need to be mindful about the limitations of the current diagnostic approach for SMA in detecting non-deletion genotypes.

Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder.

Importance: Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal gene-sequencing test provides comparable molecular diagnostic yields and times to return of results. Objective: To compare outcomes of genomic sequencing with those of a targeted neonatal gene-sequencing test. Design, Setting, and Participants: The Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a prospective, comparative, multicenter study of 400 hospitalized infants younger than 1 year of age (proband) and their parents, when available, suspected of having a genetic disorder. The study was conducted at 6 US hospitals from June 2019 to November 2021. Exposure: Enrolled participants underwent simultaneous testing with genomic sequencing and a targeted neonatal gene-sequencing test. Each laboratory performed an independent interpretation of variants guided by knowledge of the patient's phenotype and returned results to the clinical care team. Change in clinical management, therapies offered, and redirection of care was provided to families based on genetic findings from either platform. Main Outcomes and Measures: Primary end points were molecular diagnostic yield (participants with ≥1 pathogenic variant or variant of unknown significance), time to return of results, and clinical utility (changes in patient care). Results: A molecular diagnostic variant was identified in 51% of participants (n = 204; 297 variants identified with 134 being novel). Molecular diagnostic yield of genomic sequencing was 49% (95% CI, 44%-54%) vs 27% (95% CI, 23%-32%) with the targeted gene-sequencing test. Genomic sequencing did not report 19 variants found by the targeted neonatal gene-sequencing test; the targeted gene-sequencing test did not report 164 variants identified by genomic sequencing as diagnostic. Variants unidentified by the targeted genomic-sequencing test included structural variants longer than 1 kilobase (25.1%) and genes excluded from the test (24.6%) (McNemar odds ratio, 8.6 [95% CI, 5.4-14.7]). Variant interpretation by laboratories differed by 43%. Median time to return of results was 6.1 days for genomic sequencing and 4.2 days for the targeted genomic-sequencing test; for urgent cases (n = 107) the time was 3.3 days for genomic sequencing and 4.0 days for the targeted gene-sequencing test. Changes in clinical care affected 19% of participants, and 76% of clinicians viewed genomic testing as useful or very useful in clinical decision-making, irrespective of a diagnosis. Conclusions and Relevance: The molecular diagnostic yield for genomic sequencing was higher than a targeted neonatal gene-sequencing test, but the time to return of routine results was slower. Interlaboratory variant interpretation contributes to differences in molecular diagnostic yield and may have important consequences for clinical management.

Evidence and Recommendation for Guanidinoacetate Methyltransferase Deficiency Newborn Screening.

Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine biosynthesis due to pathogenic variants in the GAMT gene that lead to cerebral creatine deficiency and neurotoxic levels of guanidinoacetate. Untreated, GAMT deficiency is associated with hypotonia, significant intellectual disability, limited speech development, recurrent seizures, behavior problems, and involuntary movements. The birth prevalence of GAMT deficiency is likely between 0.5 and 2 per million live births. On the basis of small case series and sibling data, presymptomatic treatment with oral supplements of creatine, ornithine, and sodium benzoate, and a protein-restricted diet to reduce arginine intake, appear to substantially improve health and developmental outcomes. Without newborn screening, diagnosis typically happens after the development of significant impairment, when treatment has limited utility. GAMT deficiency newborn screening can be incorporated into the tandem-mass spectrometry screening that is already routinely used for newborn screening, with about 1 per 100 000 newborns screening positive. After a positive screen, diagnosis is established by finding an elevated guanidinoacetate concentration and low creatine concentration in the blood. Although GAMT deficiency is significantly more rare than other conditions included in newborn screening, the feasibility of screening, the low number of positive results, the relative ease of diagnosis, and the expected benefit of presymptomatic dietary therapy led to a recommendation from the Advisory Committee on Heritable Disorders in Newborns and Children to the Secretary of Health and Human Services that GAMT deficiency be added to the Recommended Uniform Screening Panel. This recommendation was accepted in January 2023.

Insights into the perinatal phenotype of Kabuki syndrome in infants identified by genome-wide sequencing.

Increasing use of unbiased genomic sequencing in critically ill infants can expand understanding of rare diseases such as Kabuki syndrome (KS). Infants diagnosed with KS through genome-wide sequencing performed during the initial hospitalization underwent retrospective review of medical records. Human phenotype ontology terms used in genomic analysis were aggregated and analyzed. Clinicians were surveyed regarding changes in management and other care changes. Fifteen infants met inclusion criteria. KS was not suspected prior to genomic sequencing. Variants were classified as Pathogenic (n = 10) or Likely Pathogenic (n = 5) by American College of Medical Genetics and Genomics Guidelines. Fourteen variants were de novo (KMT2D, n = 12, KDM6A, n = 2). One infant inherited a likely pathogenic variant in KMT2D from an affected father. Frequent findings involved cardiovascular (14/15) and renal (7/15) systems, with palatal defects also identified (6/15). Three infants had non-immune hydrops. No minor anomalies were universally documented; ear anomalies, micrognathia, redundant nuchal skin, and hypoplastic nails were common. Changes in management were reported in 14 infants. Early use of unbiased genome-wide sequencing enabled a molecular diagnosis prior to clinical recognition including infants with atypical or rarely reported features of KS while also expanding the phenotypic spectrum of this rare disorder.

Evidence and recommendation for mucopolysaccharidosis type II newborn screening in the United States.

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is an X-linked condition caused by pathogenic variants in the iduronate-2-sulfatase gene. The resulting reduced activity of the enzyme iduronate-2-sulfatase leads to accumulation of glycosaminoglycans that can progressively affect multiple organ systems and impair neurologic development. In 2006, the US Food and Drug Administration approved idursulfase for intravenous enzyme replacement therapy for MPS II. After the data suggesting that early treatment is beneficial became available, 2 states, Illinois and Missouri, implemented MPS II newborn screening. Following a recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children in February 2022, in August 2022, the US Secretary of Health and Human Services added MPS II to the Recommended Uniform Screening Panel, a list of conditions recommended for newborn screening. MPS II was added to the Recommended Uniform Screening Panel after a systematic evidence review reported the accuracy of screening, the benefit of presymptomatic treatment compared with usual case detection, and the feasibility of implementing MPS II newborn screening. This manuscript summarizes the findings of the evidence review that informed the Advisory Committee's decision.

Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.

Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in DVL2. We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with FZD2 variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1, DVL2, and DVL3 variants, demonstrating no phenotypic distinction between the NXN-autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing WNT5A, FZD2, and ROR2 apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins.

Kinetic and Computational Analysis of CO Substitution in a Dinuclear Osmium Carbonyl Complex: Intersection between Dissociative and Dissociative-Interchange Mechanisms.

The mechanism for the CO substitution reaction involving the diosmium carbonyl sawhorse complex Os2(µ-O2CH)2(CO)6, which contains an Os-Os single bond, two axial CO ligands, and four equatorial CO ligands, was investigated experimentally and theoretically. Kinetic measurements show 13CO axial substitution proceeding by a dissociative reaction that is first-order in the complex and zero-order in 13CO but with an unexpectedly negative entropy of activation. The corresponding electronic structure calculations yield an enthalpy of activation for axial CO dissociation that is much larger than that determined by the kinetic experiments, but in agreement with the complex's stability with respect to CO loss. Additional calculations yield a dissociative interchange transition state whose free energy, enthalpy, and entropy of activation are in good agreement with those obtained from the kinetic measurements for the apparently dissociative substitution. These results point to an exchange reaction mechanism that is surprisingly close to the poorly understood transition from a dissociative mechanism with a CO-loss intermediate to a dissociative interchange mechanism with a transition state involving both the entering and the leaving COs. The key to explain these findings is provided by the vibrational analysis, which shows very low energy wagging motions for the axial COs. Thus, the incoming CO only displaces the outgoing CO when the complex has an outgoing CO near the wag's turning point. This dissociative interchange mechanism predicted by the calculation explains the unexpected combination of kinetics and stability characteristics. Kinetics reveals that the reaction is first-order in the Os dimer with a negative Eyring entropy, while a stability study shows that the Os dimer's decomposition rate is several orders of magnitude slower than CO exchange.

Virtual Shadowing Program for Preclinical Medical Students.

Our annual summer shadowing program for preclinical medical students faced significant challenges due to COVID-19-related safety and resource concerns during Summer 2020. We created a pilot 7-week virtual shadowing program with the goal of providing virtual observational clinical experiences to increase students' clinical exposure and understanding of medical specialties. Faculty and preclinical medical students were matched via student preference selection and mentor availability. A practice guide was developed that outlined suggested virtual shadowing procedures. Afterward, participating faculty and students were surveyed on their experience. Overall, both faculty and students found the program effective and experienced limited technological difficulty.

A Voluntary Statewide Newborn Screening Pilot for Spinal Muscular Atrophy: Results from Early Check.

Prior to statewide newborn screening (NBS) for spinal muscular atrophy (SMA) in North Carolina, U.S.A., we offered voluntary screening through the Early Check (EC) research study. Here, we describe the EC experience from October 2018 through December 2020. We enrolled a total of 12,065 newborns and identified one newborn with 0 copies of SMN1 and two copies of SMN2, consistent with severe early onset of SMA. We also detected one false positive result, likely stemming from an unrelated blood disorder associated with a low white blood cell count. We evaluated the timing of NBS for babies enrolled prenatally (n = 932) and postnatally (n = 11,133) and reasons for delays in screening and reporting. Although prenatal enrollment led to faster return of results (median = 13 days after birth), results for babies enrolled postnatally were still available within a timeframe (median = 21 days after birth) that allowed the opportunity to receive essential treatment early in life. We evaluated an SMA q-PCR screening method at two separate time points, confirming the robustness of the assay. The pilot project provided important information about SMA screening in anticipation of forthcoming statewide expansion as part of regular NBS.

Actionability of commercial laboratory sequencing panels for newborn screening and the importance of transparency for parental decision-making.

BACKGROUND: Newborn screening aims to identify individual patients who could benefit from early management, treatment, and/or surveillance practices. As sequencing technologies have progressed and we move into the era of precision medicine, genomic sequencing has been introduced to this area with the hopes of detecting variants related to a vastly expanded number of conditions. Though implementation of genomic sequencing for newborn screening in public health and clinical settings is limited, commercial laboratories have begun to offer genomic screening panels for neonates. METHODS: We examined genes listed on four commercial laboratory genomic screening panels for neonates and assessed their clinical actionability using an established age-based semi-quantitative metric to categorize them. We identified genes that were included on multiple panels or distinct between panels. RESULTS: Three hundred and nine genes appeared on one or more commercial panels: 74 (23.9%) genes were included in all four commercial panels, 45 (14.6%) were on only three panels, 76 (24.6%) were on only two panels, and 114 (36.9%) genes were listed on only one of the four panels. Eighty-two genes (26.5%) listed on one or more panels were assessed by our method to be inappropriate for newborn screening and to require additional parental decision-making. Conversely, 249 genes that we previously identified as being highly actionable were not listed on any of the four commercial laboratory genomic screening panels. CONCLUSIONS: Commercial neonatal genomic screening panels have heterogeneous content and may contain some conditions with lower actionability than would be expected for public health newborn screening; conversely, some conditions with higher actionability may be omitted from these panels. The lack of transparency about how conditions are selected suggests a need for greater detail about panel content in order for parents to make informed decisions. The nuanced activity of gene list selection for genomic screening should be iteratively refined with evidence-based approaches to provide maximal benefit and minimal harm to newborns.

Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing: An Interim Report of the Genomic Medicine for Ill Neonates and Infants (GEMINI) Study.

Importance: A targeted genomic sequencing platform focused on diseases presenting in the first year of life may minimize financial and ethical challenges associated with rapid whole-genomic sequencing. Objective: To report interim variants and associated interpretations of an ongoing study comparing rapid whole-genomic sequencing with a novel targeted genomic platform composed of 1722 actionable genes targeting disorders presenting in infancy. Design, Setting, and Participants: The Genomic Medicine in Ill Neonates and Infants (GEMINI) study is a prospective, multicenter clinical trial with projected enrollment of 400 patients. The study is being conducted at 6 US hospitals. Hospitalized infants younger than 1 year of age suspected of having a genetic disorder are eligible. Results of the first 113 patients enrolled are reported here. Patient recruitment began in July 2019, and the interim analysis of enrolled patients occurred from March to June 2020. Interventions: Patient (proband) and parents (trios, when available) were tested simultaneously on both genomic platforms. Each laboratory performed its own phenotypically driven interpretation and was blinded to other results. Main Outcomes and Measures: Variants were classified according to the American College of Medical Genetics and Genomics standards of pathogenic (P), likely pathogenic (LP), or variants of unknown significance (VUS). Chromosomal and structural variations were reported by rapid whole-genomic sequencing. Results: Gestational age of 113 patients ranged from 23 to 40 weeks and postmenstrual age from 27 to 83 weeks. Sixty-seven patients (59%) were male. Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%) had negative results. Results were concordant between platforms in 83 patients (73%). Thirty-seven patients (33%) were found to have a P/LP variant by 2 or both platforms and 14 (12%) had a VUS possibly related to phenotype. The median day of life at diagnosis was 22 days (range, 3-313 days). Significant alterations in clinical care occurred in 29 infants (78%) with a P/LP variant. Incidental findings were reported in 7 trios. Of 51 positive cases, 34 (67%) differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, filtering discrepancies, or multiple causes. Conclusions and Relevance: As comprehensive genetic testing becomes more routine, these data highlight the critically important variant detection capabilities of existing genomic sequencing technologies and the significant limitations that must be better understood.

A behavior-theoretic evaluation of values clarification on parental beliefs and intentions toward genomic sequencing for newborns.

Decision aids commonly include values clarification exercises to help people consider which aspects of a choice matter most to them, and to help them make decisions that are congruent with their personal values and preferences. Using a randomized online experiment, we examined the influence of values clarification on parental beliefs and intentions about having genomic sequencing for newborns. We recruited 1186 women and men ages 18-44 who were pregnant or whose partner was pregnant or planning to become pregnant in the next two years. Participants (N = 1000) completed one of two versions of an online decision aid developed as part of a larger project examining the technical, clinical, and social aspects of using exome sequencing to screen newborns for rare genetic conditions. The education-only version provided information about using genomic sequencing to screen newborns for medically treatable conditions. The education-plus-values-clarification version included the same information, along with a values clarification exercise in which participants classified as important or unimportant five reasons in support of having and five reasons against having their newborn undergo genomic sequencing. We conducted partial correlations, regression analysis, and MANCOVAs with sex, health literacy, and experience with genetic testing as covariates. Participants who completed the decision aid with the values clarification exercise agreed less strongly with four of the five statements against sequencing compared to participants who viewed the education-only decision aid. The groups did not differ on agreement with reasons in support of sequencing. Agreement with four of five reasons against genomic sequencing was negatively associated with intentions to have their newborn sequenced, whereas agreement with all five reasons in support of sequencing were positively associated with intentions.

Outreach to new mothers through direct mail and email: recruitment in the Early Check research study.

Meeting recruitment targets for clinical trials and health research studies is a notable challenge. Unsuccessful efforts to recruit participants from traditionally underserved populations can limit who benefits from scientific discovery, thus perpetuating inequities in health outcomes and access to care. In this study, we evaluated direct mail and email outreach campaigns designed to recruit women who gave birth in North Carolina for a statewide research study offering expanded newborn screening for a panel of rare health conditions. Of the 54,887 women who gave birth in North Carolina from September 28, 2018, through March 19, 2019, and were eligible to be included on the study's contact lists, we had access to a mailing address for 97.9% and an email address for 6.3%. Rural women were less likely to have sufficient contact information available, but this amounted to less than a one percentage point difference by urbanicity. Native American women were less likely to have an email address on record; however, we did not find a similar disparity when recruitment using direct-mail letters and postcards was concerned. Although we sent letters and emails in roughly equal proportion by urbanicity and race/ethnicity, we found significant differences in enrollment across demographic subgroups. Controlling for race/ethnicity and urbanicity, we found that direct-mail letters and emails were effective recruitment methods. The enrollment rate among women who were sent a recruitment letter was 4.1%, and this rate increased to 5.0% among women who were also sent an email invitation. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Under-representation by traditionally underserved populations in clinical trials and health research is a challenge that may in part reflect inequitable opportunities to participate. WHAT QUESTION DID THIS STUDY ADDRESS? Are direct-mail and email outreach strategies effective for reaching and recruiting women from traditionally underserved and rural populations to participate in large-scale, population-based research? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Despite sending recruitment letters and email invitations in roughly equal proportion by urbanicity and race/ethnicity, women living in rural areas were less likely to enroll (2.8%) than women from urban areas (4.2%). Additionally, enrollment rates decreased as the probability that women were members of a racial or ethnic minority group increased. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Results from this study might encourage researchers to take a holistic and participant-centered view of barriers to study enrollment that may disproportionately affect underserved communities, including differences in willingness to participate, trust, and access to resources needed for uptake.

Mindful Mentors: Is a Longitudinal Mind-Body Skills Training Pilot Program Feasible for Pediatric Cardiology Staff?

BACKGROUND: Stress and burnout among medical professionals are common and costly, placing professionals, organizations, and patients at risk. OBJECTIVES: To determine feasibility and acceptability of a longitudinal mind-body skills training initiative to help staff decrease stress and burnout, improve well-being, and empower them to utilize basic mindfulness methods with coworkers, patients, and families. METHODS: Prospective cohort, mixed methods approach. Nurses, doctors, technicians, social workers, child life specialists were eligible to participate. The 12-month curriculum consisted of 16 hours of intensive education/practice over 2 days, with training in mindfulness skills, self-compassion, nonviolent communication, overcoming barriers to practice, and mindful listening/speaking, followed by monthly 1 hour booster/debriefing sessions. RESULTS: A total of 37 staff participated (RN = 18, MD = 5, Technician = 6, Social Worker = 3, Child life = 3, others = 2) in the initial training, and 24 (65%) completed the 3- and 12-month follow-up surveys. Compared with pretraining scores, there were significant improvements 3 to 12 months after the initial training in stress (P < .0001), distress (P ≤ .04), anxiety (P = .01), self-efficacy in providing non-drug therapies (P < .0001), mindfulness (P = .002), burnout (P < .0001), and confidence in providing compassionate care (P < .0001). In addition, 25 (67%) participants initiated projects incorporating what they learned into staff/patient wellness activities. CONCLUSION: This longitudinal pilot program was feasible and was associated with improvements in measures of psychological well-being over the 12-month intervention. The innovative approach of training participants to teach basic techniques to coworkers and other staff can increase the impact of this program beyond any individual participant. Future research will investigate the aspects of implementation and potential effects on patient care and experience.

Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project.

Newborn screening (NBS) was established as a public health program in the 1960s and is crucial for facilitating detection of certain medical conditions in which early intervention can prevent serious, life-threatening health problems. Genomic sequencing can potentially expand the screening for rare hereditary disorders, but many questions surround its possible use for this purpose. We examined the use of exome sequencing (ES) for NBS in the North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project, comparing the yield from ES used in a screening versus a diagnostic context. We enrolled healthy newborns and children with metabolic diseases or hearing loss (106 participants total). ES confirmed the participant's underlying diagnosis in 15 out of 17 (88%) children with metabolic disorders and in 5 out of 28 (∼18%) children with hearing loss. We discovered actionable findings in four participants that would not have been detected by standard NBS. A subset of parents was eligible to receive additional information for their child about childhood-onset conditions with low or no clinical actionability, clinically actionable adult-onset conditions, and carrier status for autosomal-recessive conditions. We found pathogenic variants associated with hereditary breast and/or ovarian cancer in two children, a likely pathogenic variant in the gene associated with Lowe syndrome in one child, and an average of 1.8 reportable variants per child for carrier results. These results highlight the benefits and limitations of using genomic sequencing for NBS and the challenges of using such technology in future precision medicine approaches.

Correction: An approach to integrating exome sequencing for fetal structural anomalies into clinical practice.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.