Trust in prenatal exome sequencing for expectant families facing unexplained fetal anomalies.

Objective: Despite exome sequencing (ES) becoming increasingly incorporated into the prenatal setting, few studies have elucidated motivations for and trust in ES and genomic research among a diverse cohort of patients and their partners.

Methods: This is a qualitative study that involved semi-structured interviews with pregnant or recently pregnant individuals and their partners, interviewed separately, in the setting of ES performed through research for a fetal structural anomaly. All interview transcripts were coded thematically and developed by a multidisciplinary team.

Intrauterine enzyme replacement therapies for lysosomal storage disorders: Current developments and promising future prospects.

Lysosomal storage disorders (LSDs) are a group of monogenic condition, with many characterized by an enzyme deficiency leading to the accumulation of an undegraded substrate within the lysosomes. For those LSDs, postnatal enzyme replacement therapy (ERT) represents the standard of care, but this treatment has limitations when administered only postnatally because, at that point, prenatal disease sequelae may be irreversible. Furthermore, most forms of ERT, specifically those administered systemically, are currently unable to access certain tissues, such as the central nervous system (CNS), and furthermore, may initiate an immune response.

Access to prenatal exome sequencing for fetal malformations: A qualitative landscape analysis in the US.

Objective: There is increasing evidence supporting the clinical utility of next generation sequencing for identifying fetal genetic disorders. However, there are limited data on the demand for and accessibility of these tests, as well as payer coverage in the prenatal context. We sought to identify clinician perspectives on the utility of prenatal exome sequencing (ES) and on equitable access to genomic technologies for the care of pregnancies complicated by fetal structural anomalies.

The utility of gene sequencing in identifying an underlying genetic disorder in prenatally suspected lower urinary tract obstruction.

Objective: Fetal megacystis generally presents as suspected lower urinary tract obstruction (LUTO), which is associated with severe perinatal morbidity. Genetic etiologies underlying LUTO or a LUTO-like initial presentation are poorly understood. Our objectives are to describe single gene etiologies in fetuses initially ascertained to have suspected LUTO and to elucidate genotype-phenotype correlations.

In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease.

Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe's disease. The family history was positive for infantile-onset Pompe's disease with cardiomyopathy in two previously affected deceased siblings.

Investigating attitudes toward prenatal diagnosis and fetal therapy for spinal muscular atrophy.

Objective: In utero SMA treatment could improve survival and neurologic outcomes. We investigated the attitudes of patients and parents with SMA regarding prenatal diagnosis, fetal therapies, and clinical trials.

Methods: A multidisciplinary team designed a questionnaire that Cure SMA electronically distributed to parents and patients (>18 years old) affected by SMA.

The utility of pathologic examination and comprehensive phenotyping for accurate diagnosis with perinatal exome sequencing.

Objective: Exome sequencing (ES) offers the ability to assess for variants in thousands of genes and is particularly useful in the setting of fetal anomalies. However, the ES pipeline relies on a thorough understanding of an individual patient's phenotype, which may be limited in the prenatal setting. Additional pathology evaluations in the pre- and postnatal settings can add phenotypic details important for clearly establishing and characterizing a diagnosis.

"Let's Just Wait Until She's Born": Temporal Factors That Shape Decision-Making for Prenatal Genomic Sequencing Amongst Families Underrepresented in Genomic Research.

Genomic sequencing has been increasingly utilized for prenatal diagnosis in recent years and this trend is likely to continue. However, decision-making for parents in the prenatal period is particularly fraught, and prenatal sequencing would significantly expand the complexity of managing health risk information, reproductive options, and healthcare access. This qualitative study investigates decision-making processes amongst parents who enrolled or declined to enroll in the prenatal arm of the California-based Program in Prenatal and Pediatric Genome Sequencing (P3EGS), a study in the Clinical Sequencing Evidence-Generating Research (CSER) consortium that offered whole exome sequencing for fetal anomalies with a focus on underrepresented groups in genomic research.

Perspectives and preferences regarding genomic secondary findings in underrepresented prenatal and pediatric populations: A mixed-methods approach.

Purpose: Patients undergoing clinical exome sequencing (ES) are routinely offered the option to receive secondary findings (SF). However, little is known about the views of individuals from underrepresented minority pediatric or prenatal populations regarding SF.

Methods: We explored the preferences for receiving hypothetical categories of SF (H-SF) and reasons for accepting or declining actual SF through surveying (n = 149) and/or interviewing (n = 47) 190 families undergoing pediatric or prenatal ES.

Fetal therapies and trials for lysosomal storage diseases: a survey of attitudes of parents and patients.

Background: Lysosomal storage diseases (LSDs) are inherited metabolic disorders that may lead to severe multi-organ disease. Current ERTs are limited by anti-drug antibodies, the blood-brain barrier, and early disease onset and progression before ERT is started. We have opened a phase I clinical trial of enzyme replacement therapy (ERT) for fetuses with LSDs (NCT04532047).

Exome sequencing vs targeted gene panels for the evaluation of nonimmune hydrops fetalis.

Background: Next-generation sequencing is increasingly used in prenatal diagnosis. Targeted gene panels and exome sequencing are both available, but the comparative diagnostic yields of these approaches are not known.

Objective: We compared the diagnostic yield of exome sequencing with the simulated application of commercial targeted gene panels in a large cohort of fetuses with nonimmune hydrops fetalis.

Exome sequencing of fetuses with congenital diaphragmatic hernia supports a causal role for NR2F2, PTPN11, and WT1 variants.

Background: To identify genes associated with congenital diaphragmatic hernia (CDH) to help understand the etiology and inform prognosis.

Methods: We performed exome sequencing on fetuses with CDH and their parents to identify rare genetic variants likely to mediate risk. We reviewed prenatal characteristics and neonatal outcomes.

Preference for secondary findings in prenatal and pediatric exome sequencing.

Objective: We aimed to determine the frequency of accepting secondary findings in families undergoing exome sequencing in prenatal and pediatric settings.

Methods: This was a secondary analysis of prospectively enrolled patients undergoing trio exome sequencing for congenital anomalies or developmental disorders in prenatal and pediatric settings, in which families were offered receiving secondary findings (initially assessed in the proband and, if identified, then in the parents). The primary outcome was frequency of accepting secondary findings.

Genomic Sequencing Results Disclosure in Diverse and Medically Underserved Populations: Themes, Challenges, and Strategies from the CSER Consortium.

Genomic sequencing results need to be effectively communicated across all populations and practice settings. Projects in the Clinical Sequencing Evidence-Generating Research (CSER) consortium enroll diverse racial/ethnic and medically underserved participants across various clinical contexts. This article explores a set of CSER results disclosure cases to expand the evidence base on experiences returning genomic results.

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis.

Background: The cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear.

Nonimmune hydrops fetalis: identifying the underlying genetic etiology.

Purpose: Numerous etiologies may lead to nonimmune hydrops fetalis (NIHF), and the underlying cause often remains unclear. We aimed to determine the proportion of NIHF cases in which the etiology was clearly determined in a large, contemporary, and diverse cohort, as well as to describe the etiologies with a focus on genetic causes.

Methods: Retrospective review of NIHF cases between 2015 and 2017 from the five University of California Fetal-Maternal Consortium sites.

Favorable outcomes after in utero transfusion in fetuses with alpha thalassemia major: a case series and review of the literature.

Objective: Alpha thalassemia major (ATM) is often fatal in utero due to severe hydrops fetalis. Although in utero transfusions (IUTs) are increasingly used to allow fetal survival in ATM, prenatal and postnatal outcomes are not well described.

Methods: We retrospectively reviewed cases of ATM at our institution treated with consecutive IUT.