Objective

To determine which types of fetal anomalies are associated with postnatal diagnoses of genetic diseases by genomic sequencing and to assess how prenatal genomic sequencing could affect clinical management.

Method

This was a secondary analysis of the second Newborn Sequencing in Genomic Medicine and Public Health study that compared fetal imaging results in critically ill infants who had actionable versus negative postnatal genomic sequencing results.

Results

Of 213 infants who received genomic sequencing, 80 had available prenatal ultrasounds. Twenty-one (26%) of these were found to have genetic diseases by genomic sequencing. Fourteen (67%) of the 21 with genetic diseases had suspected anomalies prenatally, compared with 33 (56%) of 59 with negative results. Among fetuses with suspected anomalies, genetic diseases were 4.5 times more common in those with multiple anomalies and 6.7 times more common in those with anomalies of the extremities compared to those with negative results. Had the genetic diseases been diagnosed prenatally, clinical management would have been altered in 13 of 14.

Conclusion

Critically ill infants with diagnostic genomic sequencing were more likely to have multiple anomalies and anomalies of the extremities on fetal imaging. Among almost all infants with suspected fetal anomalies and diagnostic genomic sequencing results, prenatal diagnosis would have likely altered clinical management.

IPEX syndrome (Immune dysregulation, Polyendocrinopathy, X-linked) should be tested for in males under 6 months old presenting with diabetes, even without other IPEX features. Early diagnosis and bone marrow transplantation can improve outcomes.

Background

Congenital heart defects (CHD) and congenital anomalies of the kidney and urinary tract (CAKUT) account for significant morbidity and mortality in childhood. Dozens of monogenic causes of anomalies in each organ system have been identified. However, even though 30% of CHD patients also have a CAKUT and both organs arise from the lateral mesoderm, there is sparse overlap of the genes implicated in the congenital anomalies for these organ systems. We sought to determine whether patients with both CAKUT and CHD have a monogenic etiology, with the long-term goal of guiding future diagnostic work up and improving outcomes.

Methods

Retrospective review of electronic medical records (EMR), identifying patients admitted to Rady Children's Hospital between January 2015 and July 2020 with both CAKUT and CHD who underwent either whole exome sequencing (WES) or whole genome sequencing (WGS). Data collected included demographics, presenting phenotype, genetic results, and mother's pregnancy history. WGS data was reanalyzed with a specific focus on the CAKUT and CHD phenotype. Genetic results were reviewed to identify causative, candidate, and novel genes for the CAKUT and CHD phenotype. Associated additional structural malformations were identified and categorized.

Results

Thirty-two patients were identified. Eight patients had causative variants for the CAKUT/CHD phenotype, three patients had candidate variants, and three patients had potential novel variants. Five patients had variants in genes not associated with the CAKUT/CHD phenotype, and 13 patients had no variant identified. Of these, eight patients were identified as having possible alternative causes for their CHD/CAKUT phenotype. Eighty-eight percent of all CAKUT/CHD patients had at least one additional organ system with a structural malformation.

Conclusions

Overall, our study demonstrated a high rate of monogenic etiologies in hospitalized patients with both CHD and CAKUT, with a diagnostic rate of 44%. Thus, physicians should have a high suspicion for genetic disease in this population. Together, these data provide valuable information on how to approach acutely ill patients with CAKUT and CHD, including guiding diagnostic work up for associated phenotypes, as well as novel insights into the genetics of CAKUT and CHD overlap syndromes in hospitalized children.

Adeno-associated viruses (AAVs) are being increasingly used as gene therapy vectors in clinical studies especially targeting central nervous system (CNS) disorders. Correspondingly, host immune responses to the AAV capsid or the transgene-encoded protein have been observed in various clinical and preclinical studies. Such immune responses may adversely impact patients' health, prevent viral transduction, prevent repeated dosing strategies, eliminate transduced cells, and pose a significant barrier to the potential effectiveness of AAV gene therapy. Consequently, multiple immunomodulatory strategies have been used in attempts to limit immune-mediated responses to the vector, enable readministration of AAV gene therapy, prevent end-organ toxicity, and increase the duration of transgene-encoded protein expression. Herein we review the innate and adaptive immune responses that may occur during CNS-targeted AAV gene therapy as well as host- and treatment-specific factors that could impact the immune response. We also summarize the available preclinical and clinical data on immune responses specifically to CNS-targeted AAV gene therapy and discuss potential strategies for incorporating prophylactic immunosuppression regimens to circumvent adverse immune responses.

Pediatric stroke can be either hemorrhagic or ischemic, with ∼5% of hemorrhagic strokes being caused by genetic coagulopathies. We report an 8 mo old presenting with a hemorrhagic stroke caused by severe Factor XIII deficiency (OMIM # 613225) in whom rapid whole-genome sequencing identified a novel variant in the F13A1 gene c.1352_1353delAT (p.His451ArgfsTer29).

Rapid diagnostic genomic sequencing recently became feasible for infants in intensive care units (ICUs). However, research regarding parents perceived utility, adequacy of consent, and potential harms and benefits is lacking. Herein we report results of parental surveys of these domains from the second Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT2) study, a randomized, controlled trial of rapid diagnostic genomic sequencing of infants in regional ICUs. More than 90% of parents reported feeling adequately informed to consent to diagnostic genomic sequencing. Despite only 23% (27) of 117 infants receiving genomic diagnoses, 97% (156) of 161 parents reported that testing was at least somewhat useful and 50.3% (88/161) reported no decisional regret (median 0, mean 10, range 0-100). Five of 117 families (4.3%) reported harm. Upon follow-up, one (1%) confirmed harm to child and parent related to negative results/no diagnosis, two (2%) reported stress or confusion, and two (2%) denied harm. In 81% (89) of 111 infants, families and clinicians agreed that genomic results were useful. Of the families for whom clinicians perceived harm from genomic testing, no parents reported harm. Positive tests/genomic diagnosis were more frequently perceived to be useful by parents, to benefit their infant, and to help manage potential symptoms (p < .05). In summary, the large majority of parents felt that first-tier, rapid, diagnostic genomic sequencing was beneficial for infants lacking etiologic diagnoses in ICUs. Most parents in this study perceived being adequately informed to consent, understood their childs results, and denied regret or harm from undergoing sequencing.

We aimed to characterize knowledge and attitudes about rapid whole genome sequencing (rWGS) implementation of a broad constituency of healthcare professionals at hospitals participating in a statewide initiative to implement rWGS for hospitalized neonates and children up to 18 years of age meeting clinical criteria for testing. We surveyed 307 healthcare professionals from eight hospitals about their knowledge and attitudes regarding rWGS. We examined survey internal reliability using exploratory factor analysis and associations between respondent characteristics and attitudes toward rWGS with linear regression. We thematically analyzed free-text responses. Views about rWGS implementation in respondents' own setting and respondents' personal capability to implement rWGS were generally neutral (M = 3.44 (SD = 0.74); M = 3.30 (SD = 0.85), respectively). Views about the potential for rWGS in clinical practice were overall positive (M = 4.12 (SD = 0.57)). The degree of positivity of attitudes about rWGS was strongly influenced by perceived knowledge, clinical or non-clinical role, concerns about future insurance coverage for rWGS as a first-tier test, and future adverse impact of genomics health information on patients or families. We identified several actionable factors influencing attitudes toward rWGS of pediatric healthcare professionals. Expanded education and ongoing implementation research are needed for the full potential of rWGS in pediatrics to be realized.

Neonatal diabetes mellitus (NDM) is a rare condition that presents with diabetes in the first few months of life. The treatment of NDM may differ depending on the genetic etiology, with numerous studies showing the benefit of sulfonylurea therapy in cases caused by mutations in KCNJ11 or ABCC8 Mutations in the insulin gene (INS) have also been identified as causes of NDM; these cases are generally best treated with insulin alone. We report a case of a female infant born small for gestational age (SGA) at late preterm diagnosed with NDM at 7 wk of life who was found by rapid whole-genome sequencing to harbor a novel de novo c.26C>G (p.Pro9Arg) variant in the INS gene. She presented with diabetic ketoacidosis, which responded to insulin therapy. She did not respond to empiric trial of sulfonylurea therapy early in her hospital course, and it was discontinued once a genetic diagnosis was made. Early genetic evaluation in patients presenting with NDM is essential to optimize therapeutic decision-making.