Genetic aetiology of early infant deaths in a neonatal intensive care unit

Yang, Lin; Liu, Xu; Li, Zixiu; Zhang, Peng; Wu, Bingbing; Wang, Huijun; Hu, Liyuan; Cheng, Guoqiang; Wang, Laishuan; Zhou, Wenhao

doi:10.1136/jmedgenet-2019-106221

Cited by 31 publications

(35 citation statements)

References 44 publications

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“…Little, however, has yet been published with regard to the contribution of genetic diseases to infant mortality using this technology. In six published studies and the cohort reported herein a weighted average of 21% of infant deaths was attributable to single locus genetic diseases 25 , 28 , 45 , 63 – 65 . However, the range of attribution varied widely between studies (6%-86%), reflecting different experimental designs and inclusion and exclusion criteria.…”

Section: Discussionmentioning

confidence: 92%

“…To evaluate whether the findings reported herein were generalizable, we searched the literature for genomic sequencing studies in acutely ill infants in which mortality was recorded. Six additional studies were identified that utilized current genetic disease databases and current variant detection and interpretation methods (Table 4 ) 25 , 28 , 45 , 63 – 66 . Three studies had similar experimental designs as herein–diagnostic genomic sequencing was performed in infant inpatients in United States hospitals who had acute diseases of unknown etiology and in whom genetic diseases were suspected 25 , 28 , 45 .…”

Section: Resultsmentioning

confidence: 99%

“…Three studies had similar experimental designs as herein–diagnostic genomic sequencing was performed in infant inpatients in United States hospitals who had acute diseases of unknown etiology and in whom genetic diseases were suspected 25 , 28 , 45 . In two studies, genome sequencing was performed post mortem 63 , 64 . One study had both ante and post mortem genomic sequencing 65 .…”

Section: Resultsmentioning

confidence: 99%

“…It should be noted that most studies excluded infants with known chromosomal anomalies and those who died prior to enrollment, resulting in under-reporting of these. In two of the studies, a further 8% of infant deaths were associated with variants of uncertain significance (VUS) in established disease loci 63 , 64 . Infant mortality attributable to genetic diseases was not restricted to congenital malformations, nor were all infant deaths associated with congenital malformations attributable to genetic diseases.…”

Section: Resultsmentioning

confidence: 99%

“…This estimate excluded VUS in disease genes known to be associated with infant mortality. In two studies, the contribution of genetic disease to infant mortality increased 8% upon inclusion of VUS 63 , 64 . These data also excluded genes of uncertain significance that are known to be loss of function intolerant or associated with perinatal death in animal models.…”

Section: Discussionmentioning

confidence: 99%

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Measurement of genetic diseases as a cause of mortality in infants receiving whole genome sequencing

et al. 2020

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Understanding causes of infant mortality shapes public health policy and prioritizes diseases for investments in surveillance, intervention and medical research. Rapid genomic sequencing has created a novel opportunity to decrease infant mortality associated with treatable genetic diseases. Herein, we sought to measure the contribution of genetic diseases to mortality among infants by secondary analysis of babies enrolled in two clinical studies and a systematic literature review. Among 312 infants who had been admitted to an ICU at Rady Children’s Hospital between November 2015 and September 2018 and received rapid genomic sequencing, 30 (10%) died in infancy. Ten (33%) of the infants who died were diagnosed with 11 genetic diseases. The San Diego Study of Outcomes in Mothers and Infants platform identified differences between in-hospital and out-of-hospital causes of infant death. Similarly, in six published studies, 195 (21%) of 918 infant deaths were associated with genetic diseases by genomic sequencing. In 195 infant deaths associated with genetic diseases, locus heterogeneity was 70%. Treatment guidelines existed for 70% of the genetic diseases diagnosed, suggesting that rapid genomic sequencing has substantial potential to decrease infant mortality among infants in ICUs. Further studies are needed in larger, comprehensive, unbiased patient sets to determine the generalizability of these findings.

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Section: Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Measurement of genetic diseases as a cause of mortality in infants receiving whole genome sequencing

et al. 2020

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Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

et al. 2023

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ImportanceUnderstanding the causes of infant mortality shapes public health, surveillance, and research investments. However, the association of single-locus (mendelian) genetic diseases with infant mortality is poorly understood.ObjectiveTo determine the association of genetic diseases with infant mortality.Design, Setting, and ParticipantsThis cohort study was conducted at a large pediatric hospital system in San Diego County (California) and included 546 infants (112 infant deaths [20.5%] and 434 infants [79.5%] with acute illness who survived; age, 0 to 1 year) who underwent diagnostic whole-genome sequencing (WGS) between January 2015 and December 2020. Data analysis was conducted between 2015 and 2022.ExposureInfants underwent WGS either premortem or postmortem with semiautomated phenotyping and diagnostic interpretation.Main Outcomes and MeasuresProportion of infant deaths associated with single-locus genetic diseases.ResultsAmong 112 infant deaths (54 girls [48.2%]; 8 [7.1%] African American or Black, 1 [0.9%] American Indian or Alaska Native, 8 [7.1%] Asian, 48 [42.9%] Hispanic, 1 [0.9%] Native Hawaiian or Pacific Islander, and 34 [30.4%] White infants) in San Diego County between 2015 and 2020, single-locus genetic diseases were the most common identifiable cause of infant mortality, with 47 genetic diseases identified in 46 infants (41%). Thirty-nine (83%) of these diseases had been previously reported to be associated with childhood mortality. Twenty-eight death certificates (62%) for 45 of the 46 infants did not mention a genetic etiology. Treatments that can improve outcomes were available for 14 (30%) of the genetic diseases. In 5 of 7 infants in whom genetic diseases were identified postmortem, death might have been avoided had rapid, diagnostic WGS been performed at time of symptom onset or regional intensive care unit admission.Conclusions and RelevanceIn this cohort study of 112 infant deaths, the association of genetic diseases with infant mortality was higher than previously recognized. Strategies to increase neonatal diagnosis of genetic diseases and immediately implement treatment may decrease infant mortality. Additional study is required to explore the generalizability of these findings and measure reduction in infant mortality.

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Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease

et al. 2021

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The NICUSeq Study Group IMPORTANCE Whole-genome sequencing (WGS) shows promise as a first-line genetic test for acutely ill infants, but widespread adoption and implementation requires evidence of an effect on clinical management.OBJECTIVE To determine the effect of WGS on clinical management in a racially and ethnically diverse and geographically distributed population of acutely ill infants in the US. DESIGN, SETTING, AND PARTICIPANTSThis randomized, time-delayed clinical trial enrolled participants from September 11, 2017, to April 30, 2019, with an observation period extending to July 2, 2019. The study was conducted at 5 US academic medical centers and affiliated children's hospitals. Participants included infants aged between 0 and 120 days who were admitted to an intensive care unit with a suspected genetic disease. Data were analyzed from January 14 to August 20, 2020.INTERVENTIONS Patients were randomized to receive clinical WGS results 15 days (early) or 60 days (delayed) after enrollment, with the observation period extending to 90 days. Usual care was continued throughout the study. MAIN OUTCOMES AND MEASURESThe main outcome was the difference in the proportion of infants in the early and delayed groups who received a change of management (COM) 60 days after enrollment. Additional outcome measures included WGS diagnostic efficacy, within-group COM at 90 days, length of hospital stay, and mortality.RESULTS A total of 354 infants were randomized to the early (n = 176) or delayed (n = 178) arms. The mean participant age was 15 days (IQR, 7-32 days); 201 participants (56.8%) were boys; 19 (5.4%) were Asian; 47 (13.3%) were Black; 250 (70.6%) were White; and 38 (10.7%) were of other race. At 60 days, twice as many infants in the early group vs the delayed group received a COM (34 of 161 [21.1%; 95% CI, 15.1%-28.2%] vs 17 of 165 [10.3%; 95% CI, 6.1%-16.0%]; P = .009; odds ratio, 2.3; 95% CI, 1.22-4.32) and a molecular diagnosis (55 of 176 [31.0%; 95% CI, 24.5%-38.7%] vs 27 of 178 [15.0%; 95% CI, 10.2%-21.3%]; P < .001). At 90 days, the delayed group showed a doubling of COM (to 45 of 161 [28.0%; 95% CI, 21.2%-35.6%]) and diagnostic efficacy (to 56 of 178 [31.0%; 95% CI, 24.7%-38.8%]). The most frequent COMs across the observation window were subspecialty referrals (39 of 354; 11%), surgery or other invasive procedures (17 of 354; 4%), condition-specific medications (9 of 354; 2%), or other supportive alterations in medication (12 of 354; 3%). No differences in length of stay or survival were observed. CONCLUSIONS AND RELEVANCEIn this randomized clinical trial, for acutely ill infants in an intensive care unit, introduction of WGS was associated with a significant increase in focused clinical management compared with usual care. Access to first-line WGS may reduce health care disparities by enabling diagnostic equity. These data support WGS adoption and implementation in this population.

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Genetic aetiology of early infant deaths in a neonatal intensive care unit

Cited by 31 publications

References 44 publications

Measurement of genetic diseases as a cause of mortality in infants receiving whole genome sequencing

Measurement of genetic diseases as a cause of mortality in infants receiving whole genome sequencing

Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease

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