Application of Whole Genome Sequencing Technology in the Investigation of Genetic Causes of Fetal, Perinatal, and Early Infant Death

Armes, Jane E.; Williams, Mark; Price, Gareth; Wallis, Tristan P.; Gallagher, Renee; Matsika, Admire; Joy, Christopher; Gardener, Glenn; Leach, Rick; Swagemakers, Sigrid; Tearle, Rick; Stubbs, Andrew; Harraway, James; Spek, Peter J. van der; Venter, Deon J.

doi:10.1177/1093526617715528

Cited by 22 publications

(23 citation statements)

References 43 publications

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“…On the one hand, the full clinical phenotype is not manifested 5. On the other hand, genetic heterogeneity in the death cohort is immense 6 7. Both of these lead to difficulties in identifying the genetic causes of newborn deaths.…”

Section: Introductionmentioning

confidence: 99%

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

Yang

Liu

et al. 2019

J Med Genet

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BackgroundCongenital anomalies are the leading cause of early neonatal death in neonatal intensive care units (NICUs), but the genetic causes are unclear. This study aims to investigate the genetic causes of infant deaths in a NICU in China.MethodsNewborns who died in the hospital or died within 1 week of discharge were enrolled from Children’s Hospital of Fudan University between January 1, 2015 and December 31, 2017. Whole exome sequencing was performed in all patients after death.ResultsThere were 223 deceased newborns with a median age at death of 13 days. In total, 44 (19.7%) infants were identified with a genetic finding, including 40 with single nucleotide variants (SNVs), two with CNVs and two with both SNVs and CNVs. Thirteen (31%, 13/42) patients with SNVs had medically actionable disorders based on genetic diagnosis, which included 10 genes. Multiple congenital malformation was identified as the leading genetic cause of death in NICUs with 13 newborns identified with variants in genes related to multiple congenital malformations. For newborns who died on the first day, the most common genetic cause of death was major heart defects, while metabolic disorders and respiratory failure were more common for newborns who died in the first 2 weeks.ConclusionOur study shows genetic findings among early infant deaths in NICUs and provides critical genetic information for precise genetic counselling for the families. Effective therapies enable the improvement of more than a quarter of newborns with molecular diagnoses if diagnosed in time.

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Section: Introductionmentioning

confidence: 99%

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

Yang

Liu

et al. 2019

J Med Genet

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“…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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“…Genetic testing alone without a full phenotype is unlikely to have arrived at the correct diagnosis, given the presence of the RecNcil mutation and large number of variants of uncertain significance often found with “blinded” exome sequencing of preterm fetal deaths. We have recently reported on the diagnostic challenges and role of whole genome sequencing on the next generation platform in perinatal death investigations [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

Perinatal Lethal Gaucher Disease due to RecNcil Recombinant Mutation in the GBA Gene Presenting with Hydrops Fetalis and Severe Congenital Anemia

Bhutada

Pyragius

Petersen

et al. 2018

Case Reports in Pathology

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A 35-year-old woman presented at 27-week gestation with hypertension and pedal edema. Antenatal scan showed hydrops fetalis and growth restriction. Cordocentesis showed severe fetal anemia. This was treated with multiple in utero blood transfusions with no clinically significant improvement and intrauterine death occurred at 28 weeks. Perinatal autopsy confirmed severe hydrops with hepatosplenomegaly and visceral effusions. Microscopic examination of the reticuloendothelial organs showed widespread infiltration by large mono- and multinucleate histiocytic cells with fibrillary appearance (“Gaucher cells”). DNA extracted from fetal tissue was submitted for analysis by next generation sequencing which revealed homozygosity for the RecNcil mutation in the GBA gene. Both parents were found to be heterozygous for the variant. The case report highlights a severe form of Gaucher disease with histopathological and molecular confirmation that presents with hydrops fetalis and severe refractory anemia. It also emphasizes the importance of perinatal autopsy coupled with exome sequencing in confirming syndromic diagnosis in the modern area.

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Application of Whole Genome Sequencing Technology in the Investigation of Genetic Causes of Fetal, Perinatal, and Early Infant Death

Cited by 22 publications

References 43 publications

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

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

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

Perinatal Lethal Gaucher Disease due to RecNcil Recombinant Mutation in the GBA Gene Presenting with Hydrops Fetalis and Severe Congenital Anemia

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