Novel Factor XIII variant identified through whole-genome sequencing in a child with intracranial hemorrhage

Briggs, Benjamin; James, Kiely N.; Chowdhury, Shimul; Thornburg, Courtney D.; Farnaes, Lauge; Dimmock, David

doi:10.1101/mcs.a003525

Cited by 12 publications

(16 citation statements)

References 15 publications

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“…Genomic sequencing has greatly increased the number of infants in ICUs who are diagnosed with genetic diseases and holds promise to decrease infant mortality in this setting 15 – 45 . Little, however, has yet been published with regard to the contribution of genetic diseases to infant mortality using this technology.…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that it is now possible to diagnose a genetic disease in 19 h by ultra-rapid whole genome sequencing 17 , albeit such testing is not yet reimbursed by most healthcare payers. There is now a growing literature of infants whose lives have been saved by early diagnosis of genetic diseases and timely implementation of targeted treatments 15 – 45 .…”

Section: Discussionmentioning

confidence: 99%

“…Many infant deaths occur in hospitals, particularly in neonatal, pediatric and cardiovascular intensive care units (ICUs) 13 , 14 . Rapid genomic or precision medicine has created a new opportunity to decrease infant mortality associated with genetic diseases in ICUs 15 – 45 . Many genetic diseases have specific, effective, evidence-based treatments.…”

Section: Introductionmentioning

confidence: 99%

“…However, when diagnosis of a genetic disease is delayed or absent, treatments must be chosen empirically, with suboptimal outcomes, including unnecessary infant mortality. In response, rapid and ultra-rapid clinical genomic sequencing methods have been developed for prompt diagnosis in infants and children in ICUs who may have a genetic disorder for which effective treatment exists 15 – 45 . It is estimated that genetic diseases occur in about 16% of infants in regional ICUs 24 , 46 .…”

Section: Introductionmentioning

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: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…WGS was performed as previously described [8,9]. Variants were prioritized by allele frequency, conservation, and predicted effect on protein function and confirmed by Sanger sequencing.…”

Section: Sequencingmentioning

confidence: 99%

Failure to thrive - an overlooked manifestation of KMT2B-related dystonia: a case presentation

Galosi

Salz

et al. 2020

BMC Neurol

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Background: KMT2B-related dystonia is a recently described form of childhood onset dystonia that may improve with deep brain stimulation. Prior reports have focused on neurologic features including prominent bulbar involvement without detailing general health consequences that may result from orolingual dysfunction. We describe a family with novel KMT2B mutation with several members with failure to thrive to highlight this nonneurologic, but consequential impact of mutation in this gene. Case presentation: We present a case of a 15-year old female who was admitted and evaluated for failure to thrive. On exam, she had severe speech dysfluency, limited ability to protrude the tongue, and generalized dystonia involving the oromandibular region, right upper and left lower extremity with left foot inversion contracture. The proband and her parents underwent whole genome sequencing. A previously undescribed variant, c.4960 T > C (p.Cys1654Arg), was identified in the KMT2B gene in the proband and mother, and this variant was subsequently confirmed in two maternal cousins, one with failure to thrive. Literature review identified frequent reports of prominent bulbar involvement but failure to thrive is rarely mentioned. Conclusion: Failure to thrive is a common pediatric clinical condition that has consequences for growth and development. In the presence of an abnormal neurologic exam, a search for a specific underlying genetic etiology should be pursued. With this case series, we highlight an unusual potentially treatable cause of failure to thrive, reinforce the importance of precise molecular diagnosis for patients with failure to thrive and an abnormal neurologic exam, and underscore the importance of cascade screening of family members.

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Ending a diagnostic odyssey: Moving from exome to genome to identify cockayne syndrome

Friedman

Bird

Haas

et al. 2021

Molec Gen & Gen Med

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Background Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by growth failure and multisystemic degeneration. Excision repair cross‐complementation group 6 (ERCC6 OMIM: *609413) is the gene most frequently mutated in CS. Methods A child with pre and postnatal growth failure and progressive neurologic deterioration with multisystem involvement, and with nondiagnostic whole‐exome sequencing, was screened for causal variants with whole‐genome sequencing (WGS). Results WGS identified biallelic ERCC6 variants, including a previously unreported intronic variant. Pathogenicity of these variants was established by demonstrating reduced levels of ERCC6 mRNA and protein expression, normal unscheduled DNA synthesis, and impaired recovery of RNA synthesis in patient fibroblasts following UV‐irradiation. Conclusion The study confirms the pathogenicity of a previously undescribed upstream intronic variant, highlighting the power of genome sequencing to identify noncoding variants. In addition, this report provides evidence for the utility of a combination approach of genome sequencing plus functional studies to provide diagnosis in a child for whom a lengthy diagnostic odyssey, including exome sequencing, was previously unrevealing.

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Novel Factor XIII variant identified through whole-genome sequencing in a child with intracranial hemorrhage

Cited by 12 publications

References 15 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

Failure to thrive - an overlooked manifestation of KMT2B-related dystonia: a case presentation

Ending a diagnostic odyssey: Moving from exome to genome to identify cockayne syndrome

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