ID

45465

Description

Principal Investigator: Stephen Kingsmore, MB, ChB, BAO, DSc, FRCPath, Children's Mercy Hospital, Kansas City, MO, USA MeSH: Congenital, Hereditary, and Neonatal Diseases and Abnormalities,Developmental Disabilities,Cerebellar Ataxia,Epidermolysis Bullosa,Epilepsy,Heterotaxy Syndrome,Mitochondrial Diseases,Growth and Development,Malformations of Cortical Development,Macrocephaly,Menkes Kinky Hair Syndrome,Microcephaly,Myotonia,Seizures,Tay-Sachs Disease https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000564 Monogenic diseases are frequent causes of neonatal morbidity and mortality, and disease presentations are often undifferentiated at birth. More than 3,500 monogenic diseases have been characterized, but clinical testing is available for only some of them and many feature clinical and genetic heterogeneity. As such, an immense unmet need exists for improved molecular diagnosis in infants. Because disease progression is extremely rapid, albeit heterogeneous, in newborns, molecular diagnoses must occur quickly to be relevant for clinical decision-making. We describe 50-hour differential diagnosis of genetic disorders by whole-genome sequencing (WGS) that features automated bioinformatic analysis and is intended to be a prototype for use in neonatal intensive care units. Retrospective 50-hour WGS identified known molecular diagnoses in two children. Prospective WGS disclosed potential molecular diagnosis of a severe *GJB2*-related skin disease in one neonate; *BRAT1*-related lethal neonatal rigidity and multifocal seizure syndrome in another infant, identified *BCL9L* as a novel, recessive visceral heterotaxy gene (*HTX6*) in a pedigree, and ruled out known candidate genes in one infants. Sequencing of parents or affected siblings expedited the identification of disease gene in prospective cases. Thus, rapid WGS can potentially broaden and foreshorten differential diagnosis, resulting in fewer empirical treatments and faster progression to genetic and prognostic counseling. Reprinted from Saunders et. al, Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units. Sci. Transl. Med. 4, 154ra135 (2012; PMID: 23035047) with permission from AAAS.

Link

dbGap study = phs000564

Keywords

Versions (2)
  1. 10/27/22 10/27/22 - Simon Heim
  2. 12/13/22 12/13/22 - Kristina Keller
Copyright Holder

Stephen Kingsmore, MB, ChB, BAO, DSc, FRCPath, Children's Mercy Hospital, Kansas City, MO, USA

Uploaded on

December 13, 2022

DOI

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License

Creative Commons BY 4.0
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dbGaP phs000564 Rapid Whole Genome Sequencing for Genetic Disease Diagnosis in the NICU

English

Eligibility Criteria

6 forms  
Inclusion and exclusion criteria
Description

Inclusion and exclusion criteria

To assess the ability to recapitulate known results, whole genome sequencing was performed retrospectively on two infants with molecular diagnoses that had previously been identified by clinical testing. These samples (UDXXXX) were selected from a validation set of 384 samples with known molecular diagnoses for one or more genetic diseases.
Description

To assess the ability to recapitulate known results, whole genome sequencing was performed retrospectively on two infants with molecular diagnoses that had previously been identified by clinical testing. These samples (UDXXXX) were selected from a validation set of 384 samples with known molecular diagnoses for one or more genetic diseases.

Data type

boolean

Alias
UMLS CUI [1,1]
C4744597
UMLS CUI [1,2]
C1516048
UMLS CUI [1,3]
C3640076
UMLS CUI [1,4]
C1514923
UMLS CUI [1,5]
C0021270
UMLS CUI [1,6]
C1513388
UMLS CUI [1,7]
C5236074
UMLS CUI [1,8]
C1516634
UMLS CUI [2,1]
C1519941
UMLS CUI [2,2]
C0150098
UMLS CUI [2,3]
C1513388
UMLS CUI [2,4]
C0019247
To assess the potential diagnostic use of WGS, sequencing was prospectively performed on four undiagnosed newborns with clinical presentations that strongly suggested a genetic disorder as well as one affected sibling and their unaffected parents. Seven prospective samples were selected from families with probands that presented in infancy, among 143 individuals without molecular diagnoses who were enrolled between November 2011 and April 2012 for exome or genome sequencing.
Description

To assess the potential diagnostic use of WGS, sequencing was prospectively performed on four undiagnosed newborns with clinical presentations that strongly suggested a genetic disorder as well as one affected sibling and their unaffected parents. Seven prospective samples were selected from families with probands that presented in infancy, among 143 individuals without molecular diagnoses who were enrolled between November 2011 and April 2012 for exome or genome sequencing.

Data type

boolean

Alias
UMLS CUI [1,1]
C1516048
UMLS CUI [1,2]
C3245505
UMLS CUI [1,3]
C0430022
UMLS CUI [1,4]
C3640076
UMLS CUI [1,5]
C0033522
UMLS CUI [1,6]
C0021289
UMLS CUI [1,7]
C2708283
UMLS CUI [1,8]
C0019247
UMLS CUI [1,9]
C0037047
UMLS CUI [1,10]
C0392760
UMLS CUI [1,11]
C2986417
UMLS CUI [1,12]
C0030551
UMLS CUI [2,1]
C0021289
UMLS CUI [2,2]
C0332288
UMLS CUI [2,3]
C1513388
UMLS CUI [2,4]
C3640077
UMLS CUI [2,5]
C3640076
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Similar models

Eligibility Criteria

6 forms
Name
Type
Description | Question | Decode (Coded Value)
Data type
Alias
Item Group
Inclusion and exclusion criteria
To assess the ability to recapitulate known results, whole genome sequencing was performed retrospectively on two infants with molecular diagnoses that had previously been identified by clinical testing. These samples (UDXXXX) were selected from a validation set of 384 samples with known molecular diagnoses for one or more genetic diseases.
Item
To assess the ability to recapitulate known results, whole genome sequencing was performed retrospectively on two infants with molecular diagnoses that had previously been identified by clinical testing. These samples (UDXXXX) were selected from a validation set of 384 samples with known molecular diagnoses for one or more genetic diseases.
boolean
C4744597 (UMLS CUI [1,1])
C1516048 (UMLS CUI [1,2])
C3640076 (UMLS CUI [1,3])
C1514923 (UMLS CUI [1,4])
C0021270 (UMLS CUI [1,5])
C1513388 (UMLS CUI [1,6])
C5236074 (UMLS CUI [1,7])
C1516634 (UMLS CUI [1,8])
C1519941 (UMLS CUI [2,1])
C0150098 (UMLS CUI [2,2])
C1513388 (UMLS CUI [2,3])
C0019247 (UMLS CUI [2,4])
To assess the potential diagnostic use of WGS, sequencing was prospectively performed on four undiagnosed newborns with clinical presentations that strongly suggested a genetic disorder as well as one affected sibling and their unaffected parents. Seven prospective samples were selected from families with probands that presented in infancy, among 143 individuals without molecular diagnoses who were enrolled between November 2011 and April 2012 for exome or genome sequencing.
Item
To assess the potential diagnostic use of WGS, sequencing was prospectively performed on four undiagnosed newborns with clinical presentations that strongly suggested a genetic disorder as well as one affected sibling and their unaffected parents. Seven prospective samples were selected from families with probands that presented in infancy, among 143 individuals without molecular diagnoses who were enrolled between November 2011 and April 2012 for exome or genome sequencing.
boolean
C1516048 (UMLS CUI [1,1])
C3245505 (UMLS CUI [1,2])
C0430022 (UMLS CUI [1,3])
C3640076 (UMLS CUI [1,4])
C0033522 (UMLS CUI [1,5])
C0021289 (UMLS CUI [1,6])
C2708283 (UMLS CUI [1,7])
C0019247 (UMLS CUI [1,8])
C0037047 (UMLS CUI [1,9])
C0392760 (UMLS CUI [1,10])
C2986417 (UMLS CUI [1,11])
C0030551 (UMLS CUI [1,12])
C0021289 (UMLS CUI [2,1])
C0332288 (UMLS CUI [2,2])
C1513388 (UMLS CUI [2,3])
C3640077 (UMLS CUI [2,4])
C3640076 (UMLS CUI [2,5])
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