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Article: COngenital heart disease and the Diagnostic yield with Exome sequencing (CODE Study): prospective cohort study and systematic review

TitleCOngenital heart disease and the Diagnostic yield with Exome sequencing (CODE Study): prospective cohort study and systematic review
Authors
Keywordscardiac
congenital heart disease
exome sequencing
fetus
prenatal diagnosis
Issue Date2020
PublisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.interscience.wiley.com/jpages/0960-7692/
Citation
Ultrasound in Obstetrics and Gynecology, 2020, Epub 2020-05-10 How to Cite?
AbstractOBJECTIVES: To determine the yield of antenatal exome sequencing (ES) over chromosome microarray (CMA) / conventional karyotyping in; (i) any prenatally diagnosed congenital heart disease (CHD); (ii) isolated CHD; (iii) multi‐system CHD and; (iv) CHD by phenotypic subgroup. METHODS A prospective cohort study of 197 trios undergoing ES following CMA/karyotype because CHD was identified prenatally and a systematic review of the literature was performed. MEDLINE, EMBASE and CINAHL (2000–Oct 2019) databases were searched electronically. Selected studies included those with; (i) >3 cases; (ii) initiation of testing based upon a prenatal phenotype only and; (iii) where CMA/karyotyping was negative. PROSPERO No. CRD42019140309 RESULTS: In our cohort ES gave an additional diagnostic yield in; (i) all CHD; (ii) isolated CHD and; (iii) multi‐system CHD of 12.7% (n=25/197), 11.5% (n=14/122) and 14.7% (n=11/75) (p=0.81). The pooled incremental yields for the aforementioned categories from 18‐studies (n=636) were 21% (95% CI, 15‐27%), 11% (95% CI, 7‐15%) and 37% (95% CI, 18%‐56%) respectively. This did not differ significantly when sub‐analyses were limited to studies including >20 cases. In instances of multi‐system CHD in the primary analysis, the commonest extra‐cardiac anomalies associated with a pathogenic variant were those affecting the genitourinary system 44.2% (n=23/52). Cardiac shunt lesions had the greatest incremental yield, 41% (95% CI, 19‐63%), followed by right‐sided lesions 26% (95% CI, 9‐43%). In the majority of instances pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease genes (68/96; 70.8%). The commonest monogenic syndrome identified was Kabuki syndrome (n=19/96; 19.8%). CONCLUSIONS: Despite the apparent incremental yield of prenatal exome sequencing in congenital heart disease, the routine application of such a policy would require the adoption of robust bioinformatic, clinical and ethical pathways. Whilst the greatest yield is with multi‐system anomalies, consideration may also be given to performing ES in the presence of isolated cardiac abnormalities. This article is protected by copyright. All rights reserved.
Descriptionlink_to_subscribed_fulltext
Persistent Identifierhttp://hdl.handle.net/10722/282948
ISSN
2019 Impact Factor: 5.571
2015 SCImago Journal Rankings: 1.766

 

DC FieldValueLanguage
dc.contributor.authorMone, F-
dc.contributor.authorEberhardt, RY-
dc.contributor.authorMorris, RK-
dc.contributor.authorHurles, ME-
dc.contributor.authorMcMullan, DJ-
dc.contributor.authorMaher, ER-
dc.contributor.authorLord, J-
dc.contributor.authorChitty, LS-
dc.contributor.authorGiordano, JL-
dc.contributor.authorWapner, RJ-
dc.contributor.authorKilby, MD-
dc.contributor.authorThe CODE Study Collaborators-
dc.contributor.authorChung, BHY-
dc.date.accessioned2020-06-05T06:23:24Z-
dc.date.available2020-06-05T06:23:24Z-
dc.date.issued2020-
dc.identifier.citationUltrasound in Obstetrics and Gynecology, 2020, Epub 2020-05-10-
dc.identifier.issn0960-7692-
dc.identifier.urihttp://hdl.handle.net/10722/282948-
dc.descriptionlink_to_subscribed_fulltext-
dc.description.abstractOBJECTIVES: To determine the yield of antenatal exome sequencing (ES) over chromosome microarray (CMA) / conventional karyotyping in; (i) any prenatally diagnosed congenital heart disease (CHD); (ii) isolated CHD; (iii) multi‐system CHD and; (iv) CHD by phenotypic subgroup. METHODS A prospective cohort study of 197 trios undergoing ES following CMA/karyotype because CHD was identified prenatally and a systematic review of the literature was performed. MEDLINE, EMBASE and CINAHL (2000–Oct 2019) databases were searched electronically. Selected studies included those with; (i) >3 cases; (ii) initiation of testing based upon a prenatal phenotype only and; (iii) where CMA/karyotyping was negative. PROSPERO No. CRD42019140309 RESULTS: In our cohort ES gave an additional diagnostic yield in; (i) all CHD; (ii) isolated CHD and; (iii) multi‐system CHD of 12.7% (n=25/197), 11.5% (n=14/122) and 14.7% (n=11/75) (p=0.81). The pooled incremental yields for the aforementioned categories from 18‐studies (n=636) were 21% (95% CI, 15‐27%), 11% (95% CI, 7‐15%) and 37% (95% CI, 18%‐56%) respectively. This did not differ significantly when sub‐analyses were limited to studies including >20 cases. In instances of multi‐system CHD in the primary analysis, the commonest extra‐cardiac anomalies associated with a pathogenic variant were those affecting the genitourinary system 44.2% (n=23/52). Cardiac shunt lesions had the greatest incremental yield, 41% (95% CI, 19‐63%), followed by right‐sided lesions 26% (95% CI, 9‐43%). In the majority of instances pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease genes (68/96; 70.8%). The commonest monogenic syndrome identified was Kabuki syndrome (n=19/96; 19.8%). CONCLUSIONS: Despite the apparent incremental yield of prenatal exome sequencing in congenital heart disease, the routine application of such a policy would require the adoption of robust bioinformatic, clinical and ethical pathways. Whilst the greatest yield is with multi‐system anomalies, consideration may also be given to performing ES in the presence of isolated cardiac abnormalities. This article is protected by copyright. All rights reserved.-
dc.languageeng-
dc.publisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.interscience.wiley.com/jpages/0960-7692/-
dc.relation.ispartofUltrasound in Obstetrics and Gynecology-
dc.rightsPreprint This is the pre-peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Postprint This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.-
dc.subjectcardiac-
dc.subjectcongenital heart disease-
dc.subjectexome sequencing-
dc.subjectfetus-
dc.subjectprenatal diagnosis-
dc.titleCOngenital heart disease and the Diagnostic yield with Exome sequencing (CODE Study): prospective cohort study and systematic review-
dc.typeArticle-
dc.identifier.emailChung, BHY: bhychung@hku.hk-
dc.identifier.authorityChung, BHY=rp00473-
dc.identifier.doi10.1002/uog.22072-
dc.identifier.pmid32388881-
dc.identifier.hkuros309991-
dc.identifier.volumeEpub 2020-05-10-
dc.publisher.placeUnited Kingdom-

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