| Title: |
COngenital heart disease and the Diagnostic yield with Exome sequencing (CODE Study): prospective cohort study and systematic review |
| Authors: |
Mone, F; Eberhardt, RY; Morris, RK; Hurles, ME; Mcmullan, DJ; Maher, ER; Lord, J; Chitty, LS; Giordano, JL; Wapner, RJ; Kilby, MD |
| Source: |
Ultrasound in Obstetrics & Gynecology , 57 (1) pp. 43-51. (2021) |
| Publisher Information: |
Wiley |
| Publication Year: |
2021 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
cardiac; congenital heart disease; exome sequencing; fetus; prenatal diagnosis; next generation sequencing |
| Description: |
OBJECTIVES: 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, ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10104430/1/Chitty_COngenital%20heart%20disease%20and%20the%20Diagnostic%20yield%20with%20Exome%20sequencing%20%28CODE%20Study%29_AAM.pdf; https://discovery.ucl.ac.uk/id/eprint/10104430/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10104430/1/Chitty_COngenital%20heart%20disease%20and%20the%20Diagnostic%20yield%20with%20Exome%20sequencing%20%28CODE%20Study%29_AAM.pdf; https://discovery.ucl.ac.uk/id/eprint/10104430/ |
| Rights: |
open |
| Accession Number: |
edsbas.36C70846 |
| Database: |
BASE |