TY - JOUR
T1 - The prevalence of genetic diagnoses in fetuses with severe congenital heart defects
AU - van Nisselrooij, Amber E L
AU - Lugthart, Malou A
AU - Clur, Sally-Ann
AU - Linskens, Ingeborg H
AU - Pajkrt, Eva
AU - Rammeloo, Lukas A
AU - Rozendaal, Lieke
AU - Blom, Nico A
AU - van Lith, Jan M M
AU - Knegt, Alida C
AU - Hoffer, Mariëtte J V
AU - Aten, Emmelien
AU - Santen, Gijs W E
AU - Haak, Monique C
PY - 2020/7/1
Y1 - 2020/7/1
N2 - PURPOSE: Congenital heart defects (CHD) are associated with genetic syndromes. Rapid aneuploidy testing and chromosome microarray analysis (CMA) are standard care in fetal CHD. Many genetic syndromes remain undetected with these tests. This cohort study aims to estimate the frequency of causal genetic variants, in particular structural chromosome abnormalities and sequence variants, in fetuses with severe CHD at mid-gestation, to aid prenatal counselling.METHODS: Fetuses with severe CHD were extracted from the PRECOR registry (2012-2016). We evaluated pre- and postnatal genetic testing results retrospectively to estimate the frequency of genetic diagnoses in general, as well as for specific CHDs.RESULTS: 919 fetuses with severe CHD were identified. After exclusion of 211 cases with aneuploidy, a genetic diagnosis was found in 15.7% (111/708). These comprised copy number variants in 9.9% (70/708). In 4.5% (41/708) sequence variants were found that would have remained undetected with CMA. Interrupted aortic arch, pulmonary atresia with ventricular septal defect and atrioventricular septal defect were most commonly associated with a genetic diagnosis.CONCLUSION: In case of normal CMA results, parents should be offered exome sequencing sequentially, if time allows for it, especially if the CHD is accompanied by other structural malformations due to the large variety in genetic syndromes.
AB - PURPOSE: Congenital heart defects (CHD) are associated with genetic syndromes. Rapid aneuploidy testing and chromosome microarray analysis (CMA) are standard care in fetal CHD. Many genetic syndromes remain undetected with these tests. This cohort study aims to estimate the frequency of causal genetic variants, in particular structural chromosome abnormalities and sequence variants, in fetuses with severe CHD at mid-gestation, to aid prenatal counselling.METHODS: Fetuses with severe CHD were extracted from the PRECOR registry (2012-2016). We evaluated pre- and postnatal genetic testing results retrospectively to estimate the frequency of genetic diagnoses in general, as well as for specific CHDs.RESULTS: 919 fetuses with severe CHD were identified. After exclusion of 211 cases with aneuploidy, a genetic diagnosis was found in 15.7% (111/708). These comprised copy number variants in 9.9% (70/708). In 4.5% (41/708) sequence variants were found that would have remained undetected with CMA. Interrupted aortic arch, pulmonary atresia with ventricular septal defect and atrioventricular septal defect were most commonly associated with a genetic diagnosis.CONCLUSION: In case of normal CMA results, parents should be offered exome sequencing sequentially, if time allows for it, especially if the CHD is accompanied by other structural malformations due to the large variety in genetic syndromes.
KW - chromosome microarray analysis
KW - congenital heart defects
KW - exome sequencing
KW - genetic syndrome
KW - prenatal counseling
UR - http://www.scopus.com/inward/record.url?scp=85084133900&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41436-020-0791-8
DO - https://doi.org/10.1038/s41436-020-0791-8
M3 - Article
C2 - 32341573
SN - 1098-3600
VL - 22
SP - 1206
EP - 1214
JO - Genetics in medicine
JF - Genetics in medicine
IS - 7
ER -