Genetic characterisation of 22q11.2 variations and prevalence in patients with congenital heart disease

Hou, Hongying; Chen, Huanxin; Wang, Xiuli; Yuan, Chao; Yang, Qin; Liu, Zhigang; He, Guo‐Wei

doi:10.1136/archdischild-2018-316634

Cited by 19 publications

(24 citation statements)

References 41 publications

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“…43 Genetic analysis reveals that the TBX1 gene at the 22q11.2 region is an important pathogenic gene for CHD. 44 In this study, all six fetuses with the 22q11.2 microdeletion syndrome had diverse ultrasound findings, but all had cardiac malformations, including three fetuses that had complicated extracardiac malformations on ultrasonography. SNP array analysis showed a 3.1 Mb duplication at the chromosome 22q11.2 region in a fetus, which was identified as the 22q11.2 microduplication syndrome.…”

Section: Discussionmentioning

confidence: 63%

SNP Array as a Tool for Prenatal Diagnosis of Congenital Heart Disease Screened by Echocardiography: Implications for Precision Assessment of Fetal Prognosis

Huang¹,

Cai²,

Wang³

et al. 2021

RMHP

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Objective This study aimed to examine the effectiveness of the SNP array for the prenatal diagnosis of congenital heart disease (CHD) screened by echocardiography. Patients and Methods A total of 356 pregnant women with fetal congenital heart malformations revealed by echocardiography at the Center for Prenatal Diagnosis of Fujian Maternal and Children Hospital during the period from November 2016 through July 2019 were recruited. The fetuses were assigned into three cohorts, including 142 with a single cardiac malformation, 106 with multiple cardiac malformations and 108 with cardiac and extracardiac malformations. All fetuses underwent chromosomal karyotyping and SNP array simultaneously, and the effectiveness of the SNP array for the prenatal diagnosis of CHD was evaluated. Results The overall prevalence of abnormal karyotypes was 9.3% among the 356 fetuses with CHD, and a higher proportion was found in fetuses with cardiac and extracardiac malformations (18.5%) than in those with single (5.6%) or multiple cardiac malformations (4.7%) ( P <0.05). Consistent with karyotype analysis, SNP array detected an additional 25 fetuses with pathogenic copy number variations (CNVs), seven with variant of unknown significance (VOUS) and seven with benign CNVs, and a lower proportion of abnormal CNV was found in fetuses with a single cardiac malformation (4.2%) than in those with multiple cardiac malformations (9.4%) or cardiac and extracardiac malformations (14.8%) ( P <0.05). Among the 33 fetuses with chromosomal abnormality, postnatal follow-up showed termination of pregnancy in 25 with pathogenic CNVs, one with VOUS, and six with normal karyotypes and SNP array findings but severe multiple malformations by ultrasonography. Conclusion SNP array increases the overall detection of abnormal CNVs by 9%, which improves the detection of CNVs associated with CHD. SNP array may serve as a tool for prenatal diagnosis of CHD that facilitates the discovery of pathogenic genes associated with CHD and provide valuable insights into the precision assessment of fetal prognosis during the prenatal counseling.

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Section: Discussionmentioning

confidence: 63%

SNP Array as a Tool for Prenatal Diagnosis of Congenital Heart Disease Screened by Echocardiography: Implications for Precision Assessment of Fetal Prognosis

Huang¹,

Cai²,

Wang³

et al. 2021

RMHP

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“…The Crkl gene is related to lens formation in mice [ 37 ]. ZNF74 is found at a relatively high frequency in patients with CHD with deletions/amplifications in the 22q11.2 region [ 38 ]. MED15 is related to heart development [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic findings in patients with congenital cataract and heart diseases

Song

et al. 2021

Orphanet J Rare Dis

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Background Congenital cataract (CC) and congenital heart disease (CHD) are significant birth defects. In clinical practice, the concurrence of CC and CHD is frequently observed in patients. Additionally, some monogenic diseases, copy number variation (CNV) syndromes, and diseases associated with intrauterine infection involve both cataract and heart defects. However, little is known about the association between CC and CHD. Here, we characterised the demographic, clinical, and genetic features of patients with CC and heart defects. Methods Medical records for 334 hospitalised patients diagnosed with CC were reviewed. Demographic and clinical features of patients with CC with and without CHD were compared. Clinical and genomic information for patients with ‘cataract’ and ‘cardiac defects’ were reviewed from Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER). Microarray-based comparative genomic hybridisation and whole-exome sequencing were performed in 10 trio families with CC and CHD to detect de novo genomic alterations, including copy number variants and single nucleotide changes. Results In a retrospective analysis of 334 patients with CC over the past 10 years at our hospital, we observed a high proportion of patients (41.13%) with CHD (including innocent CHD, which reported as left-to-right shunt in echocardiography test). The CC with CHD group had higher incidences of preterm birth and Down’s syndrome than the CC without CHD group. Atrial septal defect was the most frequent heart defect. A total of 44 cases with cataracts and heart diseases were retrieved from Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER). In total, 52 genomic alterations were reported, 44% of which were de novo germline variants. In the 10 trio families with CC and CHD, we found de novo CNVs responsible for two well-known chromosomal disorders and identified a novel pathogenic mutation in GJA8 responsible for CC. Conclusions We observed significant associations between CHD and CC in our 10-year patient cohort. Based on the cohort and data from DECIPHER, developmental syndromes in some patients were due to genetic defects, thus explaining the concurrence of CC and CHD. Additionally, we detected de novo mutations as an independent cause of cataracts. Our findings suggest that developmental syndromes in patients with CC deserve more attention in clinical practice by ophthalmologists.

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“…CLTCL1 is a member of the family of heavy chains of clathrins and plays an essential role in the neural crest development, which is an important component for the morphogenesis of pharyngeal arches (Nahorski et al, 2015). Chromosomal alterations involving CLTCL1 are also associated with DiGeorge syndrome, velo‐cardio‐facial syndrome (Long, Trofatter, Ramesh, McCormick, & Buckler, 1996), Down syndrome and cardiac malformations, mainly in typical 3 Mb deletion of LCR22A‐LCR22D, a region extensively studied in DiGeorge syndrome (Hou et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Candidate genes of oculo‐auriculo‐vertebral spectrum in 22q region: A systematic review

Glaeser

Santos

Diniz

et al. 2020

American J of Med Genetics Pt A

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Oculo-auriculo-vertebral spectrum (hemifacial microsomia/OAVS, OMIM #164210) is a heterogenous and congenital condition caused by a morphogenesis defect of the first and second pharyngeal arches. Etiology includes unknown genetic, environmental factors and chromosomal alterations, which 22q11.2 region is the most frequently reported. Several candidate genes for OAVS have been proposed; however, none has been confirmed as causative of the phenotype. This review aims to sum up all clinical and molecular findings in 22q region of individuals diagnosed with OAVS and to investigate genes that may be involved in the development of the spectrum. A search was performed in PubMed using all entry terms to OAVS and Chromosome 22q11. After screening, 11 papers were eligible for review. Deletions and duplications in the q11.2 region were the most frequent (18/22) alterations reported and a total of 68 genes were described. Our systematic review reinforces the hypothesis that 22q11 region is a candidate locus for OAVS as well as CLTCL1, GSC2, HIRA, MAPK1, TBX1, and YPEL1 as potential candidates genes for genotype-phenotype correlation. Complementary studies regarding genes interaction involved in the 22q11 region are still necessary in the search for a genotype-phenotype association, since the diagnosis of OAVS is a constant medical challenge.

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Genetic characterisation of 22q11.2 variations and prevalence in patients with congenital heart disease

Cited by 19 publications

References 41 publications

SNP Array as a Tool for Prenatal Diagnosis of Congenital Heart Disease Screened by Echocardiography: Implications for Precision Assessment of Fetal Prognosis

SNP Array as a Tool for Prenatal Diagnosis of Congenital Heart Disease Screened by Echocardiography: Implications for Precision Assessment of Fetal Prognosis

Clinical and genetic findings in patients with congenital cataract and heart diseases

Candidate genes of oculo‐auriculo‐vertebral spectrum in 22q region: A systematic review

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