RASopathies due to de novo pathogenic variants: clinical features, genetic findings and outcomes in nine neonates born with congenital heart defects

There are limited information available related to neonatal characteristics of RASopathies, a group of autosomal dominant syndromes with considerable phenotypic overlap. The retrospective review revealed 9 neonates born with congenital heart defects (CHDs) and diagnosed as RASopathies due to de novo...

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Bibliographic Details
Published in:BMC medical genomics 2022-08, Vol.15 (1), p.1-184, Article 184
Main Authors: Zheng, Simin, Huang, Huanyang, Ma, Li, Zhu, Tianwen
Format: Article
Language:English
Subjects:
Amino acids
Chromosome abnormalities
Complications and side effects
Congenital diseases
Congenital heart defect
Congenital heart disease
Congestive heart failure
De novo mutation
Demographic aspects
Echocardiography
Etiology
Family-based exome sequencing
Genes
Genetic aspects
Genotype & phenotype
Hospitals
Magnetic resonance imaging
Males
Mutation
Neonatal
Neonates
Patient outcomes
Patients
Protein structure
RASopathies
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Summary:There are limited information available related to neonatal characteristics of RASopathies, a group of autosomal dominant syndromes with considerable phenotypic overlap. The retrospective review revealed 9 neonates born with congenital heart defects (CHDs) and diagnosed as RASopathies due to de novo mutations (DNMs) by trio-based exome sequencing (ES) between January 2017 and December 2020. We report in details of the neonatal course, molecular analysis and 180-days of age follow-up in affected individuals. The early clinical spectrum included various types of CHDs, less noticeable multiple extracardiac anomalies and unspecific symptoms like poor feeding. Of the 8 variants identified from 6 genes, 2 in RASA1 were novel: (NM_002890.2: c.2828 T > C (p.Leu943Pro)) and (NM_002890.2: c.2001del (p.Pro668Leufs*10)), which functionally impaired the protein structure. There was a relatively high mortality rate of 33.33% (3/9) for all the defects combined. A RAF1-deficient male and a RASA1-deficient male survived from severe heart failure by surgical interventions in early life. Our results revealed that family-based ES was useful in identifying DNMs and causal genes for sporadic diseases and screening Rasopathies shortly after birth. We recommended a family-based ES and a full phenotypic evaluation including echocardiogram, magnetic resonance imaging, ultrasonography and coagulation screening in neonates with CHDs and a suspected genetic etiology.
ISSN:1755-8794
1755-8794
DOI:10.1186/s12920-022-01336-3