Congenital heart defects (CHD) refer to a wide range of heart structural abnormalities that exist at birth, ranging from malformations with a good prognosis to more complicated and severe lesions. Congenital heart defects can result from mutations in genes encoding cell signaling transducers such as Jagged-1 (JAG1). Mutations in JAG1 are linked to rare autosomal-dominant disorders, often resulting from haploinsufficiency in the Notch signaling pathway, which affects organ development. Reporting novel mutations and associated phenotypes emphasizes the importance of tailored approaches based on individual phenotypic and genotypic profiles. Next-generation sequencing techniques facilitate the detection of disease-associated mutations, enabling the development of personalized management strategies. Here, we present a case of a Saudi Arabian female child who was born extremely preterm. She required intubation and mechanical ventilation immediately after birth. She developed bronchopulmonary dysplasia and pulmonary hypertension. At 8 months old, her echocardiogram revealed a large atrial septal defect and a patent ductus arteriosus. She underwent successful patent ductus arteriosus closure. She exhibited severe failure to thrive and was frequently admitted for respiratory infections. Tragically, she passed away at 11 years of age due to pneumonia and pulmonary hypertensive crises. Exome sequencing of the proband, her parents, and her brother identified a previously undescribed likely pathogenic heterozygous missense variant (c.1127A>G) in the JAG1 gene, inherited from her presumed healthy mother, that is associated with an isolated cardiac phenotype. Although JAG1 mutations typically manifest as Alagille syndrome, this case underscores their phenotypic variability, specifically presenting as an isolated congenital heart defect. The clinical course demonstrates that pulmonary hypertension is a severe complication of an atrial septal defect (ASD), where persistent left-to-right shunting triggers irreversible vascular remodeling and terminal right heart failure. Ultimately, this report confirms the incomplete penetrance characteristic of JAG1 variants and suggests that extreme prematurity may function as a significant epigenetic or environmental modifier.
Alahmed et al. (Wed,) studied this question.