Familial Isolated Tetralogy of Fallot Associated With JAG1 Variant: Justifying Phenotype-Agnostic Genetic Workup for...

Alagille syndrome (ALGS) is a rare, typically multisystem genetic disorder that impacts the liver, heart, eyes, vertebrae, and other areas of development. A clinical diagnosis can be established through defined clinical diagnostic criteria, while a molecular diagnosis requires the presence of a heterozygous pathogenic variant in JAG1 or NOTCH2 detected through molecular genetic testing. Disruption of either gene product results in disrupted Notch signaling pathways, resulting in the broad spectrum of clinical manifestations. The estimated incidence of ALGS is approximately 1 in 30,000-70,000 newborns. Here, we present a case report of a female neonate that presented at birth to the cardiothoracic intensive care unit with critical congenital heart disease (CHD), specifically, Tetralogy of Fallot (ToF). The patient and her parents were enrolled in a translational genomics protocol, COURAGE for Kids, aimed at performing research genome sequencing (GS) on neonates with critical CHD, in a phenotype-agnostic manner, to characterize genetic associations with disease and longitudinal outcomes. This family's GS uncovered a paternally inherited heterozygous missense variant in JAG1 (NM_000214.3:c.806C>T:p.Pro269Leu), which is associated with ALGS type 1 (MIM #118450). Segregation analysis revealed that the proband's paternal grandfather, who also had ToF as a child, carries the same familial variant. A subsequent dysmorphology assessment revealed typical ALGS facial features in the proband, as well as her father, who does not have a history of CHD (prominent forehead, deeply set eyes, wide nasal bridge, bulbous nose, and pointed chin). Thus, this variant is likely causing incomplete ALGS in the proband, father, and paternal grandfather. This variant may have also contributed to vascular events that have occurred within this family, an important example of how an uncovered molecular diagnosis can guide care even for isolated disease. We report a familial JAG1 variant (p.Pro269Leu) in a family with incomplete ALGS presenting as isolated ToF. Given the proband's clinical features alone were not suspicious of a molecular diagnosis of ALGS or other multisystem genetic disorder, this case underscores the potential importance of phenotype-agnostic genetic workup for critical CHD in the neonatal setting.