Background: The "double bubble" sign is an ultrasonographic finding that commonly represents duodenal atresia and is associated with trisomy 21. Objectives: We sought to evaluate the positive predictive value of a prenatally identified double bubble sign for duodenal atresia and the genetic etiologies associated with it. Methods: We examined a retrospective cohort with prenatal double bubble sign between January 1, 2008, and June 30, 2017. Postnatal diagnoses were determined by review of operative reports and additional postnatal evaluation including cytogenetic analysis, molecular analysis, and/or clinical genetic evaluation. Results: All live births at our institution with a prenatal double bubble sign had confirmed duodenal atresia. Additional anatomic anomalies and/or genetic abnormalities were identified in 62% of cases. Out of 21 cases, 6 had trisomy 21. Of the remaining 15 cases, 8 were nonisolated duodenal atresia, 3 of which had a heterotaxy syndrome. In the 7 isolated cases, 1 likely pathogenic chromosomal microdeletion was identified. Conclusions: Prenatal double bubble sign is a reliable predictor of duodenal atresia. In addition to trisomy 21, heterotaxy may be encountered. ZIC3 mutations as well as microdeletion of 4q22.3 may be underlying genetic etiologies to be considered in the diagnostic evaluation of a prenatal double bubble sign.

Background: Deleterious mutations in cytosolic leucine-tRNA synthetase (LARS) cause infantile liver failure syndrome, type 1 (ILFS1), a recently recognized, rare autosomal recessive disorder (OMIM151350). Only six families with ILFS1 have been reported in the literature. Patients with ILFS1 are typically diagnosed between 5 and 24 months of age with failure to thrive, developmental delays, encephalopathy, microcytic anemia, and chronic liver dysfunction with recurrent exacerbations following childhood illnesses. Neonatal manifestations of this disorder have not been well documented. Case Report: We report a premature female newborn with intrauterine growth restriction, failure to thrive, congenital anemia, anasarca, and fulminant liver failure leading to lethal multiple organ failure. Liver failure in this infant was characterized by a disproportionate impairment of liver synthetic function, including severe coagulopathy and hypoalbuminemia without significant defects in liver detoxification or evidence of hepatocellular injury during early phase of the disease. Whole-exome sequencing of child-parent trio identified two inherited missense mutations in LARS in this patient. One, c.1292T>A; p.Val431Asp, has been reported in patients with ILFS1, while the other, c.725C>T; p.Pro242Leu, is novel. Both mutations involve amino acid residues in the highly conserved editing domain of LARS, are predicted to be functionally deleterious, and presumably contribute to the clinical manifestations in this patient. Conclusion: This is the first case documenting neonatal manifestation of ILFS1, highlighting early, severe, and disproportionate defects in liver synthetic function. Timely diagnosis of ILFS1 is crucial to guide critical clinical management and improve outcomes of this rare and potentially life-threatening disorder.

Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by recurrent attacks of dyskinetic movements without alteration of consciousness that are often triggered by the initiation of voluntary movements. Whole-exome sequencing has revealed a cluster of pathogenic variants in PRRT2 (proline-rich transmembrane protein), a gene with a function in synaptic regulation that remains poorly understood. Here, we report the discovery of a novel PRRT2 pathogenic variant inherited in an autosomal dominant pattern in a family with PKD and benign familial infantile seizures (BFIS). After targeted Sanger sequencing did not identify the presence of previously described PRRT2 pathogenic variants, we carried out whole-exome sequencing in the proband and her affected paternal grandfather. This led to the discovery of a novel PRRT2 variant, NM_001256442:exon3:c.C959T/NP_660282.2:p.A320V, altering an evolutionarily conserved alanine at the amino acid position 320 located in the M2 transmembrane region. Sanger sequencing further confirmed the presence of this variant in four affected family members (paternal grandfather, father, brother, and proband) and its absence in two unaffected ones (paternal grandmother and mother). This newly found variant further reinforces the importance of PRRT2 in PKD, BFIS, and possibly other movement disorders. Future functional studies using animal models and human pluripotent stem cell models will provide new insights into the role of PRRT2 and the significance of this variant in regulating neural development and/or function.