Diminished 100 Expression in a Newborn With Acinar Dysplasia and a Novel Variant: A Case Report

Acinar dysplasia (AcDys) of the lung is a rare lethal developmental disorder in neonates characterized by severe respiratory failure and pulmonary arterial hypertension refractory to treatment. Recently, abnormalities of TBX4-FGF10-FGFR2-TMEM100 signaling regulating lung development have been reported in patients with AcDys due to heterozygous single-nucleotide variants or copy-number variant deletions involving , , or . Here, we describe a female neonate who died at 4 hours of life due to severe respiratory distress related to AcDys diagnosed by postmortem histopathologic evaluation. Genomic analyses revealed a novel deleterious heterozygous missense variant c.728A>C (p.Asn243Thr) in that arose de novo on paternal chromosome 17. We also identified 6 candidate hypomorphic rare variants in the enhancer in to coding variant. Gene expression analyses of proband's lung tissue showed a significant reduction of expression with near absence of TMEM100 within the endothelium of arteries and capillaries by immunohistochemistry. These results support the pathogenicity of the detected variant and provide further evidence that disrupted signaling between TBX4 and TMEM100 may contribute to severe lung phenotypes in humans, including AcDys.