ARHGAP42 encodes Rho GTPase activating protein 42 that belongs to a member of the GTPase Regulator Associated with Focal Adhesion Kinase (GRAF) family. ARHGAP42 is involved in blood pressure control by regulating vascular tone. Despite these findings, disorders of human variants in the coding part of ARHGAP42 have not been reported. Here, we describe an 8-year-old girl with childhood interstitial lung disease (chILD), systemic hypertension, and immunological findings who carries a homozygous stop-gain variant (c.469G>T, p.(Glu157Ter)) in the ARHGAP42 gene. The family history is notable for both parents with hypertension. Histopathological examination of the proband lung biopsy showed increased mural smooth muscle in small airways and alveolar septa, and concentric medial hypertrophy in pulmonary arteries. ARHGAP42 stop-gain variant in the proband leads to exon 5 skipping, and reduced ARHGAP42 levels, which was associated with enhanced RhoA and Cdc42 expression. This is the first report linking a homozygous stop-gain variant in ARHGAP42 with a chILD disorder, systemic hypertension, and immunological findings in human patient. Evidence of smooth muscle hypertrophy on lung biopsy and an increase in RhoA/ROCK signaling in patient cells suggests the potential mechanistic link between ARHGAP42 deficiency and the development of chILD disorder.

Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts United States of America

Department of Cardiology Boston Children's Hospital and Harvard Medical School Boston Massachusetts United States of America

Department of Cell Biology Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University Průmyslová 595 Vestec u Prahy Czech Republic

Department of Cell Biology Charles University Prague Viničná 7 Prague Czech Republic

Department of Pathology Boston Children's Hospital and Harvard Medical School Boston Massachusetts United States of America

Dept Pathology and Laboratory Medicine University of North Carolina Chapel Hill North Carolina United States of America

Division of Genetics and Genomics Boston Children's Hospital and Harvard Medical School Boston Massachusetts United States of America

Division of Immunology Boston Children's Hospital and Harvard Medical School Boston Massachusetts United States of America

Division of Newborn Medicine Boston Children's Hospital and Harvard Medical School Boston Massachusetts United States of America

Division of Pulmonary Medicine Boston Children's Hospital and Harvard Medical School Boston Massachusetts United States of America

Pulmonary and Critical Care Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts United States of America

The Manton Center for Orphan Disease Research Boston Children's Hospital and Harvard Medical School Boston Massachusetts United States of America

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