PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects

Florence Petit, Mauro Longoni, Julie Wells, Richard S. Maser, Eric L. Bogenschutz, Matthew J. Dysart, Hannah T.M. Contreras, Frederic Frénois, Barbara R. Pober, Robin D. Clark, Philip F. Giampietro, Hilger H. Ropers, Hao Hu, Maria Loscertales, Richard Wagner, Xingbin Ai, Harrison Brand, Anne Sophie Jourdain, Marie Ange Delrue, Brigitte Gilbert-DussardierLouise Devisme, Boris Keren, David J. McCulley, Lu Qiao, Rebecca Hernan, Julia Wynn, Tiana M. Scott, Daniel G. Calame, Zeynep Coban-Akdemir, Patricia Hernandez, Andres Hernandez-Garcia, Hagith Yonath, James R. Lupski, Yufeng Shen, Wendy K. Chung, Daryl A. Scott, Carol J. Bult, Patricia K. Donahoe, Frances A. High*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder.

Original languageEnglish
Pages (from-to)1787-1803
Number of pages17
JournalAmerican Journal of Human Genetics
Issue number10
StatePublished - 5 Oct 2023


FundersFunder number
Gabriella Miller Kids First Pediatric Research ProgramX01 HL136998, X01 HL132366, X01 HL140543
National Human Genome Research InstituteUM1 HG006542
National Human Genome Research Institute
National Institute of Neurological Disorders and StrokeHHSN268201100037C, R35NS105078
National Institute of Neurological Disorders and Stroke
National Institute of Child Health and Human DevelopmentR01 HD057036, 2P01HD068250, R01 HD098458
National Institute of Child Health and Human Development


    • PLS3, plastin
    • X-linked
    • abdominal hernia
    • actin-binding protein
    • congenital diaphragmatic hernia
    • fimbrin
    • omphalocele
    • umbilical hernia


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