Overgrowth syndrome is a rare genetic childhood disorder commonly caused by pathogenic genetic variants in epigenetic writers, such as DNA or histone methyltransferases. A researcher at Children’s National Hospital identified a new genetic cause of overgrowth syndrome in Spindlin Family Member 4 (SPIN4), an epigenetic reader, in which a loss-of-function variant in SPIN4 causes a prenatal onset of extreme tall stature in a male individual, inherited in an X-linked semi-dominant fashion.
The study, published in JCI Insight, reported Spin4 knockout pre-clinical models recapitulating human phenotype and found evidence that SPIN4 normally binds specific modified histone peptides, promotes canonical WNT signaling and inhibits cell proliferation in vitro and that the identified frameshift variant lost all of these functions.
How does this work move the field forward?
“These findings prove that SPIN4 negatively regulates mammalian body growth, and loss of SPIN4 causes an overgrowth syndrome in humans and pre-clinical models, expanding our knowledge of the epigenetic regulation of human growth and development,” says Youn Hee Jee, M.D., endocrinologist at Children’s National and co-senior author of the study.
What did you find that excites you?
SPIN4 is the first epigenetic reader gene identified to cause overgrowth syndrome in humans.
“Understanding the full characteristics of the phenotype caused by SPIN4 variants will greatly advance our knowledge in epigenetic regulation of childhood growth and SPIN4-associated disorders,” Dr. Jee says.
How is Children’s National leading in this space?
Dr. Jee is leading a follow-up translational study to dissect the precise underlying pathobiology of overgrowth syndrome due to SPIN4 mutations. Using the knowledge, the ultimate goal of her work is to develop novel interventional approaches to treat childhood growth disorders.