Germline deletion of the miR-17-92 cluster causes growth and skeletal defects in humans

MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness , and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR7~92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR7~92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR7~92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR7~92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.

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