Deleterious growth restricting effects of human SAMD9 mutations are rescued by dynamic genomic changes

Abstract

Intrauterine growth restriction (IUGR) is a common condition that is sometimes associated with additional features, and in some cases endocrine dysfunction. We investigated eight children who had IUGR together with a complex multisystem disorder involving gonadal, adrenal and bone marrow failure. Several children died in the first 2 years of life. Using NGS and targeted capture, heterozygous de novo missense mutations in SAMD9 (chr 7q21•2) were identified in all eight children. SAMD9 was shown to be a growth repressor and these mutations result in gain-of-function, leading to reduced cell proliferation. Furthermore, progressive loss of the mutated gene through the development of monosomy 7 (-7), deletions of 7q (7q-) and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth restricting effects of the mutant proteins in bone marrow and was associated with increased length of survival. However, two patients with-7/-7q developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.1 genes. These findings provide strong evidence that dynamic somatic changes can occur in specific tissues. These changes can modify disease phenotype and influence survival. Tissue-specific adaptability such as this may be an under-recognised mechanism modifying the phenotype of human genetic.L6195234222017-12-08 <br />