Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans.

Area of Science:

• Genetics
• Developmental Biology
• Genomic Instability

Background:

• Somatic genomic changes impact cancer phenotypes, but their role in developmental disorders is unclear.
• MIRAGE syndrome is a severe multisystem disorder characterized by intrauterine growth restriction and organ failure.

Purpose of the Study:

• Identify genetic causes of MIRAGE syndrome.
• Investigate the role of somatic adaptive changes in disease progression and survival.

Main Methods:

• Next-generation sequencing to identify de novo mutations.
• Analysis of somatic genomic alterations (monosomy 7, 7q deletions, loss-of-function mutations) in affected individuals.

Main Results:

• Identified de novo heterozygous mutations in SAMD9 (sterile alpha motif domain-containing protein 9) in 8 children with MIRAGE syndrome.
• Mutations lead to a gain of function in SAMD9, a growth repressor.
• Progressive loss of mutant SAMD9 via monosomy 7 or 7q deletions rescued growth restriction in bone marrow, improving survival.
• Two patients developed myelodysplastic syndrome, potentially due to haploinsufficiency of other 7q21.2 genes.

Conclusions:

• Somatic genomic changes can progressively modify disease phenotypes and survival in developmental disorders.
• Tissue-specific adaptive genomic alterations may be a significant, under-recognized mechanism in human genetic conditions.