Background: The association of intrauterine growth restriction (IUGR), adrenal insufficiency and gonadal dysgenesis is well recognised. Some children have been reported to develop monosomy 7 and myelodysplasia. However, the genetic basis of this condition was poorly understood.
Objective and hypotheses: Our aim was to investigate the genetic basis of eight children with IUGR, adrenal insufficiency and gonadal failure and additional features including severe infections and high mortality in the first 2 years of life.
Methods: A combination of whole exome sequencing and targeted Haloplex array analysis was undertaken in the eight children. All had a 46,XY karyotype, IUGR, adrenal insufficiency and testicular dysfunction, and female external genitalia in 6 out of 8 patients. Expression studies were done using qRTPCR and immunohistochemistry (IHC). Genetic studies included array CGH, single-nucleotide primer extension assays, subcloning and sequencing of PCR-amplified DNA. Functional analysis of the mutants was performed with proliferation assays, EM and confocal imaging studies in patient derived cells.
Results: Heterozygous mutations in sterile alpha motif-containing protein, SAMD9 (OMIM 610456, chr 7q21.2), were found in all cases. These changes were all de novo (7/8 children tested), affected highly conserved regions and were not in control DNA (>100,000 alleles). With qRTPCR and IHC of human fetal and adult tissues, SAMD9 was most highly expressed in the fetal adrenal gland, with high expression also in the colon, thymus, bone marrow, liver and testis correlating well with patient phenotypes. Cell profileration was reduced consistent with gain of function changes in a growth suppressor. Five patients had partial or complete monosomy 7 in their bone marrow or blood and four had mosaic somatic second hit mutations disrupting the SAMD9 gene. By analysing serial samples, we were able to show that the monosomy 7 was an acquired phenomenon leading to loss of the mutated allele and thereby partially rescuing the life-threatening phenotype.
Conclusion: This novel rare congenital disease provides evidence that secondary somatic events can partially rescue lethal developmental defects. The life of affected patients can potentially be saved by bone marrow transplantation, if mutations are detected early.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology