De NOVO mutation
The research by Hoischen et al. (2011) results in a third important conclusion:
3. It is a NOVO mutation; a genetic mutation in the ASXL1 gene that occurred at conception, because the ASXL1 mutation was not present in any of their unaffected parents (Hoischen et al. 2011).
Further to point 3.) There is no medical publication stating that a mutation of the ASXL1 gene (which is responsible for BOS among other unknown reasons) can be passed to the child from their parents. However, one parent in our FB group does have the mutation of the ASXL1 gene. This mutation occurred at a later stage of the foetal development meaning that the parent does not have the characteristics of BOS and is completely healthy. The mutation is only found in the blood cells and is not detectable in the body cells yet. According to their geneticist any parent can be a carrier of a germline mosaicism mutation of the ASXL1 gene. Thus, we suspect that BOS is theoretically hereditary.
In most of the cases Bohring-Opitz syndrome (BOS) is the result of a novo mutation in the ASXL1 gene. The risk of having another child with Bohring-Opitz Syndrome is low. (Russell, B. et al. 2018)
To date, no confirmed severely affected BOS patient has become a parent themselves. (Russel, B. et al. 2018)
“This is the first report of Bohring-Opitz syndrome caused by a mutation inherited from an unaffected, somatic mosaic parent with presumed germline mosaicism. This phenomenon has been reported for other traditionally de novo dominant disorders like CHARGE syndrome and Cornelia de Lange syndrome (2)(3). This case demonstrates that haploinsufficiency of ASXL1 is not lethal in the germline, and emphasizes the need for accurate low but non-negative recurrence risk counseling for families with children with Bohring-Opitz syndrome.” – Deborah Copenheaver et.al.
We have learned that germline mutations of human ASXL1 could be causing Bohring-Opitz syndrome (BOS). Germline means its a novo ASXL1 mutation, the gene mutates at conception, creating a developmental disorder that leads to BOS. Patients with somatic ASXL1 mutation (the mutation formed during later life) have an increased risk of myelodysplasia (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemia (AML) acute myeloid leukemia (AML), forms of blood cancer.
Karen Seiter and colleges present a father and son who have a identical mutation of ASXL1 with the inference that these cases support the diagnosis of a germline mutation of ASXL1. Interestingly this specific mutation has been reported in one case of Bohring-Opitz syndrome. Both, father and son have developed myelodysplasia to myeloid leukemia but have no Bohring-Opitz Syndrome.
An article by Emma Bedoukian and collegues present the first report of germline inheritance of Bohring-Opitz Syndrome.
“[…] Most patients [affected with Bohring-Opitz Syndrome (BOS)] […] have a de novo nonsense or frameshift variant in ASXL1. We report a case of BOS caused by a pathogenic ASXL1 variant inherited from a germline mosaic mother. The ASXL1 mutation was detected via trio exome sequencing. The sequencing data demonstrated that the variant was inherited maternally but that the maternal variant was under-represented in comparison to the normal allele. These results suggested maternal mosaicism for the variant. Additional testing on the mother was performed on buccal cell DNA, which was also consistent with mosaicism. The mother had been reported to be healthy and the family history is unremarkable. This is the first report of BOS caused by a mutation inherited from an unaffected, presumed germline mosaic parent. This phenomenon has been reported for other traditionally de novo dominant disorders like CHARGE syndrome and Cornelia de Lange syndrome. This case emphasizes the need for accurate low but non‐negative recurrence risk counseling for families with children with BOS and it impacts exome interpretation strategy.”
» Read here the article of Karen Seiter and colleges: “Acute myeloid leukemia in a father and son with a germline mutation of ASXL1″ (Biomarker Research 20186:7, https://doi.org/10.1186/s40364-018-0121-3)
» Read also our blog post https://bohring-opitz.org/2017/10/30/bos-inherited-by-germline-mosaicism/
» Bedoukian E, Copenheaver D, Bale S, Deardorff M. Bohring‐Opitz syndrome caused by an ASXL1 mutation inherited from a germline mosaic mother.Am J Med Genet Part A. 2018;176A:1249–1252. https://doi.org/10.1002/ajmg.a.38686