Inheritance

The risk of having another child with Bohring-Opitz Syndrome is low.
Bianca Russell, 2018

Researchers at the Radboud University Nijmegen discovered that 7 of 13 examined patients with the BOS phenotype had the mutation in the ASXL1 gene. The final results of the research carried out at Radboud University Nijmegen medical center:

1. A de novo mutation of the ASXL1 gene causes BOS. 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).
2. BOS is genetically heterogeneous (miscellaneous), meaning there must be at least one other cause of BOS.

Because another 6 children with clinical diagnosis of BOS didn’t have this mutation in this study, this indicates that other genes may be involved in this syndrome (Radboud UMC^[3], Hoischen et al. 2011) or that

3. somatic mosaicism should be considered as cause in patients with a typical phenotype and no detectable mutation (Russell et al. 2015). Meanwhile, mosaicism is confirmed and two families with gonadal mosaicism including an affected sibship are known in medical literature. (Russell et al. 2023)

In most of the cases, Bohring-Opitz syndrome (BOS) is the result of a de novo mutation in the ASXL1 gene. The risk of having another child with Bohring-Opitz Syndrome is low. (Russell et al. 2018)

To date, no confirmed severely affected BOS patient has become a parent themselves. (Russell et al. 2018)

Germline Mosaicism

The first report of Bohring-Opitz syndrome caused by a mutation inherited from an unaffected, somatic mosaic parent with presumed germline mosaicism 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. 2018)

We have learned that germline mutations of human ASXL1 could be causing Bohring-Opitz syndrome (BOS). Germline means it’s a de 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 (2018) presented a father and son who have an 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 colleagues (2018) 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, and emphasizes the need for accurate low but non‐negative recurrence risk counseling for families with children with BOS, and it impacts exome interpretation strategy.”

Go to Clinical Features

» Read here the poster of “Bohring-Opitz Syndrome caused by an ASXL1 mutation inherited from a germline mosaic mother” by Deborah Copenheaver

» 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)

» 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