Bohring-Opitz Syndrome / ASXL1

Bohring-Opitz Syndrome (BOS) is a very rare congenital disorder. In 2015, there are less than 60 children in the world, diagnosed with this syndrome and presented in medical articles (Russell, B. et al. 2015).


HistoryHistory

Bohring et al. (1999) presented four patients who had similar features to two cases that had already been reported by Oberklaid et al. (1975) and Addor et al. (1995). Bohring suggested that these six children either represented the severe end of the clinical spectrum of ‘Opitz trigonocephaly C syndrome’ or comprised a separate entity. Since then there have been further reports of individual patients with similar findings. The terms ‘Bohring’, ‘Bohring-Opitz’ and ‘C-like syndrome’ have all been used to describe this condition (Greenhalgh et al. 2003). Because Oberklaid et al. (1975) reported another case there is also the name ‘Oberklaid-Danks-Syndrome’ for ‘Bohring-Opitz-Syndrome’ (Hasting et al. 2011).

diagnosticClinical Diagnosis

The delineation of Bohring-Opitz Syndrome (BOS) was made by Bohring on the basis of a complex phenotype characterized by IUGR (Intrauterine growth restriction), feeding problems, severe intellectual and motor disability, trigonocephaly (forehead have a triangular shape), facial dysmorphisms, frontal nevus flammeus, exophthalmos (bulging eyeball, prominent eyes), cleft palate, flexion of elbows and wrists, hirsutism (excess body hair) (Scarselli et al. 2012). Additional characteristics are severe failure to thrive, retinal abnormalities, hypertelorism (large distance between the eyes), cleft lip and/or palate and death often early in childhood (Bohring et al. 2012). Members of the Bohring-Opitz Facebook group has often stated that BOS children look very alike, which is confirmed by Scarselli et al. (2012) when he noted that BOS children have extremely similar clinical phenotype at birth with characteristic face, frontal nevus flammeus, severe myopia[1] (nearsightedness) and BOS “attitude”. For more details about phenotype and symptoms please take a look to our overview Symptoms[2]. and the clinical features of BOS. The infant mortality is high. 40% of the reported BOS children passed away before reaching 6 years of age  and 26% with 11 deaths at less than 1 year-of-age (Russell et al. 2015). A few (5) patients has now reached adulthood (Hoischen et al. 2011, FB group 2013).

dnaOne Cause of BOS: Novo mutation ASXL1

Prior to 2011, geneticists relied on making a clinical diagnosis by recognizing the distinguishable physical characteristics in the appearance of their patients. In 2011, researchers at the Radboud University Nijmegen medical centre used “next generation sequencing” to find the genetic cause of Bohring-Opitz Syndrome. Since then it has been possible to confirm the BOS diagnosis with a genetic DNA test. They found 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 centre:

1. A novo mutation of the ASXL1 gene causes BOS
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, this indicates that other genes may be involved in this syndrome (Radboud UMC[3], Hoischen et al. 2011) or  that a somatic mosaicism should be considered as cause in patients with a typical phenotype and no detectable mutation. (Russell et al. 2015)

erfelijkheidInheritance

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.

To date, no confirmed severely affected BOS patient has become a parent themselves.

The ASXL1 gene

The ASXL1 gene (OMIM 605039) is located on the chromosome 20q11.21.

chromosom

The ASXL1 gene plays an important role in activating and deactivating HOX genes. These HOX genes are essential for the development of fertilized ovum to adult organism. The ASXL1 gene is already known to geneticists: a link with cancer has been established. There are two possible situations:

1. The novo ASXL1 mutation: this causes Bohring-Opitz Syndrome. The gene mutates at conception, creating a developmental disorder that leads to Bohring-Opitz Syndrome.
2. The somatic ASXL1 mutation: The mutation occurs during later life. The patient has an increased risk of acute myeloid leukaemia, a form of blood cancer (AML).[4]

TEsting Bohring-Opitz syndrome 

Prior to 2011 there was no DNA test to confirm a diagnosis of Bohring-Opitz Syndrome.  Geneticists relied on making a clinical diagnosis by recognizing the distinguishable physical characteristics in the appearance of the child, and with the aid of clinical research. Now it is possible to confirm the BOS diagnosis with a genetic DNA test (whole exome sequencing, or whole genome decoding).

Researchers at the Radboud University Nijmegen medical centre found with next generation sequencing a mutation in ASXL1 gene one genetic cause of Bohring-Opitz-Syndrome. (Radboud UMC)

A selection of diagnostics labs for clinical testing ASXL1:

Radboud University Medical Center – Genome Diagnostic

Fulgent Diagnostics provides a wide array of genetic testing ranging from 4,600+ single gene tests, 170+ preset panels, rearrangement testing, and our All-in-One reflex test. Most importantly, Fulgent Diagnostics provides flexibility.  You can add a gene to a current panel or create your own personalized test.  We tailor our tests to your unique requirements at the most competitive pricing available compared to any CLIA lab in the industry. You can search for a gene by the “gene name” or browse our tests by using the “category” drop-down or simply scroll down the lists of preset panels.

GeneDx specializes in genetic testing for rare hereditary disorders. Our mission is to make clinical testing available to people with rare genetic conditions and their families.


[1] Andrew R.H. Simpson, Caspar E.A. Gibbon, Anthony G. Quinn, Peter D. Turnpenny: Infantile high myopia in Bohring-Opitz syndrome, Journal of American Association for Pediatric Ophthalmology and Strabismus, Volume 11, Issue 5, October 2007, Pages 524–525

[2] https://bohring-opitz.org/about/list-of-symptoms/ 22. March 2015

[3]http://nieuws.radboudumc.nl/onvoorspelbare-mutaties-veroorzaken-bohring-opitz-syndroom 4 November 2015

[4]http://nieuws.radboudumc.nl/onvoorspelbare-mutaties-veroorzaken-bohring-opitz-syndroom  4 November 2015