More information about the first Research Symposium about all ASXL Families you can find on the website of the AЯRE Foundation.
Register here: 
BOS Gen found in a boy and ExAC
Again the recent publication by Urreizti et al. shows that pathogenic gene variants are part in a reference database should be taken into account. In order to assess genetic variants, reference population databases such as the Exome Aggregation Consortium (ExAC) database are part of researches. It is assumed that in this population database pathogenic gene variants are absent or rare. Urreitzi et al. present a boy who has already been clinically diagnosed with Bohring-Opitz Syndrome (BOS). Sanger sequencing of ASXL1 revealed the p.Gly646Trpfs*12 mutation, an ASXL1 variant that is considered as causing Bohring-Opitz Syndrome. This variant is present in 132 persons from the reference database ExAC. Even though Carlston et al. 2017 discovered that in the ExAC database are BOS causing ASXL1 variants in individuals who are healthy with the conclusion that somatic mosaic of ASXL1 variants should be taken into account.
» Urreizti R, Gürsoy S, Castilla‐Vallmanya L, et al. The ASXL1 mutation p.Gly646Trpfs*12 found in a Turkish boy with Bohring‐Opitz Syndrome. Clin Case Rep. 2018;00:1–5. https://doi.org/10.1002/ccr3.1603
» Carlston CM, O’Donnell‐Luria AH, Underhill HR, et al. Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring‐Opitz Syndrome. Human Mutation. 2017;38:517–523. https://doi.org/10.1002/humu.23203
Pulmonary hypertension
A new case report at Kagoshima City Hospital, Kagoshima, Japan describes in a newborn with Bohring-Opitz Syndrome Pulmonary Hypertension (PH). Children with Pulmonary (= lungs) hypertension (= high blood pressure) have small passageways, blood vessels, in the lungs and because these passageways are so narrow, there is a very high blood pressure in the pulmonary blood vessels. The heart therefore has to work much harder than normal so that the body gets enough oxygen. Children with PH may occasionally suffer from shortness of breath.
Despite treatment, the infant died from the consequences of severe heart failure.
» Read here the article “Lethal persistent pulmonary hypertension of the newborn in Bohring–Opitz syndrome” by Masaya Kibe et al. (https://doi.org/10.1002/ajmg.a.38681)
Maternal Mosaicism
This new 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 underrepresented 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.”
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)
»Read also our blog post https://bohring-opitz.org/2017/10/30/bos-inherited-by-germline-mosaicism/
Research for ASXL Syndromes
We are thrilled to announce the launch of the ASXL Rare Research Endowment (AЯRE) Foundation (www.arrefoundation.org)! AЯRE will provide sustainable support for evidence-based research that will increase our understanding of the ASXL genes and improve the treatment of individuals with congenital ASXL mutations.
Our ASXL families — who have Bohring-Opitz Syndrome (ASXL1), Bainbridge-Ropers Syndrome (ASXL3), and Shashi-Pena Syndrome (ASXL2) – face extraordinary challenges and uncertainty. AЯRE will bring together the medical and scientific leaders to study ASXL genes and clinical challenges so that we can improve care management strategies, assist with patient advocacy, and ultimately introduce potential treatments/cure.
I would like to thank our incredible team of officers & board volunteers for all their efforts to make this possible! We are on this journey together and need your help to realize this vision. Please consider to rally family & friends to support this important cause through volunteer efforts and donations.
AЯRE has more exciting news and actionable information ahead. Check out our website (www.arrefoundation.org) to learn more about our plans, join us on Facebook, and sign up for our newsletters.
Our ASXL children are an incredible inspiration and have changed our perspective on life. Let’s join together so that we can become stronger advocates and provide our children with the best lives possible.
I am excited about our road ahead and look forward to hearing from you!
Best,
Laura Badmaev
Chair, AЯRE Foundation
laura@arrefoundation.org
Bohring-Opitz Syndrome
Bianca Russell, Wen-Hann Tan and John M Graham have published a new comprehensive overview about Bohring-Opitz Syndrome (BOS) in GeneReviews.
After the publication of the Unique leaflet by Joanna Kennedy (2017), the “Clinical management of patients with ASXL1 mutation and Bohring-Opitz Syndrome […]” by Bianca Russell and colleagues (2015) and previously published article about BOS (Magini, P. et al. 2012, Hoischen, A. et al. 2011 and Hasting,R. et al. 2011) this review is an excellent resource to understand and learn about Bohring-Opitz Syndrome. Part of the publication are summary, diagnosis, clinical characteristics, genetically related disorders and management of Bohring-Opitz Syndrome as well as genetic counselling and because it is written in understandable language it is an exceptional reference work not only for experts but for parents also!
Please read the full text of “Bohring-Opitz Syndrome” here: https://www.ncbi.nlm.nih.gov/books/NBK481833/
Germline mutation but no BOS
We have learned that germline mutations of human ASXL1 is the cause of 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.
» 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)
News from the ASXL Registry
Exciting news from the ASXL Registry! Out of 33 families who have completed the enrolment, 15 surveys are completed! To obtain accurate knowledge about causes, symptoms, quality of life and treatments for Bohring-Opitz Syndrome, it is important that more families enrol the ASXL Registry and we need your support. A well run registry helps produce scientific literature and leads to research findings which is crucial to help our children live a better life.
Do you want to be part of the ASXL Registry? Please follow these steps:
- Step 1: Email ASXLRegistry@cchmc.org
- Step 2: 15-30 minute phone call to review the consent form and answer questions
- Step 3: Sign consent form and send it back.
More information you can find in the first newsletter of the ASXL Registry!
Thank you!
Merry Christmas!
Documentary worldwide
KULUUT, the documentary about Coen and his family finding happiness despite of living with a syndrome, can now be seen worldwide. Until now it was broadcasted just for the Dutch public, but now we all can enjoy this beautiful and eagerly awaited documentary worldwide! Coen has the rare Bohring-Opitz Syndrome and we, the BOS Family are extremely grateful that Charlotte Driessen made this film possible. Kuluut has won international attention and received several film awards. The documentary won a Hollywood International Independent Documentary Awards Award in the category of First Time Filmmaker, after that it won a Kudos Endeavor Award in the Docs Without Borders Film Festival competition and was also an official selection as a semi finalist in the Atlanta DocuFest.
Our thanks go out to the makers of KULUT and the wonderful family of Coen!
Merry Christmas!
Kuluut – English subtitles from Charlotte Driessen on Vimeo.
