Fig. 8: Hypothetical model for the epigenetic role of Asxl1 in regulating Nmyc expression during mouse fetal lung development. From: Asxl1 exerts an antiproliferative effect on mouse lung maturation via epigenetic repression of the E2f1-Nmyc axis. DOI 10.1038/s41419-018-1171-z

An important step towards a better understanding of the mechanism of ASXL1 mutation and Bohring-Opitz syndrome!

Little is known about the role of an ASXL1 mutation in the organ development. “Recent studies using Asxl1-null mouse models indicated a critical role for Asxl1 in development. Depending on the model, Asxl1 loss causes embryonic lethality and developmental abnormalities, including dwarfism, anophthalmia, microcephaly, kidney podocyte defects, and craniofacial defects.” In this study, published in ‘Cell Death and Disease’, Moon et. al. discovered that ASXL1 gene affect the lung development. They noticed that Asxl1−/− mouses were dying just after birth due to cyanosis, a respirator failure and suspected a reduced air space and a defective lung maturation. This prompted the researchers to investigate the underlying mechanism, focusing on the role of Asxl1 in lung development. Comparing a normal wild mouse, the Asxl1^−/− mouse lung sank and […] failed to inflate with air because of its thicker alveolar wall, smaller air space, and more numerous small alveoli.

In most of the patients with Bohring-Opitz Syndrome the novo mutation in ASXL1 has been identified. Respiratory infections and reactive airway disease are common in patients with BOS and leading cause of death in the first two years of live (Russell et.al. 2016).

» Read here the article: Asxl1 exerts an antiproliferative effect on mouse lung maturation via epigenetic repression of the E2f1-Nmyc axis. By Seungtae Moon, et al. Cell Death & Diseasevolume 9, Article number: 1118 (2018). https://doi.org/10.1038/s41419-018-1171-z

Having support and community resources can help increase your confidence in managing Bohring-Opitz-Syndrome (BOS), enhance quality of life, and assist in meeting the needs of other family members. Parenting is often challenging, and parenting a child with a chronic condition like BOS can add additional stress to the day-to-day challenges. It’s important to remember you’re not alone in your situation. There are people who have experience in supporting and caring for children with Bohring-Opitz Syndrome. They can provide information about all aspects of living with Bohring-Opitz Syndrome.

If you are the parent or caregiver of a child with BOS, it might be helpful to talk with other parents who have a child with the same condition in our “Bohring-Opitz Support Group”.

A child with Bohring-Opitz Syndrome will have a life that is different from than most children, but Bohring-Opitz children have delightful personalities and are extremely lovable. They will give you love that is totally unconditional.

Please feel free to meet these amazing families who have created their own personal Facebook Pages about raising a BOS child and see how they enjoy their wonderful children!

Is this list incomplete? Please feel free to send us your Story about raising a child with Bohring-Opitz Syndrome. Thank you!

More information about the first Research Symposium about all ASXL Families you can find on the website of the AЯRE Foundation.

Register here:

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

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)

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.”

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

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/

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)

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!