Craniofacial Abnormalities and Rare Muscular Dystrophy Linked To Same Gene Interview with:
Natalie Shaw, MD, MMSc
National Institute of Environmental Health Sciences
Research Triangle Park, North Carolina and
Harrison Brand, PhD
Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research
Massachusetts General Hospital, Boston
Massachusetts, USA. What is the background for this study? What are the main findings?

Response: Congenital arhinia, or absence of the nose and olfactory system, is an extremely rare malformation, often accompanied by defects in the eyes and reproductive system. Arhinia has been reported in only 80 patients in the past century and though a genetic cause had been suspected, no previous study had identified a plausible genetic candidate.

Through an international collaboration among clinicians and investigators spanning 10 different countries, we were able to assemble a cohort of 40 arhinia patients. Using whole-exome sequencing, we found that 84% of the patients had rare mutations in the same gene – SMCHD1. Further, modeling studies based on patient cells and SMCHD1 knockdown in zebrafish strongly support a role for the gene in arhinia.

We were surprised by this discovery because mutations that impair SMCHD1 function are known to interact with other regions of the genome to cause a type of muscular dystrophy (FSHD2) that does not affect the bones or cartilage of the face. Deep phenotyping of our cohort revealed that individuals with arhinia can in fact develop FSHD2, but it is still unclear why individuals with FSHD2 do not have arhinia. What should readers take away from your report?

Response: That mutations in the same gene, and indeed some of the same mutations, can result in vastly diverse clinical manifestations. We still don’t know exactly how alterations in SMCHD1 activity affect craniofacial development and how the same mutations can cause arhinia in one individual and muscular dystrophy in another. We think there may be additional genetic changes that influence the development of arhinia, and such interactions are known to underlie FSHD2.

There are two important clinical implications of the genetic overlap between these two disorders:

1) patients with arhinia may be at risk for FSHD2 (if they have the requisite changes at genetic regions other than SMCHD1) and these patients need to be monitored into late adulthood, and

2) patients with FSHD2 but without craniofacial abnormalities may be at risk of having a child with arhinia, as occurred in one of our families. What recommendations do you have for future research as a result of this study?

Response: As we mentioned, there are a lot of questions we still need to address, including the critical question of how SMCHD1 is linked to craniofacial and reproductive development. We would also advocate for in-depth studies comparing arhinia patients to FSHD2 patients to understand what molecular factors differentiate these conditions. Is there anything else you would like to add?

Response: This was a true team effort and we are indebted to the patients who entrusted us and to the many clinicians and scientists who contributed DNA samples, expertise, and their own resources to enable such a large collection, and selflessly shared the credit to make this exciting discovery possible. Thank you for your contribution to the community.


SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome
Natalie D Shaw, Harrison Brand, Michael E Talkowski et al.

Nature Genetics (2017) January 9

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on January 17, 2017 by Marie Benz MD FAAD