Genetic causes of craniofacial disorders

The aim of the study is to identify new genetic causes of craniofacial
developmental anomalies. We will focus on several disorders comprising
orofacial clefting, cranioynostosis and/or abnormal tooth development.
In nonsyndromic form, these disorders are all relatively common developmental
anomalies. They can also be part of a syndrome (syndromic forms) or occur
within families (familial forms). . These disorders can be caused by strongly
penetrant mutations in Mendelian genes, interactions between multigenic and
environmental factors, and/or stochastic factors. However, especially in
nonsyndromic forms, there is not much known about the genetic factors that are
associated with the disease. The genetic cause of these craniofacial disorders
is only identified in a small number of patients. The use of next generation
sequencing techniques will increase this number.
Genetic diagnoses will allow optimal treatment and management of the disorder.
Moreover, it is a prerequisite for adequate genetic counseling to patients and
their families. Furthermore, understanding the molecular background of these
disorders will pave the way for possibilities for development of therapy.

The objective of the study is to identify genetic causes of
developmentalanomalies of the face and skull (craniofacial anomalies), such as
orofacial clefting, craniosynostosis, abnormal dental development and rare
craniofacial syndromes.

Individual patients and families will be selected by a clinical geneticist or
other medical specialists involved in the craniofacial/cleft team. The
selection will be based on the phenotype and/or numbers of affected persons
within a family. The recruited patients will be seen by the principal
investigator (PI). During this visit a (family) history will be taken, the
patient will be physically examined and a blood sample will be obtained for the
isolation of DNA.
Within routine diagnostics known causes of craniofacial disorders will be
investigated using targeted DNA gene tests and/or microarray analysis. When no
causative defect is identified, next generation sequencing (whole exome or
whole genome sequencing) will be performed in the patient and, depending on the
probable mode of inheritance, possibly in other affected individuals in the
family.
The patient and/or his/her relatives will be counselled about the risks and
benefits of next generation sequencing by the PI prior to inclusion in the
study. The results of the investigations will be discussed with the patient or
his parents by the PI. If there is an unsollicited finding this will be
reported to the "Commissie Toevalsbevindingen" (committee of unsollicited
findings) of the Radboud University Medical Center. If the Committee decides it
is necessary to inform the patient about the unsollicited finding, this will be
done by the PI.
If segregation analysis in affected or non-affected family members of gene
variants that have been identified by exome or genome sequencing is necessary,
they will be asked for permission by the (legal representatives of the) patient
himself. The PI will subsequently inform about the study, acquire permission of
the family member, perform physical examination and obtain a blood sample.

The only physical burden is a venipuncture. There is a small chance of
unsollicited findings when whole exome or genome sequencing is performed.