Studying The Genetics Of Congenital Thoracic Anomalies In Consanguineous Kuwaiti Families Caused By Cilia Dysfunction

"Congenital thoracic anomalies are spectrum of rare heterogeneous genetic disorders affecting the organs
in the thoracic cavity such as pulmonary and cardiovascular systems. Primary ciliary dyskinesia (PCD) is one
of the congenital thoracic disorders caused by dysfunction of motile cilia resulting in insufficient mucociliary clearance of the lungs. Approximately 50% of all PCD patients have Kartagener syndrome, a triad of bronchiectasis, sinusitis and situs inversus totalis. Recent studies noted that approximately 6% of PCD patients
suffer from heterotaxy which comprises a broad spectrum of abnormalities and which intensifies morbidity
caused by complex cardiovascular anomalies.
Congenital heart disease (CHD) affects the structure and the function of the cardiovascular system and it is
the most common type of birth defect. Recent studies have shown that dysfunctions of nodal cilia during laterality development and primary cardiac cilia during cardiac differentiation are involved in the development
of many types of CHD. This indicates that CHD are congenital thoracic anomalies caused predominantly
by ciliary malfunction and PCD screening is recently recommended for patients who have congenital heart
disease (CHD). The pathogenesis of developing most types of CHD is poorly understood and the majority of
the caused genes are still unknown based on studies performed in mice.
Autozygosity mapping and exome sequencing approaches can be effectively applied in mapping novel
genes causing the phenotypes under study. The project team have previously mapped two novel PCD-causing genes CCDC103 and LRRC6. In addition, the project team very recently mapped CCNO in a multiplex
consanguineous Kuwaiti family with five affected individuals. The CCNO was the first gene reported to cause
a congenital pulmonary disease marked by a “reduced generation of multiple motile cilia” (RGMC). Further
genetic analysis has a great potential to uncover more genes and pathways associated with the occurrence
and the severity of different congenital thoracic anomalies."