Leveraging consanguinity unveils novel ciliopathy mutations

Published online 5 December 2016

A large study of Saudi patients reveals new genetic causes of disorders associated with dysfunctions in the cell’s ‘antenna’.

Nadia El-Awady

Researchers in Saudi Arabia identified dozens of new mutations in 54 genes with known links to ciliopathies – syndromes caused by mutations in genes associated with the ‘primary cilium’ which is a structure on the surface of almost all mammalian cells.

Bardet-Biedl  is an example of the ciliopathies included in the study. It's characterized by obesity, small genitalia, having more than five fingers or toes on one hand or foot, gradual degeneration of the retina and, in some cases, renal failure.

This cilium receives signals from other cells and the surrounding environment and transmits them to the nucleus so it can respond appropriately. The researchers, in collaboration with international colleagues, also identified seven novel genes that could be linked to ciliopathies.

Knowing the causal mutation is extremely important for prevention

The team conducted detailed genetic analyses on 371 people with ciliopathy-related disorders from 265 consanguineous families in Saudi Arabia. Genetic analyses were also conducted on their parents and siblings. The nature of the study cohort enabled the researchers to compare the variation in expression of specific mutations within and between families.

They found probable causal mutations in previously described ciliopathy genes in 85% of the families. 

In all these cases, two mutant copies of a ciliopathy gene were sufficient to cause the characteristic features of the disorder. Differences of ciliopathy features between two people with a mutation on the same gene were due to differences in the nature of the mutation itself and not because of the effects of other genes.

This is significant because some debate exists within the research community over the nature of inheritance and expression of ciliopathies. They also showed that the identification of a causal gene mutation can be missed in at least 10% of ciliopathy patients when conventional analyses of the exome (the portion of the genome that codes for proteins) are performed. These “missed” mutations can be found using other types of DNA sequencing.

“Knowing the causal mutation is extremely important for prevention,” explains geneticist Fowzan Alkuraya of King Faisal Specialist Hospital and Research Center in Riyadh.

“All study participants were informed of their mutation and, through proper genetic counseling, can make informed reproductive choices to avoid recurrence,” he says of the study that is yet to be published in Genome Biology

The team calculated the disease burden of ciliopathies to be 1 in 2,376 people, making them among the most common autosomal recessive diseases (an inherited disorder where two copies of the abnormal gene must be present) in Saudi Arabia.

"This paper shows the utility of utilizing next generation deep sequencing technologies, including whole exome sequencing, to study ciliopathies in consanguineous pedigrees, where the genetic yield is high," comments geneticist Chiea Chuen Khor of the Genome Institute of Singapore. Khor, who is not involved in the study, says that it managed to accurately pin down likely causal mutations in previously well-described ciliopathy genes in up to 85% of the families studied, which "is very high" in his opinion.

"From the basic research perspective, this work also provides additional biological insights into the spectrum of genetic alleles contributing to the overall genetic architecture of ciliopathies," he adds.


Shaheen, R. et al. Characterizing the morbid genome of ciliopathies. Genome Biology (2016).