Dr Emma Tonkin explains the latest gene discovery to families at the Telford meeting.

The discovery is the third gene in just three years to be clearly marked following decades of work at different labs around the world includinging Philadelphia in the USA, Newcastle in the UK and Milan in Italy.

The new gene – called SMC3 – was formally announced in the March issue of the American Journal of Human Genetics.
But Kranz suggests there is at least a fourth major gene still to be found – a view backed by UK’s SCAT (Scientific and Clinical Advisory Team) member Dr Emma Tonkin speaking at the family day at Telford.

Emma explained the science behind the discoveries to parents and showed how Dr Kranz’s latest discovery fits into the jigsaw puzzle of the Cornelia de Lange syndrome that has proved such a challenge to the researchers over the years.

The initial discovery in 2004 that alterations in the NIPBL gene caused CdLS implicated the cohesion complex (a biologic complex which plays a role in replication and segregation of chromosomes during cell division) for the first time with a developmental condition.
Thanks to the work of Dr. Dale Dorsett and his lab in the USA, we now know that the cohesion complex and the genes involved in CdLS play other important roles in our cells beyond that of chromosome segregation during cell division.

His lab has shown that this complex is very important in regulating the turning on and off of many genes important in early embryonic development.

The researchers are continuing to look at genes involved in this complex in children with CdLS who did not have an identifiable change in NIPBL.

Kranz says, “We now know that changes in three different genes (NIPBL, SMC1A and SMC3), that all act within the same biological complex, can cause CdLS.

We are now able to identify changes in at least one of these genes in close to 70% of individuals with CdLS.

We are still trying to understand what the cause of CdLS is in the 30% of individuals that we are not able to find changes in.

It is possible that these individuals have changes in one of these three genes but we are not technologically able to find them at this time.

Conversely, it could be that there is yet another gene that is responsible for causing CdLS in these individuals.”

Another thing the research doctors are trying to understand is whether there are differences amongst individuals with changes in these different genes.

“ In general, individuals with changes in SMC1A and SMC3 have a milder form of CdLS,” says Kranz. “None of these individuals have structural differences of their arms or other organs.

In addition, they seem to have milder growth and developmental delays.

More severely affected individuals with CdLS (those with severe growth and cognitive involvement as well as structural differences of their arms, heart defects, cleft palates, diaphragmatic hernias, etc.) in whom we are able to find a gene change all have had changes in NIPBL.

However not all individuals who have a change in NIPBL have severe forms of CdLS.

This seems to depend on the type of change that we find in NIPBL.

Those individuals with changes in NIPBL that significantly affect the ability of the gene to make its protein tend to be more severe, whereas those changes in NIPBL that only mildly affect the function of the protein seem to result in a more mild form of CdLS (clinically similar to individuals with changes in SMC1A and SMC3).”

The eventual filtering of the gene identifiers could lead to more accurate diagnosis – particularly among those people mildly affected by CdLS who are often passed over with an “undetermined condition”.

Kranz says “Several of the individuals with mild manifestations of CdLS and mutations identified in these genes would appear to many clinicians as having isolated developmental delay or mental retardation often with some growth delay and were only diagnosed as CdLS due to having the good fortune of being evaluated by a very astute clinical geneticist with experience in this diagnosis.

For this reason, we believe that there are likely many children and adults with a diagnosis of “isolated” cognitive delays or mental retardation with or without growth delays who will likely be found to have changes in these genes as well”.

Our ability to understand the underlying causes of CdLS has greatly improved but there are still many more questions to answer and much more work to do. Kranz says there is a clear path.

“Presently we know that having a single mutation in one of these three genes is all that is needed to cause CdLS.

However, it is unknown whether, for a child with a mutation in the NIPBL gene, additional milder variations in other genes in the pathway can modify the severity of the features in that child.

Understanding these interactions would improve prognostic testing in terms of accuracy in predicting developmental and growth outcomes in affected individuals as well as identifying genes that might have implications for therapeutic interventions in the future.
“We also need to identify the genes that are in turn regulated (i.e. turned on or off) by NIPBL and the cohesion complex.”

Since cohesion regulates important genes during development by identifying what these critical genes are, doctors will have a better understanding of how these changes result in the differences we see in CdLS.

“Our lab has begun to study individuals diagnosed with isolated cognitive delays and/or mental retardation who do not carry a diagnosis of CdLS to see what contribution changes in these cohesion genes make to this population.

This could dramatically change our understanding of not only the mildest range of CdLS, but also of how we clinically define CdLS.

We are continuing to screen the other genes involved in cohesion structure and regulation in individuals who do not have an identifiable mutation in NIPBL, SMC1A or SMC3 as well as developing new methodologies to screen these three genes to be sure we aren’t missing mutations using our current technologies.

For those individuals in whom a mutation in one of these genes has been identified, screening other family members, if applicable, is straight forward and relatively quick since the lab knows exactly where to look. This information could also be used for prenatal testing if indicated or desired,” Kranz said.

Sadly such testing is still not available in the UK. Newcastle is able to test for NIPBL with something like a 40% hit on known CdLS diagnosis. A lab in Holland is able to provide testing to include the SMC1A on a commercial basis.

The Foundation is working to find a way to make such tests affordable (they currently cost just under £1,000) as they could be essential in identifying the particular challenges an individual with CdLS may face as well as for prenatal testing.