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Joubert Syndrome Foundation

The University of Washington Joubert center is engaged in genetic research to understand cerebellar conditions, including Joubert syndrome.

September 2008

Update on the genetics of Joubert syndrome and genetic testing options

In the past 2 years, there has been a great flurry of genetic discoveries in the field of Joubert syndrome and related disorders (JSRD), with four new causative genes identified. There are now 7 genes in total that are known to cause JSRD. In addition, there are 2 more genes that, although we know their general location within the human genome, have not been discovered yet. One of the challenges in JSRD is that so many different genes can all cause the same condition. However, within an individual family, only one of these genes is likely to cause JSRD, which is due to an alteration in both copies of the same gene in the DNA of an affected child. There are other genetic conditions, such as cystic fibrosis or neurofibromatosis, with only a single causative gene, which makes identifying the specific mutations much easier.

I would like to take this opportunity to describe the 4 new genes discovered in the past 2 years, and then summarize what is known about all the genes identified for JSRD. [For details about the first 3 JSRD genes identified, please see the article on the JSF website (www.jsfrcd.org) linked to “Physician Research” and the news item on “Update on the genes that cause Joubert syndrome” dated 8-5-06.)

The MKS3 gene was actually identified first in individuals with Meckel-Gruber syndrome (MKS)¹. This is a condition that can be associated with enlarged kidneys with big cysts, brain malformations known as encephaloceles, and a congenital liver malformation. Some of the fetuses with MKS may not survive to be born or may not survive the newborn period. For the most part, the few children with JSRD who have also had mutations in this gene have not had the same appearance as MKS², but have more variable findings. One has had kidney disease and liver fibrosis. We still have much to learn about this gene and its role in JSRD. This may account for up to ~10% of Joubert syndrome.

The RPGRIP1L gene was first reported last summer by our laboratory and a group based in France^3,4. There appears to be one specific mutation in this gene that occurs in a high proportion of children with JSRD, some of whom have developed kidney disease, and others whom have had encephaloceles or extra fingers or toes. Only a few have had retinal disease that impairs vision and may lead to blindness. Some newborns with MKS have also had changes in this gene, but these infants have had more severe symptoms and often, more severe mutations. We think that ~5% of children with JSRD may have changes identified in this gene.

A gene just recently identified is the ARLB13 gene⁵. This gene was found in two families with classic features of JSRD; one family had encephaloceles and possible retinal disease. This appears to be a very rare cause of JSRD, accounting for the condition in less than 1% of children tested.

In addition, our group has just discovered another gene that causes JSRD and probably accounts for 5-10% of cases. Stay tuned for more information about this gene!

Table: Genes and estimated frequency in individuals with JSRD^6,7

Overall, less than 50% of all families with JSRD will have a mutation identified in one of the 7 known genes. The physical manifestations for children with AHI1 and NPHP1 gene changes tend to include retinal dystrophy and kidney problems in some individuals. The clinical manifestations for 4 of the other genes (CEP290, MKS3, RPGRIP1L, and ARL13B) are more variable and overlap with Meckel-Gruber syndrome. Clearly, other genes remain to be identified, and finding the specific gene in a given family may be complicated. At this time, genetic testing for clinical purposes is available through PreventionGenetics, a genetic testing company based in Wisconsin. This company can perform deletion analysis for NPHP1, and full sequence analysis of AHI1, MKS3, CEP290, and RPGRIP1L. Check with your geneticist and insurance company before pursuing testing for these genes, as it can be expensive if not covered by your policy. If the genetic cause of JSRD is known based on testing by PreventionGenetics, and you have worked with our research group, we would appreciate knowing those results, as this helps us understand how the known genes cause JSRD and may help us find new genes for JSRD.

As always, we appreciate your contributions to our research group to identify the genetic causes of Joubert syndrome and related disorders. We also appreciate the many families who have donated to the JSF & RCD BioBank to advance the cause of research.

Please contact Dana Knutzen, MS (genetic counselor and research coordinator) at Dana.Knutzen@seattlechildrens.org for information about how to participate in research studies. Our toll-free phone number is 1-800-246-6312. Additional information is available on the University of Washington Joubert Center website at http://depts.washington.edu/joubert/.

Ian Glass, MD
Medical Advisor, JSF & RCD
September 2008

References:
1. Smith UM, Consugar M, Tee LJ, et al. The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat Genet. 2006 38(2):191-6.
2. Baala L, Romano S, Khaddour R, et al. The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am J Hum Genet 2007;80(1):186-94.
3. Arts HH, Doherty D, van Beersum SEC, et al. Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome. Nat Genet. 2007 Jul;39(7):882-8.
4.  Delous M, Baala L, Salomon R, et al. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet. 2007 Jul;39(7):875-81.
5. Cantagrel V, Silhavy JL, Bielas SL, et al. Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. Am J Hum Genet. 2008;83:170-9.
6. Parisi MA, Doherty D, Chance PF, et al. 2007. Joubert syndrome (and Related Disorders) [OMIM 213300]. Eur. J. Hum. Genet., 15(5):511-21.
7. Parisi MA and Glass IA. Joubert syndrome. In: GeneReviews at GeneTests-GeneClinics: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle. 1997-2008. Available at http://www.genetests.org
 

May 2006

Dear Participants and Families in Joubert Syndrome Research,

The University of Washington Joubert Research Center has recently published two articles on Joubert syndrome. In one article, Drs. Doherty, Glass, Parisi, Chance, and others review the prenatal ultrasound and fetal MRI findings in two pregnancies at 25% risk of having an affected baby with Joubert syndrome. In one case, the fetus was suspected of having Joubert syndrome on the basis of prenatal imaging findings, which was later confirmed. In the other pregnancy, imaging results suggested that the cerebellum was intact, and an unaffected infant was born several months later. A proposed protocol for monitoring pregnancies is now available for those families wishing to have as much prenatal diagnostic information as possible.

This protocol may be accessed through the Joubert Syndrome Foundation website at http:://www.joubertsyndrome.org/ PrenatalDiagnosis.asp. A Powerpoint presentation on prenatal diagnosis in Joubert syndrome was given by Drs. Doherty and Glass at the last biennial conference in St. Louis, and can be downloaded from our website Prenatal Diagnosis presentation.

A second article by Drs. Parisi, Doherty, Glass, Chance, Dobyns, and others is available on-line. This article describes the clinical findings in 13 families with mutations identified in the AHI1 gene, a gene recently reported for Joubert syndrome. We identified a strong correlation between a child having Joubert syndrome due to AHI1 gene changes and the development of retinal dystrophy in those individuals. In addition, a few of the older subjects had kidney disease similar to nephronophthisis, but with a slower progression than typical juvenile nephronophthisis. Information is limited regarding the significance of this finding for younger children with Joubert syndrome due to AHI1 mutations. On the basis of testing 117 individuals, we found that overall, only 1-2% had Joubert syndrome related to the NPHP1 gene (which also causes classic juvenile nephronophthisis) and 11% had mutations in the AHI1 gene. This means that more genes that cause Joubert syndrome remain to be identified. In fact, this is the major focus of our research currently.

On a separate issue, over the course of this year, the Institutional Review Board (IRB) at the University of Washington has been reviewing human research studies, including our Joubert syndrome research, and making important updates and amendments to our documentation process. As we near the completion of our IRB review, we realize that we will need to re-contact some of you for additional information. If you or members of your family previously gave samples for our research, we may need you to sign new, updated consent forms. These forms will give us permission to store and study your or your family's samples long-term through the Neurogenetics Laboratory Repository, which has been created solely for this purpose. We anticipate that these forms, along with a general cover letter, will be mailed within the next 1-2 months. Please note that not all families will need to be re-contacted. If you have any questions about this process, please let us know.

We are sad to say goodbye to Melissa Eckert who has helped us make such tremendous progress on Joubert syndrome research over the past few years. We would like to welcome the following new members to our team: Jonathan Adkins, Nick Gorden and students Eugene Lee and Nell Niewiadomski.

Thank you very much for participating in our Joubert syndrome research studies. Best wishes for 2006!

Sincerely,

Phillip F. Chance, MD
Melissa A. Parisi, MD, PhD
Ian A. Glass, MD
Daniel Doherty, MD, PhD
Craig L. Bennett, PhD
Dana Knutzen, MS, CGC
Jonathan Adkins , BS
Nick Gorden, BS
Eugene Lee
Nell Niewiadomski

January 2005

A GENE FOR JOUBERT SYNDROME HAS NOW BEEN IDENTIFIED!

Our group in Seattle, working in conjunction with Drs. Bill Dobyns and Joseph Gleeson, has identified the first gene change associated with Joubert syndrome. This has been published in the July issue of the American Journal of Human Genetics (Parisi et al., "The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals of with Joubert syndrome," Am. J. Hum. Genet., 2004, 75:82-91). The gene, called NPHP1, has been known to cause a kidney disease known as juvenile nephronophthisis. Approximately 60-80% of children with nephronophthisis are missing both copies of the NPHP1 gene. Because some children with Joubert syndrome develop nephronophthisis, we tested children with kidney involvement for deletions in this gene. We found this change in 1 out of 25 children who were tested, and this child had nephrophthisis and a mild form of Joubert syndrome. When we tested 80 children with Joubert syndrome whether or not they kidney involvement, we found a total of 2 children with this deletion. This result has been confirmed by Dr. Valente's group in Italy in a child with Joubert syndrome, retinal dystrophy, and nephronophthisis.

Nephronophthisis is a form of kidney disease that is also known as medullary cystic kidney disease. It can be progressive. The symptoms may not be apparent until late childhood or early teenage years. The first symptoms are usually difficulty with concentrating the urine and sometimes anemia (low red blood cell count). This is why we recommend a complete blood count (to check hematocrit for evidence of anemia) as well as blood tests to check for kidney function (creatinine and BUN) and ultrasound examination. We also recommend a urine test to check its concentration in a sample collected when a child first wakes up (when it should be most concentrated). Later in the disease, there may be ultrasound changes such as scarring of the kidneys. Sometimes, very small cysts can be visualized in the middle of the kidney that may suggest this condition. Treatments can include medications, dialysis, and sometimes, a kidney transplant. Nephrologists or kidney doctors are the best doctors to manage this condition.

Therefore, we believe that the NPHP1 deletion represents the first molecular defect identified in a subset of children with Joubert syndrome. Children with nephronophthisis and retinal disease are at greater risk to have this genetic cause. It may also be more likely in children with milder neurologic symptoms of Joubert syndrome. However, it is important to remember that this is a very uncommon cause of Joubert syndrome, as probably less than 5% of children will have this gene deletion. We are developing recommendations for screening children with Joubert syndrome for this gene deletion. Genetic testing is probably warranted, particularly for those families interested in prenatal diagnosis, since the presence of an NPHP1 gene deletion in an older affected child would allow prenatal DNA testing as an option for first trimester diagnosis in subsequent pregnancies. We recommend annual blood and urine screening tests and ultrasound exam as outlined above for all children with Joubert syndrome. Please contact us or refer to the Health Care Recommendations for further details. Click here to download the research publication.