Recommended panel testing at Breda Genetics for this condition:
or
Summary
Joubert syndrome is a group of autosomal recessive disorders with clinical and genetic heterogeneity, characterized by hypoplasia of the cerebellar vermis with the characteristic neuroradiologic ‘molar tooth sign,’ and accompanying neurologic symptoms, including dysregulation of breathing pattern and developmental delay. Meckel-Gruber syndrome (or Meckel syndrome) is a severe pleiotropic autosomal recessive developmental disorder caused by dysfunction of primary cilia during early embryogenesis.
Detailed clinical description
Classic Joubert syndrome is characterized by three primary findings: a distinctive cerebellar and brain stem malformation called the molar tooth sign, hypotonia, developmental delay. Episodic tachypnea or apnea and/or atypical eye movements often accompany these findings. Notably, cognitive abilities are variable, ranging from severe intellectual disability to normal. Other additional findings which may vary from patient to patient (even within the same family) include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities.
The prevalence of Joubert syndrome is estimated by many authors in a range between 1:80,000 and 1:100,000, but this may represent an underestimate.
Meckel-Gruber syndrome is an autosomal recessively condition which is mainly characterized by enlarged kidneys with numerous fluid-filled cysts, often found in association with occipital encephalocele and polydactyly. Most patients also show liver fibrosis. The outcome is lethal, with death occurring mostly in the perinatal period. Meckel–Gruber syndrome is classified as aciliopathy and may show clinical and genetic overlap with other ciliopathies like Joubert syndrome (to date, at least 29 genes have been found to cause Joubert syndrome, of which 13 also cause Meckel syndrome). Other known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney, nephronophthisis, Alstrom syndrome, and some forms of retinal degeneration.
Meckel syndrome prevalence changes across different geographical regions, varying from 1 in 13,000 to 1 in 140,000 people. It is more common in certain populations, like, for example, the Finnish (1 in 9,000 people) or the Belgian (1 in 3,000 people).
Prenatal diagnosis
Prenatal diagnosis by ultrasound (US) examination (with or without fetal MRI) has been successful in both Joubert and Meckel-Gruber syndrome. In Joubert syndrome at-risk fetuses prenatal ultrasound examination of the posterior fossa and/or kidneys and digits as early as 11 to 12 weeks of gestation is recommended. In Meckel-Gruber syndrome an intracranial cystic image and/or a skull defect at the end of the first trimester, as well as abnormally enlarged kidneys may be seen. Other malformations may be detected at more advanced stages of pregnancy.
It is very important to highlight that even if significant fetal US findings are extremely indicative in couples with a previous Joubert/Meckel syndrome affected child, the absence of these signs does not preclude a diagnosis of Joubert/Meckel syndrome because of the unknown sensitivity of imaging and because of intrafamilial variability.
Molecular genetics
Mutations in several genes have been so far described to cause Joubert syndrome, which is one of the most genetically heterogeneous disorders known to date. At least 29 genes have been reported: AHI1, ARL13B, B9D1, B9D2, C5orf42, CC2D2A, CEP290, CEP41, CSPP1, INPP5E, KIF7, MKS1, NPHP1, NPHP3, OFD1, RPGRIP1L, TCTN1, TCTN2, TMEM138, TMEM216, TMEM231, TMEM237, TMEM67, TTC21B, ZNF423. Both point mutations and large deletions/duplications have been reported.
Meckel syndrome is very genetically heterogeneous as well. To date pathogenic mutations have been detected in the following subset of Joubert syndrome genes: MKS1, TMEM216, TMEM67, CEP290, RPGRIP1L, CC2D2A, NPHP3, TCTN2, B9D1, B9D2, and TMEM231. Mutations identified include point mutations and microdeletions. Point mutations may be detected by sequencing, whereas chromosomal microdeletions require special techniques like qPCR, MLPA, FISH or CGH array .
Genetic testing strategy
Like in all other genetically heterogeneous conditions, panel testing based on next generation sequencing is highly recommended for Joubert and Meckel-Gruber syndrome testing. Breda Genetics currently offers two solutions, both based on exome sequencing. The first solution is based on clinical exome sequencing to include all traditionally known Joubert/Meckel genes. The second one is based on whole exome sequencing, to include also the most recently identified genetic subtypes:Â Joubert syndrome type 22 – JBTS22 (PDE6D gene mutations), Joubert syndrome type 23 – JBTS23 (KIAA0586 gene mutations), Joubert syndrome type 25 – JBTS25 (CEP104 gene mutations), Joubert syndrome type 26 – JBTS26 (KIAA0556 gene mutations). The current mutation detection rate in Joubert syndrome testing is about 50%. In the remaining 50% the mutation remains unknown, likely because it occurs in as yet unknown gene. In this regard, the panel based on whole exome sequencing, with appropriate integrations, may be of help in discovering new disease-associated genes.
Recommended panel testing at Breda Genetics for this condition:
or
References
Joubert Syndrome. Parisi M, Glass I. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2003 Jul 9 [updated 2017 Jun 29]. PMID: 20301500
Meckel-Gruber Syndrome: An Update on Diagnosis, Clinical Management, and Research Advances. Hartill V, Szymanska K, Sharif SM, Wheway G, Johnson CA. Front Pediatr. 2017 Nov 20;5:244. PMID: 29209597
Joubert syndrome and related disorders. Valente EM, Dallapiccola B, Bertini E. Handb Clin Neurol. 2013;113:1879-88. PMID: 23622411
Genetic complexity in Joubert syndrome and related disorders. Harris PC. Kidney Int. 2007 Dec;72(12):1421-3. PMID: 18046420
Meckel syndrome: genetics, perinatal findings, and differential diagnosis. Chen CP. Taiwan J Obstet Gynecol. 2007 Mar;46(1):9-14. PMID: 17389183
The role of primary cilia in the pathophysiology of neural tube defects. Vogel TW, Carter CS, Abode-Iyamah K, Zhang Q, Robinson S. Neurosurg Focus. 2012 Oct;33(4):E2. PMID: 23025443
