Invitae Joubert and Meckel-Gruber Syndromes Panel


Test description

The Invitae Joubert and Meckel-Gruber Syndromes panel analyzes 18 genes that are associated with Joubert syndrome and related disorders (JSRD) and with Meckel-Gruber syndrome (MKS). These genes are involved in the structure of cilia, which are the hairlike structures on the surface of cells. Cilia are necessary for proper cellular motility, for the movement of material around a cell, and for chemical signaling pathways. Pathogenic variants in these genes impair the function of cilia and are described as a class of pediatric developmental disorders known as ciliopathies.

Ciliopathies share many overlapping symptoms, which makes clinical distinction between them difficult to assess. The Invitae Joubert and Meckel-Gruber Syndromes panel may provide a genetic diagnosis without the need for sequential gene testing.

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Primary panel (18 genes)


CEP290: Analysis includes the intronic variant NM_025114.3:c.2991+1655A>G.

Alternative tests to consider

Joubert and Meckel-Gruber syndromes are members of a class of disorders called ciliopathies. Ciliopathies are caused by pathogenic variants in genes that affect the function of cilia—the hair-like structures on the surface of cells. Ciliopathies share many overlapping symptoms, often making it difficult to distinguish between them based on clinical presentation alone.
The Invitae Sensory Ciliopathies Panel has been designed to provide a broad genetic analysis of this class of disorders and may be considered as an alternative to testing for a specific disorder. Depending on the individual’s clinical and family history, this broader panel may be appropriate. It can be ordered at no additional cost.

Joubert syndrome and related disorders (JSRD)
COACH syndrome
Meckel-Gruber or Meckel syndrome (MKS)

Joubert syndrome (JSRD) is characterized by congenital malformation of the brain stem and absence or underdevelopment of the cerebellar vermis (cerebellar vermis hypoplasia). These physical features are visible on an MRI as a pattern called the molar tooth sign, which is the hallmark of JSRD. Joubert syndrome typically manifests in early childhood as a spectrum of neurological symptoms that includes hypotonia, developmental delay, breathing abnormalities (e.g., episodic tachypnea, apnea), atypical eye movements (e.g., oculomotor apraxia), and progressive truncal ataxia. JSRD is a genetically heterogeneous disorder; the different subtypes of Joubert syndrome have different severities and present with different symptoms, including retinal disease, renal disease, oculorenal disease, hepatic disease, and oral-facial-digital features.

Meckel-Gruber syndrome (MKS), or Meckel syndrome, is a developmental disorder that is associated with a very severe spectrum of symptoms that includes kidney cysts, a sac-like protrusion of the brain through a hole in the skull (occipital encephalocele), extra fingers or toes (polydactyly), and other abnormalities of the head, face, liver, lungs, genitals, and urinary tract. Children born with MKS usually die in infancy. MKS has a variable clinical presentation and affected individuals may not present with all these symptoms.

Approximately 50% of patients with a clinical diagnosis of Joubert syndrome will have pathogenic variants in one of these 18 genes; however, the clinical sensitivity can be dependent on associated symptoms. For example, approximately 90% of patients with Joubert syndrome and hepatic fibrosis (JS-H) have a pathogenic variant in one of these genes.

Overall, AHI1, CC2D2A, CEP290, and TMEM67, are the most common cause of Joubert syndrome cases (7%-10%). Pathogenic variants in the remaining genes are much less common (<3%-4%).

All genes are autosomal recessive except for OFD, which is X-linked dominant for Joubert syndrome.

The penetrance of biallelic mutations in JBTS genes is 100%, with clinical variability. Some features, such as cerebral vermis hypoplasia, breathing abnormalities, and oculomotor apraxia, are present at birth. Others, such as hepatic fibrosis, nephronophthisis, and/or retinal disease, are most often progressive and develop later in life.

The estimated prevalence of Joubert syndrome is between 1 in 80,000 and 1 in 100,000 live births. In individuals of Ashkenazi Jewish ancestry, a founder mutation in the TMEM216 gene (p.Arg73Leu) is found in ~1% of the population. There is a higher prevalence of Joubert syndrome in the French Canadian population due to founder mutations in the CC2D2A, C5orf42, and TMEM231 genes. (Note: At this time, we do not yet offer testing of C5orf42 or TMEM231.)

The prevalence of Meckel syndrome is estimated at 1 in 50,000 births in Europe. The worldwide prevalence is reported to be between 1 in 13,250 and 1 in 140,000 live births.

  1. Coene, KL, et al. OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin. Am. J. Hum. Genet. 2009; 85(4):465-81. doi: 10.1016/j.ajhg.2009.09.002. PMID: 19800048
  2. Davis, EE, et al. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat. Genet. 2011; 43(3):189-96. doi: 10.1038/ng.756. PMID: 21258341
  3. Gunay-Aygun, M. Liver and kidney disease in ciliopathies. Am J Med Genet C Semin Med Genet. 2009; 151C(4):296-306. doi: 10.1002/ajmg.c.30225. PMID: 19876928
  4. Hildebrandt, F, et al. Ciliopathies. N. Engl. J. Med. 2011; 364(16):1533-43. doi: 10.1056/NEJMra1010172. PMID: 21506742
  5. Logan, CV, et al. Molecular genetics and pathogenic mechanisms for the severe ciliopathies: insights into neurodevelopment and pathogenesis of neural tube defects. Mol. Neurobiol. 2011; 43(1):12-26. doi: 10.1007/s12035-010-8154-0. PMID: 21110233
  6. Parisi, M, Glass, I. Joubert Syndrome and Related Disorders. 2003 Jul 09. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 20301500
  7. Parisi, MA. Clinical and molecular features of Joubert syndrome and related disorders. Am J Med Genet C Semin Med Genet. 2009; 151C(4):326-40. doi: 10.1002/ajmg.c.30229. PMID: 19876931
  8. Romani, M, et al. Mutations in B9D1 and MKS1 cause mild Joubert syndrome: expanding the genetic overlap with the lethal ciliopathy Meckel syndrome. Orphanet J Rare Dis. 2014; 9:72. doi: 10.1186/1750-1172-9-72. PMID: 24886560
  9. Valente, EM, et al. Clinical utility gene card for: Joubert syndrome--update 2013. Eur. J. Hum. Genet. 2013; 21(10):None. doi: 10.1038/ejhg.2013.10. PMID: 23403901
  10. Valente, EM, et al. Primary cilia in neurodevelopmental disorders. Nat Rev Neurol. 2014; 10(1):27-36. doi: 10.1038/nrneurol.2013.247. PMID: 24296655
  11. Wang, S, Dong, Z. Primary cilia and kidney injury: current research status and future perspectives. Am. J. Physiol. Renal Physiol. 2013; 305(8):F1085-98. doi: 10.1152/ajprenal.00399.2013. PMID: 23904226

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
AHI1 NM_017651.4
ARL13B NM_182896.2
B9D1 NM_015681.3
B9D2 NM_030578.3
CC2D2A NM_001080522.2
CEP290* NM_025114.3
INPP5E NM_019892.4
MKS1 NM_017777.3
MRE11A NM_005591.3
NPHP1 NM_000272.3
NPHP3 NM_153240.4
OFD1 NM_003611.2
RPGRIP1L NM_015272.2
TCTN1 NM_001082538.2
TCTN2 NM_024809.4
TMEM216 NM_001173990.2
TMEM67 NM_153704.5
TTC21B NM_024753.4

CEP290: Analysis includes the intronic variant NM_025114.3:c.2991+1655A>G.