• Test code: 04111
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit

Invitae Joubert and Meckel-Gruber Syndromes Panel

Test description

The Invitae Joubert and Meckel-Gruber Syndromes Panel analyzes 31 genes that are associated with Joubert syndrome and related disorders (JSRD) and with Meckel-Gruber syndrome (MKS). These syndromes are characterized by congenital brain malformations, renal disease, retinal dystrophies, and oral-facial-digital features. These genes were selected based on the available evidence to date to provide Invitae’s broadest test for JSRD and MKS.

Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant can inform recurrence-risk assessment and genetic counseling.

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

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Primary panel (31 genes)


Alternative tests to consider

Joubert and Meckel-Gruber syndromes are members of a class of disorders called ciliopathies. Ciliopathies share many overlapping symptoms, often making it difficult to distinguish between them based on clinical presentation alone. Depending on the individual’s clinical and family history, the broader Invitae Ciliopathies Panel may be appropriate. It can be ordered at no additional cost.

  • COACH syndrome
  • Joubert syndrome and related disorders (JSRD)
    • Joubert syndrome with retinal disease (JS-Ret)
    • Joubert syndrome with renal disease (JS-Ren)
    • Joubert syndrome with oculorenal disease (JS-OR)
    • Joubert syndrome with hepatic disease (JS-H)
    • Joubert syndrome with orofaciodigital features (JS-OFD)
  • Meckel syndrome (MKS) – also known as Meckel-Gruber 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. JSRD 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 JSRD 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 JSRD/MKS will have pathogenic variants in one of these 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, mutations in AHI1, CC2D2A, CEP290, and TMEM67 are the most common cause of JSRD cases. Pathogenic variants in the remaining genes are much less common.

Disorders% of JSRD/MKS attributed to pathogenic variants in each gene
AHI1 ~7-10%
ARL13B <1%
CC2D2A ~10%
CEP41 <1%
CEP290 ~10%
NPHP1 ~1-2%
RPGRIP1L ~2-4%
TMEM216 ~3%
TMEM237 <1%
TMEM67 ~10%
B9D1, B9D2,C5orf42, CEP104, CEP120, CSPP1, INPP5E, KIAA0586, KIF7, MRE11A, MKS1, NPHP3, PDE6D, OFD1, TCTN1, TCTN2, TCTN3, TMEM138, TMEM231, TTC21B, ZNF423 Unknown, rare

Most JSRD and MKS syndromes are inherited in an autosomal recessive manner except for OFD-related Joubert syndrome, which is X-linked.

The penetrance of biallelic mutations in JSRD 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 JSRD 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 JSRD in the French Canadian population due to founder mutations in the CC2D2A, C5orf42, and TMEM231 genes.

The prevalence of MKS 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.

This test can be considered for individuals who present with the following features, which are common in “classic” JSRD:

  • molar tooth sign (MTS)
  • hypotonia
  • developmental delay

Additional clinical findings may include tachypnea and/or apnea, abnormal eye movements, retinal dystrophy, renal disease, ocular colobomas, and polydactyly.

  1. 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
  2. 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: http://www.ncbi.nlm.nih.gov/books/NBK1325/ PMID: 20301500
  3. Hildebrandt, F, et al. Ciliopathies. N. Engl. J. Med. 2011; 364(16):1533-43. doi: 10.1056/NEJMra1010172. PMID: 21506742
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. Roosing, S, et al. Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes. J. Med. Genet. 2016; 53(9):608-15. PMID: 27208211

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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

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
CEP104 NM_014704.3
CEP120 NM_153223.3
CEP290* NM_025114.3
CEP41 NM_018718.2
CPLANE1 NM_023073.3
CSPP1 NM_024790.6
INPP5E NM_019892.4
KIAA0586 NM_001244189.1
KIF7 NM_198525.2
MKS1 NM_017777.3
MRE11 NM_005591.3
NPHP1 NM_000272.3
NPHP3 NM_153240.4
OFD1 NM_003611.2
PDE6D NM_002601.3
RPGRIP1L NM_015272.2
TCTN1 NM_001082538.2
TCTN2 NM_024809.4
TCTN3 NM_015631.5
TMEM138 NM_016464.4
TMEM216 NM_001173990.2
TMEM231 NM_001077416.2
TMEM237 NM_001044385.2
TMEM67 NM_153704.5
TTC21B NM_024753.4
ZNF423 NM_015069.3

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