Card kit

Invitae Joubert and Meckel-Gruber Syndromes Panel

Test code: 04111 •

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.

Disorders tested

  • 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

Ordering information

Turnaround time:

10–21 calendar days (14 days on average)

New York approved:

Yes

Preferred specimen:

3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)

Alternate specimens:

Saliva, buccal swab, and gDNA are also accepted.Learn more about specimen requirementsRequest a specimen collection kit

Clinical description and sensitivity

Clinical description:

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.

Clinical description and sensitivity

Clinical description:

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.


Clinical sensitivity:


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

Assay 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, depending on the specific gene or test. In addition, the analysis covers select non-coding variants. 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.

Assay 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, depending on the specific gene or test. In addition, the analysis covers select non-coding variants. 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.

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Primary panel

31 genes selected
AHI1
ARL13B
B9D1
B9D2
CC2D2A
CEP104
CEP120
CEP290
CEP41
CPLANE1
CSPP1
INPP5E
KIAA0586
KIF7
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