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  1. NGS panel - Genetic testing for Joubert syndrome

Joubert syndrome

July 12, 2017

Disease synonyms

Joubert syndrome, JBTS, Joubert syndrome and related disorders, JSRD, JS, Joubert-Boltshauser syndrome, Cerebelloparenchymal disorder, CPD, Cerebellooculorenal syndrome; CORS


Inheritance pattern

Autosomal recessive


Clinical features

Joubert syndrome and related disorders (JSRD) are a group of rare autosomal recessive conditions characterized with developmental delay and multiple congenital anomalies. The obligatory hallmark of JRSD is the molar tooth sign (MTS), a complex midbrain-hindbrain malformation visible on brain imaging 1. The estimated prevalence of Joubert syndrome and related disorders is between 1:80,000 and 1:100,000 2.

The diagnosis of classic Joubert syndrome is based on the presence of the following three primary criteria 1:

  • The molar tooth sign. The MRI appearance of hypoplasia of the cerebellar vermis and accompanying brain stem abnormalities in an axial plane through the junction of the midbrain and pons
  • Hypotonia in infancy with later development of ataxia
  • Developmental delays and intellectual disability.

Additional features often identified in individuals with Joubert syndrome include 1:

  • Abnormal breathing (tachypnea and/or apnea)
  • Abnormal eye movements, typically oculomotor apraxia
  • Retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and other abnormalities.

The findings of abnormal breathing patterns, nystagmus and oculomotor apraxia can be observed in all clinical subtypes of JSRD. Most affected individuals with Joubert syndrome develop truncal ataxia and developmental delay. Central nervous system findings include variable dysfunctions, speech apraxia, seizures, and autistic behavior.

Based on the major presenting clinical features, Joubert syndrome and related disorders can be classified as follows:

Joubert syndrome Infographics

Joubert syndrome with retinal disease is characterized by a pigmentary retinopathy that may be indistinguishable from classic retinitis pigmentosa and may also resemble Leber congenital amaurosis. A large study of 235 families with JSRD identified retinal dystrophy in 30% of cases 1, 27.

Joubert syndrome with renal disease has been reported as nephronophthisis or cystic dysplasia. Juvenile nephronophthisis, a form of chronic tubulointerstitial nephropathy, often presents in the first or second decade of life with polydipsia, polyuria, urine concentrating defects, growth retardation, and/or anemia. Progression to end-stage renal disease (ESRD) occurs on average by age 13 years 1, 28.

Joubert syndrome with oculorenal disease is characterized by retinal disease and renal impairment. Retinal and renal impairment often occur together in the same individual, and the majority of Joubert syndrome causative genes are associated with both renal cystic disease and retinal dystrophy.

Joubert syndrome with hepatic disease is characterized by progressive hepatic fibrosis already presenting at birth. This is a developmental disorder of the portobiliary system characterized histologically by abnormal branching of the intrahepatic portal veins and progressive fibrosis of the portal tracts. Clinical findings include enlarged, abnormally shaped liver and portal hypertension resulting in splenomegaly, hypersplenism, and gastroesophageal varices.

Joubert syndrome with orofacialdigital features is characterized by skeletal malformations including polydactyly (described in 8-19% of those affected 1, 2).

More than 20 genes have been associated with Joubert syndrome and related disorders (Table).


Table 1. Overview of genes associated with Joubert syndrome

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
AHI1 608894 Joubert syndrome 3 AR 18
ARL13B 608922 Joubert syndrome 8 AR 4
B9D1 614144 Meckel Syndrome, Type 9 AR 12
B9D2 611951 Meckel syndrome 10 AR 4
C5orf42 614571 oral-facial-digital syndrome 6; Joubert syndrome 17 AR 37
CC2D2A 612013 COACH syndrome; Meckel syndrome 6; Joubert syndrome 9 AR 22
CEP290 610142 Joubert syndrome type 5; Senior-Loken syndrome type 6; Meckel syndrome type 4; Leber congenital amaurosis type 10; Bardet-Biedl syndrome type 14 AR 50
CEP41 610523 Joubert syndrome 15 AR 4
CSPP1 611654 Joubert syndrome 21 AR 11
EXOC8 615283 5
GLI3 165240 Pallister-Hall syndrome; Polydactyly, postaxial, types A1 and B; Greig cephalopolysyndactyly syndrome AD 28
INPP5E 613037 Joubert syndrome 1; Mental retardation, truncal obesity, retinal dystrophy, and micropenis AR 17
KIF7 611254 Acrocallosal syndrome; Joubert syndrome 12; Hydrolethalus syndrome 2 AR 23
MKS1 609883 Meckel syndrome type 1; Bardet-Biedl syndrome type 13; Joubert syndrome type 28 AR 7
NEK8 609799 nephronophthisis 9; Renal-hepatic-pancreatic dysplasia 2 AR 2
NPHP1 607100 nephronophthisis 1; Joubert syndrome 4 AR 18
NPHP3 608002 Renal-hepatic-pancreatic dysplasia 1; Meckel syndrome 7; nephronophthisis 3 AR 19
OFD1 300170 Joubert syndrome 10; oral-facial-digital syndrome 1 XLD, XLR 19
PDE6D 602676 Joubert syndrome 22 AR 2
RPGRIP1L 610937 COACH syndrome; Joubert syndrome 7; Meckel syndrome type 5 AR 21
TCTN1 609863 Joubert syndrome 13 AR 5
TCTN2 613846 Meckel syndrome 8 AR 24
TCTN3 613847 oral-facial-digital syndrome 4; Joubert syndrome 18 AR 3
TMEM138 614459 Joubert syndrome 16 AR 1
TMEM216 613277 Meckel Syndrome type 2; Joubert syndrome type 2 AR 1
TMEM231 614949 Joubert syndrome 20; Meckel syndrome, type 11 AR 9
TMEM237 614423 Joubert syndrome 14 AR 15
TMEM67 609884 COACH syndrome; Meckel Syndrome, Type 3; Joubert syndrome 6; nephronophthisis 11; Bardet-Biedl syndrome type 14 AR 16
TTC21B 612014 Short-rib thoracic dysplasia 4 with or without polydactyly; nephronophthisis 12 AD, AR 24
ZNF423 604557 nephronophthisis 14; Joubert syndrome 19 AD, AR 11

Ciliopathies are conditions caused by defects in one or more of the many proteins important in ciliary function, and they share many features including renal disease, retinal dystrophy, and polydactyly. The cilia are membrane-found, hair-like cellular projections anchored by the basal body. Genes in which mutations are known to cause Joubert syndrome (Table) encode proteins which localize to the primary cilium and centrosome, where they play a role in the formation, morphology, and function of cilia.

Pathogenic variants in genes that cause JSRD have also been identified in disorders with clinical findings that overlap with Joubert syndrome including the following:

Nephronophthisis is an autosomal recessive kidney disease characterized by renal tubular atrophy and progressive interstitial fibrosis with later development of medullary cysts. Nephronophthisis is caused by pathogenic variants in at least twelve genes, including NPHP1, CEP290, NPHP2, NPHP3, NPHP4, NPHP5, NPHP11, and others.

Cogan syndrome is an autosomal recessive familial form of congenital oculomotor apraxia, characterized by defective horizontal voluntary eye movements. Some individuals with Cogan syndrome also have cerebellar vermis hypoplasia, with evidence of the molar tooth sign. Cogan syndrome is associated with mutations in TMEM216.

Leber congenital amaurosis (LCA) is severe dystrophy of the retina, typically presenting in the first year of life. Several children with features of Joubert's syndrome and LCA have been described, with presenting symptoms of panting tachypnea in the newborn, prolonged apneic attacks in the neonatal period, global developmental delay, and failure to develop vision. LCA is caused by mutations in CEP290, RPGRIP1, AIPL1, IMPDH1, and others.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by cone-rod retinal dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, hypogonadotropic hypogonadism in males, genital malformations in females, and renal disease. Renal disease in BBS includes structural malformations, renal hypoplasia, hydronephrosis, cystic kidneys, and glomerulonephritis. Pathogenic variants in at least 15 genes, all of which play a role in the primary cilium, have been described. BBS is caused by mutations in CEP290, TTC8, BBS-genes, and others.

Meckel syndrome is an autosomal recessive disorder characterized by the triad of cystic renal disease, posterior fossa abnormalities, and hepatic fibrosis. Polydactyly is relatively common. Cerebellar vermis hypoplasia has been described in some individuals. Meckel syndrome is usually lethal in the prenatal or perinatal period. Pathogenic variants in at least six genes have been identified; variants in five of these genes, CEP290, TMEM67, RPGRIP1L, CC2D2A, and TMEM216, have also been identified in individuals with JSRD.

MORM syndrome (mental retardation, truncal obesity, retinal dystrophy, micropenis) is an autosomal recessive disorder related to Bardet-Biedl syndrome and is caused by mutations of INPP5E.

Oral-facial-digital syndrome (OFD) describes a heterogeneous group of disorders characterized by facial features, oral abnormalities and digital anomalies such as polydactyly. OFD are characterized by a broad spectrum of clinical presentations, most commonly overlapping considerably with JSRD, Meckel syndrome, or short rib-polydactyly syndrome. OFD is caused by mutations in OFD1.

Hydrolethalus syndrome (HLS) is a lethal autosomal recessive disorder characterized by midline brain anomalies (hydrocephaly or anencephaly), migrognathia, and postaxial or preaxial polydactyly. HLS is caused by mutations in HLS1, HLS2, and the gene associated with Joubert syndrome, KIF7.

Acrocallosal syndrome (ACLS) is an autosomal recessive disorder characterized by macrocephaly, intellectual disability, agenesis of the corpus callosum and occasional posterior fossa abnormalities, ocular hypertelorism and polydactyly. Mutations in KIF7 are described as causative.

Jeune asphyxiating thoracic dystrophy (JATD) is an autosomal recessive skeletal dysplasia characterized by a long, narrow thorax, short stature, short limbs, polydactyly, and renal cystic disease with skeletal findings. At least five genes have been identified, with several ciliary genes including the gene TTC21B.

Treatment of Joubert syndrome-affected patients is primarily symptomatic. Infants and children with abnormal breathing may require supplemental oxygen and mechanical support. Other interventions may include speech therapy for motor dysfunction; occupational and physical therapy; educational support, special programs for the visually impaired; and feedings through a gastrostomis tube. Surgery may be required for polydactyly and symptomatic ptosis and strabismus.

CENTOGENE offers full gene sequencing and deletion/duplication analysis for the Joubert syndrome panel. We also offer single gene tests for each gene included in the panel.


Differential diagnosis

The differential diagnosis of autosomal recessive forms of Joubert syndrome panel– depending on the major symptoms in the initial case – includes the following diseases:

  • Nephronophthisis
  • Meckel syndrome
  • Cogan syndrome
  • Oral-facial-digital syndrome type I, type IV, and type VI
  • Leber congenital amaurosis
  • Bardet-Biedl syndrome
  • Hydrolethalus syndrome
  • Acrocallosal syndrome
  • MORM (mental retardation, truncal obesity, retinal dystrophy, micropenis) syndrome.

Testing strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Joubert syndrome panel using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Joubert syndrome panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Joubert syndrome panel, we further recommend continuing the bioinformatics analysis of the data obtained using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.


Referral reasons

The following individuals are candidates for Joubert syndrome panel testing:

  • Individuals with a family history of Joubert syndrome and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling Joubert syndrome
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of Joubert syndrome related genes should be performed in all individuals suspected of having this particular phenotype. In parallel, other genes reported to be related with Joubert syndrome should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of Joubert syndrome, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.


More information on CENTOGENE´s Joubert syndrome panel can be found in our genetic test catalogue.