Classic Joubert syndrome (JS) is characterized by three primary findings:

Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.

The clinical diagnosis of JS is based on the presence of characteristic clinical features and MRI findings. To date pathogenic variants in 34 genes are known to cause JS; 33 of these are autosomal recessive and one is X-linked. A molecular diagnosis of JS can be established in about 62%-94% of individuals with a clinical diagnosis of JS by identification of biallelic pathogenic variants in one of the 33 autosomal recessive JS-related genes or a heterozygous pathogenic variant in the one X-linked JS-related gene.

Treatment of manifestations: Infants and children with abnormal breathing may require stimulatory medications (e.g., caffeine); supplemental oxygen; mechanical support; or tracheostomy in rare cases. Other interventions may include speech therapy for oromotor dysfunction; occupational and physical therapy; educational support, including special programs for the visually impaired; and feedings by gastrostomy tube. Surgery may be required for polydactyly and symptomatic ptosis and/or strabismus. Nephronophthisis, end-stage renal disease, liver failure and/or fibrosis are treated with standard approaches.

Surveillance: Annual evaluations of growth, vision, and liver and kidney function; periodic neuropsychologic and developmental testing.

Agents/circumstances to avoid: Nephrotoxic medications such as nonsteroidal anti-inflammatory drugs in those with renal impairment; hepatotoxic drugs in those with liver impairment.

JS is predominantly inherited in an autosomal recessive manner. JS caused by pathogenic variants in OFD1 is inherited in an X-linked manner. Digenic inheritance has been reported.

For autosomal recessive inheritance: at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible. For pregnancies known to be at increased risk for JS, prenatal diagnosis by ultrasound examination with or without fetal MRI has been successful.

Diagnostic criteria for Joubert syndrome (JS) continue to evolve but most authors concur that the neuroradiologic finding of the molar tooth sign is obligatory [Valente et al 2008, Parisi 2009, Brancati et al 2010].

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

Molar tooth sign in Joubert syndrome A. Axial MRI image through the cerebellum and brain stem of a normal individual showing intact cerebellar vermis (outlined by white arrows)

Additional features often identified in individuals with JS:

Other findings that may occur in fewer than half of individuals with JS include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and other abnormalities. The term "classic" or "pure" JS has been used to refer to JS without any of these other findings. In reality, however, a significant proportion of individuals diagnosed with classic JS in infancy or early childhood may manifest one or more of these findings over time.

The clinical diagnosis of JS is based on the presence of characteristic clinical features and MRI findings. To date pathogenic variants in 34 genes are known to cause JS; 33 of these are autosomal and one is X-linked. A molecular diagnosis of JS can be established in about 62%-94% of individuals with a clinical diagnosis of JS by identification of biallelic pathogenic (or likely pathogenic) variants in one of the 33 autosomal recessive JS-related genes or a heterozygous pathogenic (or likely pathogenic) variant in the one X-linked JS-related gene [Bachmann-Gagescu et al 2015a] (see Tables 1a and 1b).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (a multigene panel) and genomic testing (comprehensive genomic sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because of the extensive clinical and genetic heterogeneity in JS, Vilboux et al [2017] have suggested starting with a multigene panel, followed by exome sequencing if a molecular diagnosis has not been established.

Note: While single-gene testing or serial single-gene testing is rarely useful and typically NOT recommended because of the vast clinical and genetic heterogeneity of JS, targeted analysis for pathogenic variants in a specific gene can be performed first in individuals of the following ethnicity/ancestry if appropriate:

See Table 1a for the most common genetic causes of JS (i.e., pathogenic variants of any one of the genes included in this table account for >1% of JS) and Table 1b for less common genetic causes of JS (pathogenic variants of any one of the genes included in this table are reported in only a few families).

Molecular Genetics of Joubert Syndrome: Most Common Genetic Causes

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Pathogenic variants of any one of the genes included in this table account for >1% of JS.

Genes are listed alphabetically.

See Table A. Genes and Databases for chromosome locus and protein.

See Molecular Genetics for information on pathogenic variants detected.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Parisi et al [2006], Valente et al [2006a]

Bachmann-Gagescu et al [2015a] tested 440 individuals from 375 families for pathogenic variants in 27 JS-related genes.

Vilboux et al [2017] identified pathogenic variants in 81 (94%) of 86 families tested (100 individuals total) using a combination of 27-gene multigene panel and exome sequencing.

Three reported [Utsch et al 2006, Bachmann-Gagescu et al 2015a, Watson et al 2016]

Kroes et al [2016] evaluated 22 JS-related genes and 599 additional ciliary genes in a cohort of 51 northern Europeans with JS. Unlike other cohorts, this group identified CPLANE1 pathogenic variants in 12% of their cohort.

Gorden et al [2008], Doherty et al [2010]. The prevalence of CC2D2A pathogenic variants in one large cohort was 16/209 (7.7%) [Bachmann-Gagescu et al 2012].

Two reported [Mougou-Zerelli et al 2009, Su et al 2015]

Data from Sayer et al [2006], Valente et al [2006b], Valente et al [2008], Travaglini et al [2009] and Bachmann-Gagescu et al [2015a] support 7%-10%. In contrast, only one of 51 cases (2%) in a northern European cohort was positive [Kroes et al 2016].

Suzuki et al [2016] reported 83% yield of variant analysis in a cohort of 30 families (all but 3 were Japanese), with pathogenic variants identified in TMEM67 (26% of cohort), CEP290 (22% of cohort) and OFD1, INPP5E, AHI1, and CPLANE1 (each in 7.4% of the cohort).

One reported [Travaglini et al 2009]

Tuz et al [2014], Akizu et al [2014]

Pathogenic variants in KIAA0586 accounted for nine (2.5%) of 366 families with JS in one cohort [Bachmann-Gagescu et al 2015b] but may be more prevalent than previously realized due to the high frequency of a single-base deletion (c.428delG) in the general population [Roosing et al 2015] and a broad range of clinical phenotypes [Alby et al 2015, Malicdan et al 2015].

In three of six individuals with compound heterozygous pathogenic variants in KIAA0586, one pathogenic variant was an 800-bp deletion of exons 8-10 [Malicdan et al 2015].

MKS1 pathogenic changes were identified in two separate series: in 2/260 individuals with JS [Romani et al 2014] and in 9/371 families with JS [Slaats et al 2016].

Four reported [Kyttälä et al 2006, Frank et al 2007, Abu-Safieh et al 2012, Szymanska et al 2012]

May be higher in individuals with nephronophthisis

Homozygous deletions have been associated with rare cases of JS. Deletion/duplication analysis alone will detect a heterozygous deletion but not a single-nucleotide variant in NPHP1; this genotype is expected to be rare. The common ~290 kb deletion is the most frequently detected.

Arts et al [2007], Delous et al [2007], Parisi [2009]

Juric-Sekhar et al [2012], Bachmann-Gagescu et al [2015a]

Baala et al [2007], Brancati et al [2009], Doherty et al [2010]

One reported [Khaddour et al 2007]

Fourteen (~3%) of 462 families with JS had pathogenic variants in TMEM216 [Valente et al 2010].

Valente et al [2010], Lee et al [2012b]

Molecular Genetics of Joubert Syndrome: Less Common Genetic Causes

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Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., account for T; p.Arg18Ter) in TMEM237, reflecting a carrier frequency of 6% in this population [Huang et al 2011]. Two different Schmiedeleut Hutterite families had the same homozygous pathogenic frameshift variant, c.363_364delTA, in CSPP1 [Shaheen et al 2014], representing a separate founder variant.

In a survey of Japanese families with JS, 6/27 had pathogenic variants in CEP290, with c.6012-12T>A found on nine out of 12 disease alleles; 7/27 families had pathogenic variants in TMEM67 but no founder alleles were identified [Suzuki et al 2016].

Pathogenic variants in genes that cause Joubert syndrome (JS) have also been identified in disorders with clinical findings that overlap with JS; thus, in many instances it has become difficult to determine if a previously recognized disorder is truly distinct from JS (i.e., is an allelic disorder) or is part of the spectrum of JS (see Table 3). Brief descriptions of some of those disorders follow.

Acrocallosal syndrome (ACLS) (OMIM 200990), an autosomal recessive disorder, is characterized by macrocephaly, intellectual disability, agenesis of the corpus callosum and occasional posterior fossa abnormalities, ocular hypertelorism, polyaxial polydactyly of the hands, and preaxial polydactyly of the feet. It has been postulated that ACLS is allelic to hydrolethalus syndrome. Identification of several families with both disorders and KIF7 pathogenic variants confirms the proposed association; of note, several of the probands had evidence of the molar tooth sign (MTS) on cranial imaging, suggesting that ACLS and JS may represent overlapping ciliopathies [Putoux et al 2011].

Bardet-Biedl syndrome (BBS), usually inherited in an autosomal recessive manner, is characterized by cone-rod retinal dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, hypogonadotropic hypogonadism in males, genital malformations in females, and renal disease that may include structural malformations, renal hypoplasia, hydronephrosis, cystic kidneys, and glomerulonephritis. Progressive retinal impairment often causes blindness; renal failure may cause significant morbidity. Some affected individuals have hepatic fibrosis. Although many individuals are ataxic with poor coordination, cerebellar involvement or structural malformations are not typical [Baskin et al 2002]. Pathogenic variants in at least 19 genes, all of which play a role in the primary cilium, have been described. Pathogenic variants in CEP290, MKS1, and NPHP1 have been shown to cause both BBS and JS [Leitch et al 2008, Zaghloul & Katsanis 2009, Knopp et al 2015].

Cogan syndrome (OMIM 257550), an autosomal recessive familial form of congenital oculomotor apraxia, is characterized by defective horizontal voluntary eye movements with jerkiness. Oculomotor apraxia is also a common manifestation of JS. Detailed neuroimaging via fiber tracking suggests that there may be subtle differences in some of the pathways in Cogan syndrome versus JS [Merlini et al 2010].

Some individuals with Cogan syndrome also have cerebellar vermis hypoplasia with evidence of the molar tooth sign [Whitsel et al 1995, Sargent et al 1997], and occasionally develop nephronophthisis. The approximately 290-kb NPHP1 homozygous deletion or compound heterozygosity for the approximately 290-kb deletion and an NPHP1 sequence variant have been identified in some individuals with Cogan syndrome [Saunier et al 1997, Betz et al 2000].

Hydrolethalus syndrome (HLS) (OMIM PS236680), a lethal autosomal recessive disorder, is associated with midline brain anomalies (usually hydrocephaly or anencephaly with a keyhole foramen magnum), migrognathia, postaxial polydactyly of the hands, and preaxial polydactyly of the feet. In the Finnish population, pathogenic variants in HYLS1 have been identified [Mee et al 2005]. Pathogenic variants in KIF7 were identified in a consanguineous Algerian pedigree in which four affected fetuses had features consistent with HLS, but also a midbrain-hindbrain malformation similar to the MTS [Putoux et al 2011]. Pathogenic variants in KIAA0586 have also been described in fetuses with HLS as well as in individuals with JS and a variety of ciliopathy phenotypes [Alby et al 2015].

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 that may include cone-shaped epiphyses in hands and feet, irregular metaphyses, shortened ilium, and trident-shaped acetabulum. It is often lethal in infancy secondary to respiratory insufficiency. More than 12 ciliary genes and/or loci have been identified (including several intraflagellar transport proteins). Heterozygous pathogenic variants in TTC21B have been identified in three families with JATD with one proband demonstrating compound heterozygosity for a null allele and a hypomorphic allele [Davis et al 2011]. Pathogenic variants in CSPP1 [Tuz et al 2014] and KIAA0586 [Malicdan et al 2015] have been identified in individuals with JS and manifestations of JATD.

Leber congenital amaurosis (LCA), a severe dystrophy of the retina, typically becomes evident in the first year of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia, and keratoconus. Visual acuity is rarely better than 20/400. A characteristic finding is Franceschetti's oculodigital sign, comprising eye poking, pressing, and rubbing. The appearance of the fundus is extremely variable. While the retina may initially appear normal, a pigmentary retinopathy reminiscent of retinitis pigmentosa is frequently observed later in childhood. The electroretinogram is characteristically "nondetectable" or severely subnormal. Pathogenic variants in at least 17 genes cause LCA, and pathogenic variants in CEP290 account for about 20% of LCA, with one homozygous intronic pathogenic variant accounting for at least 20% of isolated congenital blindness in European cohorts [den Hollander et al 2006].

Mainzer-Saldino syndrome (MZSDS) is an autosomal recessive disorder described by the three diagnostic criteria of retinal dystrophy, renal disease (typically nephronophthisis), and phalangeal cone-shaped epiphyses. Variable findings include cerebellar hypoplasia, a narrow thorax, hepatic fibrosis, and dolichocephaly, with significant overlap with features of JATD and pathogenic variants in IFT140 described in both conditions [Mainzer et al 1970, Perrault et al 2012]. Pathogenic variants in IFT172, another component of the intraflagellar transport apparatus, have been described in those with JATD, MZSDS, and JS [Halbritter et al 2013].

A term that has been used to encompasse Ellis-van Creveld syndrome (EVC), short-rib polydactyly syndrome (SRPS), JATD, and MZSDS is short-rib thoracic dysplasia (SRTD) (OMIM PS208500) with or without polydactyly; these conditions are autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a "trident" appearance of the acetabular roof. There is clearly a great deal of overlap between these skeletal dysplasias and some forms of JS.

Meckel syndrome (OMIM PS249000), an autosomal recessive disorder, is characterized by the triad of cystic renal disease, posterior fossa abnormalities (usually occipital encephalocele), and the hepatic ductal plate malformation leading to hepatic fibrosis and bile duct proliferation. Polydactyly is relatively common. Cerebellar vermis hypoplasia has been described in some individuals. Meckel syndrome is usually lethal in the prenatal or perinatal period [Kyttälä et al 2006, Smith et al 2006]. Pathogenic variants in at least 21 genes have been identified in Meckel syndrome [Knopp et al 2015]. Pathogenic variants in at least 18 of these genes, CEP290, TMEM67, RPGRIP1L, CC2D2A, CEP41, MKS1, B9D1, B9D2, TMEM138, TMEM231, TCTN2, TCTN3, TMEM237, CPLANE1, CSPP1, CEP120, TMEM107, and TMEM216, have also been identified in individuals with JS [Parisi 2009, Valente et al 2010, Thomas et al 2012, Romani et al 2014, Bachmann-Gagescu et al 2015a, Knopp et al 2015, Shaheen et al 2015a, Roosing et al 2016a, Slaats et al 2016]. In many cases, pathogenic variants that predict a more severe effect on protein function such as transcription termination or null variants are associated with the lethal Meckel syndrome phenotype, while milder pathogenic variants such as missense variants are associated with JS [Romani et al 2014, Slaats et al 2016]. In some families the identical pathogenic variants can be found in a fetus with Meckel syndrome and a child with a JS, highlighting that these disorders can represent a spectrum [Valente et al 2010].

MORM (mental retardation, truncal obesity, retinal dystrophy, micropenis) syndrome (OMIM 610156), an autosomal recessive disorder, appears to be related to Bardet-Biedl syndrome and is caused by pathogenic variants in INPP5E [Bielas et al 2009, Jacoby et al 2009]. Individuals with this condition have normal growth parameters and life span with a congenital non-progressive retinal dystrophy and static mild-to-moderate cognitive impairment; in contrast to Bardet-Biedl syndrome, there is no polydactyly, apparent hypogonadism, or obvious renal disease [Hampshire et al 2006].

Nephronophthisis, an autosomal recessive kidney disease characterized by renal tubular atrophy and progressive interstitial fibrosis with later development of medullary cysts, is caused by pathogenic variants in at least 19 genes [Hildebrandt et al 2009, Hurd & Hildebrandt 2011, Wolf 2015]. The age of onset of end-stage renal disease can be variable, thereby defining subtypes such as infantile, juvenile, and adolescent. A homozygous, approximately 290-kb deletion of NPHP1 is identified in approximately 25% of individuals with juvenile nephronophthisis [Hoefele et al 2005, Saunier et al 2005, Hildebrandt et al 2009] and is causative in a small subset of individuals with JS. Note: The most common form, juvenile nephronophthisis, can also be a renal manifestation in JS. Conversely, it is estimated that 10% of individuals with nephronophthisis have extrarenal findings, which can include the molar tooth sign in some cases [Saunier et al 2005].

Oral-facial-digital syndrome describes a heterogeneous group of disorders characterized by facial features, oral abnormalities (often lobulated tongue and oral frenula), and digital anomalies such as polydactyly. Based on other associated clinical features, at least 13 clinical subtypes have been described. These features also overlap considerably with Meckel syndrome, short-rib polydactyly syndrome, and JS. Of the genes identified thus far for OFD, all have all had ciliary roles, and several overlap with JS.

Oral-facial-digital syndrome type I (OFD1) is associated with dysfunction of primary cilia and is characterized by the following abnormalities:

Up to 50% of individuals with OFD1 have some degree of intellectual disability that is usually mild. Almost all affected individuals are female. However, males with OFD1 have been described, mostly as malformed fetuses delivered by women with OFD1.

Of note, the phenotypic spectrum was broadened with recognition that the clinical features described in four individuals (hydrops fetalis, jaundice, brisk deep tendon reflexes, seizures, and trilobate left lung) [Terespolsky et al 1995, Brzustowicz et al 1999] were associated with pathogenic variants in OFD1 [Budny et al 2006]. Pathogenic variants in OFD1 have also been described in rare males with JS and features of OFD [Coene et al 2009, Field et al 2012].

Oral-facial-digital syndrome type IV (OFD IV, Mohr-Majewski syndrome) (OMIM 258860) is characterized by hallucal and postaxial polysyndactyly, tibial dysplasia, and variable short ribs, cystic kidneys, and brain anomalies. Pathogenic truncating variants in TCTN3 were identified in several pedigrees with a severe lethal OFD IV phenotype and bowing of long bones, cystic kidneys, occipital encephalocele, and bile duct proliferation of the liver but without short ribs; several of these fetuses also displayed vermis agenesis suggestive of the molar tooth sign [Thomas et al 2012]. Of note, this phenotype overlaps with Meckel syndrome and with JS.

Oral-facial-digital syndrome type VI (OFD VI, Varadi-Papp syndrome) (OMIM 277170). Individuals with OFD VI often have mesaxial polydactyly, in which the extra digit occurs between the central digits and is often accompanied by a Y-shaped metacarpal, as well as cerebellar vermis hypoplasia, oral frenulae, tongue lobulations or hamartomas (Figure 2B), and craniofacial features that include wide-spaced eyes and midline lip groove. Renal and cardiac involvement have been described [Münke et al 1990]. Problems with mastication, swallowing, and respiration may result. OFD VI has been defined as a form of JS, requiring the MTS as well as one or more of the following features: tongue hamartoma/oral frenula/upper lip notch, mesaxial polydactyly, and hypothalamic hamartoma [Poretti et al 2012]. One group identified pathogenic variants in CPLANE1 in 9/11 families with OFD VI [Lopez et al 2014]. Features of preaxial and/or mesaxial polydactyly and hypothalamic hamartoma were more likely related to CPLANE1 pathogenic variants, whereas tongue hamartomas and lingual frenula were not associated with pathogenic variants in this gene [Lopez et al 2014, Romani et al 2015]. Another group identified CPLANE1 pathogenic variants in only two of 17 individuals with OFD VI; pathogenic variants in TMEM216, TMEM107, and OFD1 have also been reported in OFD VI [Romani et al 2015, Lambacher et al 2016].

Disorders in the differential diagnosis include the disorders discussed in Genetically Related Disorders.

To establish the extent of disease in an individual diagnosed with Joubert syndrome (JS), the following baseline evaluations to identify the extent of disease in affected infants/children are recommended [Parisi et al 2007] (full text). Recommendations were developed by a consensus panel and are outlined on the Joubert Syndrome and Related Disorders Foundation website.

Respiratory

Hypotonia and therapeutic interventions

Other CNS malformations

Ophthalmologic

Renal disease

Hepatic fibrosis

Skeletal

Other

Antibiotic prophylaxis for surgical and dental procedures is indicated for individuals with structural cardiac anomalies.

Because no uniformly reliable distinguishing characteristics allow prediction of the complications that may develop in an infant or young child with Joubert syndrome, a number of annual evaluations are recommended (see also Joubert Syndrome and Related Disorders Foundation website):

Individuals with renal impairment should avoid nephrotoxic medications such as nonsteroidal anti-inflammatory drugs.

Individuals with liver impairment should avoid hepatotoxic medications.

Sibs or relatives who have clinical features similar to those of an individual with JS warrant genetic consultation. If the pathogenic variant(s) have been identified in a proband, testing symptomatic relatives for these pathogenic variants is appropriate.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Joubert syndrome (JS) is inherited predominantly in an autosomal recessive manner.

OFD1-related JS is inherited in an X-linked manner (click here (pdf) for discussion of X-linked inheritance).

Parents of a proband

Sibs of a proband

Offspring of a proband

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant in a JS-related gene.

For information about risk to family members ‒ X-linked inheritance (OFD1-related) click here (pdf).

Carrier testing for at-risk relatives requires prior identification of the JS-related pathogenic variant(s) in the family.

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirned (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Molecular genetic testing. Once the JS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for JS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Prenatal imaging. First-trimester diagnosis of JS for pregnancies at 25% risk has been reported using ultrasound examination to identify structural brain abnormalities such as encephalocele [van Zalen-Sprock et al 1996, Wang et al 1999]. More typically, prenatal diagnosis in at-risk fetuses has been accomplished by prenatal ultrasound examination of the posterior fossa and/or kidneys (for cysts and enlarged and/or hyperechoic kidneys) and digits (for polydactyly) as early as the second trimester [Ní Scanaill et al 1999, Aslan et al 2002, Doherty et al 2005]. In reality, prenatal sonographic findings in fetuses with JS are relatively nonspecific and include increased nuchal translucency, enlarged cisterna magna, cerebellar vermis aplasia/hypoplasia, occipital encephalocele, and ventriculomegaly, making definitive diagnosis of JS difficult in the absence of a family history. Moreover, the cerebellar vermis is a relatively late-developing structure, and may not cover the fourth ventricle until 18 weeks' gestation, making visualization of the molar tooth sign (MTS) difficult earlier in gestation [Bromley et al 1994]. The use of 2D ultrasound and 3D sonographic reconstruction with surface rendering has allowed visualization of the MTS as early as 22 weeks in several fetuses without a prior family history of JS [Quarello et al 2014].

Accurate prenatal diagnosis of JS in an at-risk fetus has been achieved by serial prenatal ultrasound imaging starting at 11 to 12 weeks' gestation, with detailed evaluation of cerebellar and other fetal anatomy through 20 weeks' gestation, followed by fetal MRI imaging at 20 to 22 weeks' gestation [Doherty et al 2005]. In a series of 12 pregnancies at 25% risk of having a fetus with JS, one center was able to correctly diagnose JS in the three affected fetuses based on fetal MRI findings at the pontomesencephalic junction (including the MTS) as early as 22 weeks' gestation [Saleem & Zaki 2010]. In the earliest reported diagnoses to date, MTS was identified in two separate at-risk pregnancies at 17 to 18 weeks' gestation via fetal MRI [Saleem et al 2011]. Although prenatal imaging, including fetal MRI, is useful in the diagnosis of posterior fossa anomalies, its sensitivity and specificity for the diagnosis of JS is unknown, and its use has not been systematically evaluated.

For a couple who has already had a child with JS, the presence of findings that suggest a prenatal diagnosis of Joubert syndrome and related disorders (e.g., encephalocele, renal cystic changes, polydactyly, or posterior fossa anomalies on fetal imaging) is highly significant; however, the absence of these signs does not preclude a diagnosis of Joubert syndrome and related disorders because of the unknown sensitivity of imaging and because of intrafamilial variability.

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Joubert Syndrome: Genes and Databases

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Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

OMIM Entries for Joubert Syndrome (View All in OMIM)

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All of the genes in which pathogenic variants are known to cause Joubert syndrome (JS) localize to the primary cilium and/or basal body and centrosome where they may play a role in the formation, morphology, and/or function of these organelles. The cilia are membrane-found, hair-like projections that are anchored by the basal body.

Motile cilia have a 9+2 microtubule axonemal structure that allows for movement and flow of fluids; they are found on specialized cell types such as respiratory epithelia and spermatozoa. Primary cilia have a 9+0 microtubule structure and are usually non-motile. Primary cilia are found on most cell types and appear to play a role in cellular chemo- and mechanosensation and cell signaling, including the WNT, sonic hedgehog (SHH), and PDGF signaling pathways involved in differentiation, cell division, and planar cell polarity.

Ciliopathies, conditions caused by defects in one or more of the many proteins important in ciliary function, share many features including renal disease, retinal dystrophy, and polydactyly [reviewed in Badano et al 2006]. The association of ciliary defects with specific phenotypes has not been completely elucidated, but in the case of the hindbrain malformation seen in Joubert syndrome, it is known that SHH signaling is critical for both dorsal-ventral patterning of the neural tube and cerebellar granule cell proliferation [Doherty 2009].

Note: Detailed information about JS-related genes in which pathogenic variants account for more than 1% of JS (see Table 1a) appears in this section. Detailed information about JS-related genes in which pathogenic variants account for less than 1% of JS (see Table 1b) appears here (pdf).

Gene structure. AHI1 comprises 28 exons and several alternative splice variant forms. The most common full-length transcript is 5,528 bp.

Pathogenic variants. Homozygous nonsense, missense, and splicing variants, deletions, and insertions have been reported [Dixon-Salazar et al 2004, Ferland et al 2004, Parisi et al 2006, Romano et al 2006, Utsch et al 2006]. (For more information, see Table A, Locus Specific.)

Normal gene product. 1196-amino acid protein, AHI1 (also termed jouberin). The protein includes a coiled-coil domain, an SH3 domain, and six WD40 repeats hypothesized to mediate a variety of functions including signal transduction, RNA processing, and vesicular trafficking.

Abnormal gene product. Loss of AHI1 function causes Joubert syndrome. In Ahi1-null mouse strains that survive, the phenotype ranges from a perinatal lethal phenotype to early retinal degeneration with a failure of proper development of the photoreceptor sensory cilia and outer segments [Westfall et al 2010].

Gene structure. This reference sequence (NM_023073.3) comprises 53 exons. CPLANE1 encodes a predicted 3,197-amino acid protein (NP_075561.3) [Srour et al 2012b, Srour et al 2015].

Pathogenic variants. Eight different pathogenic variants have been found in 14 affected individuals from a number of unrelated families of French Canadian descent, several are linked to a distinct haplotype that represents a different founder effect in the French Canadian population [Srour et al 2012b, Srour et al 2015]. Many affected individuals are compound heterozygotes for two different pathogenic variants. Another founder variant has been described in the Dutch population (p.Arg2904Ter) [Kroes et al 2016], and pathogenic variants have also been described in those with an OFD VI phenotype [Lopez et al 2014, Romani et al 2015].

CPLANE1 Pathogenic Variants Discussed in This GeneReview

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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

The c.4690G>A (p.Ala1564Thr) variant occurs in an alternate exon (exon 40a) suggested by Srour et al [2015].

Normal gene product. The encoded protein has features of a transmembrane protein and a putative coiled-coil domain. Proteomic studies have suggested protein interactions with proteins important in neurodevelopment. It appears to be widely expressed in a variety of tissues, including the central nervous system, but little else is known about the gene.

Abnormal gene product. The disease-associated variants are predicted to result in loss of function, aberrant splicing, exon skipping (c.7400+1G>A), or missense variants predicted by protein prediction algorithms to be damaging [Srour et al 2012b, Srour et al 2015].

Gene structure. This 38-exon gene encodes a 1620-amino acid protein that shares domains in common with the RPGRIP1L-encoded protein.

Pathogenic variants. Variants in this gene cause Meckel syndrome and JSRD, including the COACH syndrome variant; null variants are associated with the more severe (and often lethal) Meckel syndrome phenotype [Mougou-Zerelli et al 2009]. Several pathogenic variants and likely founder effects have been identified in CC2D2A in French Canadians [Srour et al 2012b, Srour et al 2015].

Normal gene product. The protein has coiled-coil and a C2 calcium-binding domain and appears to play a critical role in cilia formation. Multiple transcript variants arise from alternative splicing. CC2D2A localizes to the basal body and physically interacts with CEP290 [Gorden et al 2008].

Abnormal gene product. Loss of CC2D2A protein results in human disease.

Loss of function in the zebrafish homolog results in pronephric cysts (the equivalent of kidney cysts) and other changes consistent with ciliary dysfunction [Gorden et al 2008].

Gene structure. The gene comprises 54 exons and spans 93.2 kb of genomic DNA, with a full-length transcript size of 7972 bp. Alternative splicing results in several different isoforms.

Pathogenic variants. More than 100 distinct pathogenic variants have been identified in CEP290, with the vast majority of them predicted to be truncating (40 nonsense and 48 frameshift out of 112 total). One large heterozygous partial deletion associated with JS has also been identified, but most truncating variants are caused by small insertions or deletions. Only three variants are missense; 20 affect splicing [Coppieters et al 2010].

The spectrum of phenotypes associated with pathogenic variants in CEP290 is broad, including LCA, nephronophthisis, Senior-Løken syndrome, JS, Meckel syndrome, and Bardet-Biedl syndrome (see Table 3). Although clear genotype-phenotype correlations are difficult to establish, some limited associations have been described and are summarized in the locus-specific database CEP290base [Coppieters et al 2010].

Normal gene product. CEP290 encodes centrosomal protein of 290 kd (also termed nephrocystin-6), which comprises 2479 amino acid residues. Nephrocystin-6 is a centrosomal protein known to modulate the activity of ATF4, a transcription factor implicated in renal cyst formation. The protein contains 13 putative coiled-coil domains, a region with homology to SMC (structural maintenance of chromosomes) ATPases, six KID motifs, three tropomyosin homology domains, and an ATP/GTP binding site motif A. The protein localizes to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. Nephrocystin-6 has also been shown to interact with other JSRD-associated proteins, including CC2D2A and meckelin [Gorden et al 2008, Leitch et al 2008, Tallila et al 2008].

Abnormal gene product. Loss of CEP290 function causes disease. Knockdown experiments in zebrafish result in abnormal cerebellar, renal, and retinal development [Sayer et al 2006]. Evidence suggests that this protein is expressed in the cerebellum during murine embryogenesis [Valente et al 2006b]. Two naturally occurring animal models with pathogenic variants in cep290 have been identified, in the rd16 mouse and in Abyssinian cats; both exhibit progressive retinal degeneration but no renal or cerebellar defects [Coppieters et al 2010].

Gene structure. CSPP1 encodes a short, 876-amino acid isoform and a long, 1221-amino acid isoform [Patzke et al 2006, Tuz et al 2014].

Pathogenic variants. Nonsense truncating, frameshift truncating, and splice site variants make up the majority of reported pathogenic variants and fall throughout the protein [Akizu et al 2014, Tuz et al 2014]. One missense variant resulting in abnormal splicing and introduction of a downstream frameshift has been described [Tuz et al 2014]. There do not appear to be any clear genotype-phenotype correlations to explain the broad range of phenotypes of individuals with pathogenic variants in this gene.

CSPP1 Pathogenic Variants Discussed in This GeneReview

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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Centrosome spindle pole-associated protein 1 (CSPP1) encoded by this gene is 101.5 kd (142 kd for the long isoform) and contains five coiled-coil domains.It interacts with centrosomes and plays a role in cell-cycle progression and spindle organization during mitosis [Patzke et al 2006].

Abnormal gene product. Fibroblasts from affected individuals with CSPP1-related JS showed defects in ciliogenesis, with fewer and/or short cilia [Tuz et al 2014]. Impaired sonic hedgehog signaling has also been noted [Shaheen et al 2014].

Gene structure. INPP5E comprises nine exons and 3440 bp of mRNA and encodes a 644-amino acid protein.

Pathogenic variants. Missense variants within the catalytically active phosphatase domain in this gene cause some forms of JSRD [Bielas et al 2009]. In one family with the Bardet-Biedl syndrome-like MORM syndrome, the identified pathogenic variant results in premature truncation of the protein and deletion of the terminal 18 amino acids [Jacoby et al 2009].

Normal gene product. The protein encoded by this gene is 72-kd inositol polyphosphate 5-phosphatase (also known as inositol 1,4,5-trisphosphate [InsP3] 5-phosphatase), an enzyme that is involved in phosphatidylinositol signaling by mobilizing intracellular calcium and acting as a second messenger mediating cell responses to various stimuli. This enzyme localizes to the central core of the primary cilium and appears to affect its metabolism of phosphotidylinositol and stability [Jacoby et al 2009].

Abnormal gene product. The JS-associated pathogenic variants impair the 5-phosphatase activity of the enzyme and alter the ciliary phosphotidylinositol ratio, destabilizing the cilia. Mice with homozygous deletions of the orthologous gene die soon after birth and exhibit anophthalmos, polydactyly, cystic kidneys, skeletal abnormalities, cleft palate, and cerebral anomalies such as exencephaly [Jacoby et al 2009]. Deletion of the terminal 18 amino acids appears to affect localization of the protein within the cilium [Jacoby et al 2009].

Gene structure. KIAA0586 (TALPID3) comprises 34 exons and encodes a 1644-amino acid protein in its longest isoform, with at least six isoforms described [Roosing et al 2015].

Pathogenic variants. The pathogenic variants that cause the broad spectrum of findings are typically truncating variants or occasionally missense variants [Alby et al 2015, Bachmann-Gagescu et al 2015b, Malicdan et al 2015, Roosing et al 2015].

One relatively common pathogenic variant (c.428delG) is predicted to occur in the general population at a frequency of 1/300 [Roosing et al 2015], and in several cohorts, a second likely pathogenic variant has not yet been identified [Bachmann-Gagescu et al 2015b, Roosing et al 2015].

Of note, a recurrent multiexon deletion in KIAA0586 that results in early termination of the protein was identified by Malicdan et al [2015]; it is not clear if such a large-scale intragenic deletion was evaluated in the cohorts reported by other groups.

KIAA0586 Pathogenic Variants Discussed in This GeneReview

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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. KIAA0586 encodes a centrosomal protein that is predicted to have four coiled-coil domains and a C-terminal proline-rich domain. It is required for ciliogenesis and for hedgehog signaling. The orthologous protein in chicken is TALPID3, which is essential for sonic hedgehog transduction in the limbs, neural tube, and somites of the developing chick [Malicdan et al 2015].

Abnormal gene product. KIAA0586 assists in the assembly of the ring-like structure at the distal end of centrioles to mediate protein trafficking to the cilia; loss of KIAA0586 leads to formation of ciliary vesicles and failure of centrosome migration. Disruption of KIAA0586 expression in chick embryos, mutated mouse, and zebrafish embryos results in cells that lack primary cilia and causes facial, limb, and neural tube defects [Malicdan et al 2015]. In one series, KIAA0586 pathogenic variants all occurred before the highly conserved domain necessary for centrosome localization [Malicdan et al 2015]. Moreover, fibroblasts derived from patients with KIAA0586 pathogenic variants demonstrate reduced ciliation, shorter cilia when present, and altered sonic hedgehog signaling [Alby et al 2015, Malicdan et al 2015].

Gene structure. MKS1 is 21,170 bp in length, comprises 18 exons, and encodes a 559-amino acid protein. Multiple transcript variants encode different isoforms of this gene.

Pathogenic variants. A variety of missense, nonsense, and other truncating variants have been described in this gene, including a recurrent variant (p.Ser372del) in four out of 11 individuals with JS caused by pathogenic variants in this gene [Romani et al 2014, Slaats et al 2016]. For individuals with more severe Meckel syndrome phenotypes, the MKS1 variants are predicted to be more damaging than those with JS, who generally carry at least one nontruncating variant in this gene.

MKS1 Pathogenic Variants Discussed in This GeneReview

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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The protein encoded by this gene localizes to the transition zone of the basal body and is required for formation of the primary cilium in ciliated cells. More severe variants in this gene result in Meckel syndrome type 1 and in Bardet-Biedl syndrome type 13.

Abnormal gene product. By testing fibroblasts from individuals with JS and pathogenic variants in this gene, Slaats et al [2016] observed that the cells had a normal or reduced number of cilia that were more variable in length than those from control individuals. In addition, there was altered distribution of the key ciliary proteins ARL13B and INPP5E; INPP5E is typically distributed along the cilium in an ARL13B-dependent manner that requires a functional transition zone, which appears to be defective in these individuals [Slaats et al 2016].

Gene structure. NPHP1 comprises 20 exons; its cDNA is 3,713 bp. The gene resides in a region flanked by two large inverted repeat elements and encodes nephrocystin-1.

Pathogenic variants. In addition to a homozygous, approximately 290-kb deletion encompassing NPHP1 and portions of another gene, BENE [Saunier et al 2000, Parisi et al 2004a], occasional single-nucleotide variants in NPHP1 have also been identified [Hoefele et al 2005]. (For more information, see Table A.) Some individuals with more severe phenotypes than familial juvenile nephronophthisis type 1 or Senior-Løken syndrome (see Table 3) have the homozygous NPHP1 deletion as well as a heterozygous change in AHI1 or CEP290, suggesting the contribution of modifier genes [Tory et al 2007].

Normal gene product. Nephrocystin-1, a protein of 733 amino acids, has an src homology domain 3 (SH3) domain that may mediate interactions with other proteins. Nephrocystin appears to localize to the primary cilium of the cell, to cell-cell adherens junctions, and to the basal body, where it may function in the control of cell division and in cell-cell and cell-matrix adhesion signaling [Hildebrandt et al 2009]. Nephrocystin interacts with the AHI1 protein as well as with the proteins INVS, NPHP3, and NPHP4, which are encoded by genes mutated in other forms of nephronophthisis.

Abnormal gene product. The association of nephrocystin-1 with many other ciliary proteins and its known localization to the cilium/basal body in renal epithelium suggests a critical role in renal tubular development.

Gene structure. The gene comprises 26 exons and 3948 bp and encodes a 1315-amino acid protein.

Pathogenic variants. A wide variety of missense, nonsense, and splice variants have been identified. In general, more severe truncating variants are associated with the lethal Meckel syndrome phenotype, while less severe variants cause JSRD, including the COACH variant [Delous et al 2007, Wolf et al 2007]. In addition, the p.Ala229Thr variant is associated with the development of retinal degeneration in individuals with ciliopathies caused by pathogenic variants in other genes [Khanna et al 2009].

RPGRIP1L Pathogenic Variants Discussed in This GeneReview

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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The protein encoded by this gene (protein fantom) has coiled-coil domains, a C2 calcium-binding domain, a RPGR (retinitis pigmentosa GTPase regulator) interacting domain, and a centrosomal protein-related domain. It can localize to the basal body-centrosome complex or to primary cilia and centrosomes in ciliated cells. The protein interacts with nephrocystin-4, the protein defective in some forms of nephronophthisis and Senior-Løken syndrome [Arts et al 2007]. Two transcript variants encoding different protein isoforms have been identified for RPGRIP1L.

Abnormal gene product. Loss of RPGRIP1L function is associated with disease. In addition, the p.Ala229Thr change appears to alter the interaction of the RPGRIP1L-encoded protein with RPGR protein, resulting in loss of photoreceptor cells [Khanna et al 2009].

Gene structure. TCTN2 (tectonic family member 2) comprises 18 exons and encodes several transcripts, the longest of which is 697 amino acids. The gene encodes an N-terminal signal peptide and a C-terminal transmembrane domain that is conserved in the Drosophila ortholog [Reiter & Skarnes 2006].

Pathogenic variants. Nonsense, frameshift, and splice site variants in this gene have been implicated in JSRD and MKS [Sang et al 2011, Shaheen et al 2011].

Normal gene product. Tectonic-2. In mice, the Tctn2 protein is known to regulate hedgehog signaling and ciliogenesis. It interacts with Mks1 and Cc2d2a.

Abnormal gene product. Loss of TCNTN2 function is associated with disease. The concept of a ciliary "interactome" involving NPHP, JS, and MKS proteins has been proposed to explain the modular nature of the ciliary structure and the different functions of interacting clusters of proteins involved in a variety of cellular processes [Sang et al 2011].

Gene structure. The gene comprises 28 exons and spans 62.0 kb of genomic DNA with a full-length transcript size of 3,467 bp [Smith et al 2006]. There is at least one splice variant form of 29 exons and length of 3,280 bp encoding a protein with 995 residues [Ensembl Database].

Pathogenic variants. Pathogenic variants identified in individuals with Joubert syndrome and related disorders include splice site variants resulting in abnormal transcripts and missense variants, both presumably representing hypomorphic alleles with milder phenotypes than the more severe lethal variants causing Meckel syndrome [Smith et al 2006, Baala et al 2007]. Pathogenic variants in this gene are particularly prevalent in individuals with JS and liver involvement (the COACH variant) [Iannicelli et al 2010].

Normal gene product. Meckelin, a 995-amino acid protein with a calculated molecular weight of 108 kd, is predicted to contain a signal peptide, at least two cysteine-rich repeats, and a 490-amino acid extracellular region, followed by seven transmembrane domains and a small 30-residue cytoplasmic tail [Smith et al 2006]. The protein has been localized to the primary cilium and plasma membrane of renal and biliary epithelial cells and other ciliated cells and has been shown to interact with the MKS1 protein involved in Meckel syndrome. Meckelin is involved in centrosome migration to the apical cell surface during early ciliogenesis, and is essential for ciliary development and function [Dawe et al 2007].

Abnormal gene product. Loss of TMEM67 function is associated with disease. The spontaneous rat mutant wpk/wpk, with a single-nucleotide variant in TMEM67, exhibits polycystic kidneys and hydrocephalus with agenesis of the corpus callosum [Smith et al 2006]. A comparable phenotype is observed in the spontaneous murine deletion mutants, which typically die by age three weeks of polycystic nephropathy; some also develop hydrocephalus [Cook et al 2009].

Gene structure. TMEM216 comprises six exons. The longest splice isoform (NM_001173990) encodes a 148-amino acid protein. There are multiple splice variants. The 23-kb intergenic region between TMEM216 and TMEM138 appears to coordinate the expression of these two ciliary genes, both of which can cause JS [Lee et al 2012b].

Pathogenic variants. Pathogenic variants include missense, nonsense, and splice variants. One common variant (c.218G>T), resulting in the protein change p.Arg73Leu, appears to be a founder variant in the Ashkenazi Jewish population with carrier frequency of 1:92 to 1:100 [Edvardson et al 2010, Valente et al 2010]. Pathogenic variants, many of which are predicted to produce a truncated protein, also cause the lethal Meckel syndrome phenotype [Valente et al 2010].

TMEM216 Pathogenic Variants Discussed in This GeneReview

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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The longest isoform is transmembrane protein 216, a tetraspan transmembrane protein containing four hydrophobic transmembrane domains. These proteins appear to regulate signaling and trafficking properties of other partner proteins, including Wnt receptors. TMEM216 localizes to the base of primary cilia and forms a complex with meckelin, another transmembrane protein defective in JSRD encoded by TMEM67 [Valente et al 2010]. In addition, TMEM216 and TMEM138 are required for ciliogenesis, as each localizes to a distinct vesicle pool that carries proteins necessary for ciliary assembly from the Golgi to the primary cilia [Lee et al 2012b].

Abnormal gene product. Disruption of tmem216 in zebrafish causes defects in gastrulation as well as other changes typical of altered ciliary function [Valente et al 2010].

For information about genes in Table 1b, click here (pdf).

University of Washington Joubert Center