Joubert Syndrome, Meckel-Gruber Syndrome, and Nephronophthisis via the TMEM67 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesPrice Test CPT CodeGene CPT Codes Copy CPT Codes STAT Prenatal
4621 TMEM67$640 8140781407,81479 Add to Order

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average


Genetic Counselors


Clinical Features and Genetics

Clinical Features

Joubert Syndrome and related disorders (JBTS) is an autosomal recessive condition marked by mid-hindbrain malformation, retinal dystrophy, cystic renal disease, hepatic fibrosis and polydactyly (Doherty 2009). Mid-hindbrain malformation, which can be readily identified as a “Molar Tooth Sign” (MTS) using Magnetic Resonance Imaging (MRI), typically leads to hypotonia, ataxia, abnormal eye movements and intellectual disability; MTS is pathognomonic for JBTS (Parisi and Glass 2013). Joubert syndrome with liver fibrosis is termed COACH syndrome.

Meckel-Gruber Syndrome (MKS) is a lethal autosomal recessive condition, also marked by brain malformation, cystic renal disease and polydactyly (Alexiev et al. 2006). In MKS, the pathognomonic feature is occipital encephalocele, which is generally identified during routine sonography between 12 and 20 weeks of gestation.

Nephronophthisis (NPH) is the most common genetic cause of progressive renal failure in children and young adults. NPH is characterized by polyuria, growth retardation and progressive deterioration of renal function with normal or slightly reduced kidney size (Hildebrandt et al. 1997; Hildebrandt et al. 2009). Nephronophthisis, when associated with Leber Congenital Amaurosis, is known as Senior-Loken syndrome (SLS) (Otto et al. 2005; Hildebrandt et al. 2009). NPH clinical features overlap with a group of diseases known as ciliopathies, which includes Meckel-Gruber Syndrome, Joubert Syndrome, Bardet-Biedl Syndrome and Leber congenital amaurosis (LCA).


JBTS, MKS, and NPH are rare, genetically heterogeneous, autosomal recessive disorders. Mutations in the TMEM67 gene (also called MKS3) are known to cause JBTS, COACH syndrome, MKS and NPH (Baala et al. 2007; Smith et al. 2006; Dawe et al. 2007; Consugar et al. 2007; Otto et al. 2009; Iannicelli et al. 2010; Doherty et al. 2010). In many cases, mutations that are predicted to be more severe (nonsense, frameshift, splicing) cause Meckel-Gruber syndrome with missense variants causing JBTS and NPH (Parisi and Glass 2013).

TMEM67 localizes to the primary cilium and the plasma membrane and is required for centriole migration and formation of primary cilium (Dawe et al. 2007).

Testing Strategy

This test provides full coverage of all coding exons of the TMEM67 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Clinical Sensitivity - Sequencing and CNV

Roughly 10% of patients with Joubert syndrome and 16-30% of patients with Meckel-Gruber syndrome carry causative mutations in the TMEM67 gene (Baala et al. 2006; Consugar et al. 2007; Iannicelli et al. 2010). Nineteen of 23 families with Joubert syndrome and hepatic fibrosis (COACH syndrome) were found to have causative mutations in TMEM67 (Doherty et al. 2010).

Clinical sensitivity is expected to be low as only one gross deletion in TMEM67 has been reported in a single patient (Human Gene Mutation Database).

Indications for Test

Candidates for this test are patients with symptoms consistent with MKS, NPH, JBTS, and COACH syndrome, and family members of patients with known mutations. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in TMEM67.


Official Gene Symbol OMIM ID
TMEM67 609884
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


  • Alexiev BA, Lin X, Sun CC, Brenner DS. 2006. Meckel-Gruber syndrome: pathologic manifestations, minimal diagnostic criteria, and differential diagnosis. Arch. Pathol. Lab. Med. 130: 1236-1238. PubMed ID: 16879033
  • Baala L, Romano S, Khaddour R, Saunier S, Smith UM, Audollent S, Ozilou C, Faivre L, Laurent N, Foliguet B, Munnich A, Lyonnet S,Salomon R, Encha-Razavi F, Gubler MC, Boddaert N, de Lonlay P, Johnson CA, Vekemans M, Antignac C, Attie-Bitach T. 2007. The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am. J. Hum. Genet. 80: 186–194. PubMed ID: 17160906
  • Consugar MB, Kubly VJ, Lager DJ, Hommerding CJ, Wong WC, Bakker E, Gattone VH, Torres VE, Breuning MH, Harris PC. 2007. Molecular diagnostics of Meckel–Gruber syndrome highlights phenotypic differences between MKS1 and MKS3. Human Genetics 121: 591–599. PubMed ID: 17377820
  • Dawe HR, Smith UM, Cullinane AR, Gerrelli D, Cox P, Badano JL, Blair-Reid S, Sriram N, Katsanis N, Attie-Bitach T, Afford SC, Copp AJ, Kelly DA, Gull K, Johnson CA. 2006. The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. Human Molecular Genetics 16: 173–186. PubMed ID: 17185389
  • Doherty D, Parisi MA, Finn LS, Gunay-Aygun M, Al-Mateen M, Bates D, Clericuzio C, Demir H, Dorschner M, Essen AJ van, Gahl WA, Gentile M, Gorden NT, Hikida A, Knutzen D, Ozyurek H, Phelps I, Rosenthal P, Verloes A, Weigand H, Chance PF, Dobyns WB, Glass IA. 2010. Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). Journal of Medical Genetics 47: 8–21. PubMed ID: 19574260
  • Doherty. 2009. PubMed ID: 19778711
  • Hildebrandt et al. 1997. PubMed ID: 9326933
  • Hildebrandt F. et al. 2009. Journal of the American Society of Nephrology : Jasn. 20: 23-35. PubMed ID: 19118152
  • Human Gene Mutation Database (Bio-base).
  • Iannicelli M, Brancati F, Mougou-Zerelli S, Mazzotta A, Thomas S, Elkhartoufi N, Travaglini L, Gomes C, Luigi Ardissino G, Bertini E, Boltshauser E, Castorina P, D'Arrigo S, Fischetto R, Leroy B, Loget P, Bonnière M, Starck L, Tantau J, Gentilin B, Majore S, Swistun D, Flori E, Lalatta F, Pantaleoni C, Penzien J, Grammatico P; International JSRD Study Group, Dallapiccola B, Gleeson JG, Attie-Bitach T, Valente EM. 2010. Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies. Human Mutation 31: E1319-31. PubMed ID: 20232449
  • Otto EA, Tory K, Attanasio M, Zhou W, Chaki M, Paruchuri Y, Wise EL, Wolf MTF, Utsch B, Becker C, Nurnberg G, Nurnberg P, Nayir A, Saunier S, Antignac C, Hildebrandt F. 2009. Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11). Journal of Medical Genetics 46: 663–670. PubMed ID: 19508969
  • Otto et al. 2005. PubMed ID: 15723066
  • Parisi M, Glass I. 2013. Joubert Syndrome and Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301500
  • Smith UM, Consugar M, Tee LJ, McKee BM, Maina EN, Whelan S, Morgan NV, Goranson E, Gissen P, Lilliquist S, Aligianis IA, Ward CJ, Pasha S, Punyashthiti R, Malik Sharif S, Batman PA, Bennett CP, Woods CG, McKeown C, Bucourt M, Miller CA, Cox P, Algazali L, Trembath RC, Torres VE, Attie-Bitach T, Kelly DA, Maher ER, Gattone VH 2nd, Harris PC, Johnson CA. 2006. The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat. Genet. 38: 191–196. PubMed ID: 16415887


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