Joubert and Meckel-Gruber Syndromes Panel

Joubert Syndrome and related disorders (JSRD) are marked by hypotonia, abnormal ocular movements, neonatal respiratory difficulties, intellectual disability, hypoplasia of the cerebellar vermis, and malformation of the brainstem. The brain malformations lead to the "molar tooth sign" on cranial MRI, which is pathognomonic for JSRD. Other variable JSRD features include cystic kidneys, nephronophthisis, retinal dystrophy, ocular coloboma, occipital encephalocele, polydactyly, ataxia, and hepatic fibrosis. For more information, see Parisi et al. 2017. PubMed ID: 20301500; Doherty 2009. PubMed ID: 19778711; Parisi et al. 2007. PubMed ID: 17377524; Brancati et al. 2010. PubMed ID: 20615230.

Meckel-Gruber Syndrome (MKS) is also marked by brain malformation, cystic renal disease and polydactyly (Alexiev et al. 2006. PubMed ID: 16879033; Hartill et al. 2017. PubMed ID: 29209597). In MKS, the pathognomonic feature is occipital encephalocele, which is generally identified during routine sonography between 12 and 20 weeks of gestation. MKS is a common cause of prenatal echogenic kidneys (Chaumoitre et al. 2006. PubMed ID: 17094077). Nearly all MKS infants are stillborn or die shortly after birth (Hartill et al. 2017. PubMed ID: 29209597; Parisi et al. 2017. PubMed ID: 20301500).

JSRD and MKS are genetically heterogeneous; JSRD is known to be caused by pathogenic variants in at least 33 different genes and MKS is caused by pathogenic variants in at least 22 different genes (Hartill et al. 2017. PubMed ID: 29209597; Parisi et al. 2017. PubMed ID: 20301500; Knopp et al. 2015. PubMed ID: 26003401; Shaheen et al. 2016. PubMed ID: 27894351). JSRD and MKS are inherited in an autosomal recessive manner with the exception of OFD1, which displays an X-linked dominant inheritance pattern. Most of the genes reported to cause MKS have also been found to cause JSRD. MKS and JSRD have been proposed to represent a single clinical entity, with a spectrum of overlapping symptoms and causative genes. In support of this, the same pathogenic variants have been found in siblings; one diagnosed with MKS and another with JSRD (Valente et al. 2010. PubMed ID: 20512146). Variants predicted to be more damaging, such as nonsense or frameshift variants, are reported in fetuses with MKS, while milder variants, such as missense variants, are typically found in patients with JSRD (Romani et al. 2014. PubMed ID: 24886560; Slaats et al. 2016. PubMed ID: 26490104; Mougou-Zerelli et al. 2009. PubMed ID: 19777577; Delous et al. 2007. PubMed ID: 17558409).

All genes reported to cause MKS and JSRD play some role in the structure, function and maintenance of the primary cilia and/or basal body organelle (Hildebrandt et al. 2009. PubMed ID: 19118152). More information about the molecular biology of the gene products along with spectra of pathogenic variants may be found in the individual gene test descriptions.

Clinical sensitivity for Joubert syndrome and related disorders is 62% - 94% (Parisi et al. 2017. PubMed ID: 20301500) and 50% - 77% for Meckel-Gruber syndrome (Knopp et al. 2015. PubMed ID: 26003401; Hartill et al. 2017. PubMed ID: 29209597).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.1% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).