Meckel-Gruber Syndrome / Joubert Syndrome via the TCTN2 Gene

Meckel-Gruber syndrome (MKS; OMIM 249000) is the most common form of syndromic neural tube defect. MKS is characterized by occipital encephalocele, polycystic kidneys, and postaxial polydactyly (Alexiev et al. Arch Pathol Lab Med 130:1236-1238, 2006). MKS is a common cause of prenatal echogenic kidneys (Chaumoitre et al. Ultrasound Obstet Gynecol 28:911-917, 2006). Nearly all MKS infants are stillborn or die shortly after birth. Joubert syndrome (JS; OMIM 213300) is marked by ataxia, hypotonia, abnormal eye movements, apraxia, neonatal respiratory anomalies, mental retardation, agenesis/hypoplasia of the cerebellar vermis, and a brain malformation known as the "molar tooth sign" (MTS) on cranial MRI. MTS is considered to be the most characteristic diagnostic feature. JS patients have substantial phenotypic variation. Some JS patients develop retinal dystrophy or progressive renal failure.

Both MKS and Joubert syndrome exhibit autosomal recessive inheritance. Both disorders have high levels of locus heterogeneity. Variants in the TCTN2 gene were reported to cause MKS8 and Joubert syndrome (Shaheen et al. Hum Mut 32:573, 2011; Sang et al. Cell 145:513, 2011). The TCTN2 gene encodes the tectonic 2 protein (TCTN2), which is predicted to interact with MKS1 protein and to regulate hedgehog-dependent neural tube patterning (Shaheen et al. 2011; Sang et al. 2011). Furthermore, Tctn2 null-mouse demonstrates that Tctn2 protein is required for ciliogenesis (Shaheen et al. 2011; Sang et al. 2011; Garcia-Gonzalo et al. Nat Genet 43:776, 2011). A mix of nonsense, splicing, and frameshift variants have been reported in the TCTN2 gene (Shaheen et al. 2011; Sang et al. 2011).

The prevalence of the TCTN2 variants is currently unknown.

This test provides full coverage of all coding exons of the TCTN2 gene 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 full 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).