Nephronophthisis and Situs Inversus via the ANKS6 Gene

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 (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 (OMIM 249000), Joubert syndrome (OMIM 213300), Bardet-Biedl syndrome (OMIM 209900), and Senior-Loken syndrome (OMIM# 609294). Situs inversus is a laterality defect where the visceral and thoracic organs are reversed from their normal positions (Sutherland and Ware 2009).

NPH is a genetically heterogeneous disorder caused by mutations in at least 14 genes, including ANKS6 (Hoff et al. 2013; Taskiran et al. 2014). ANKS6-related NPH is inherited in an autosomal recessive manner. NPH is caused by mutations in genes encoding proteins involved in cilia/centrosome structure, maintenance or function (Hildebrandt et al. 2009). ANKS6 is required to localize NPHP3/NEK8 complex to the axoneme (Hoff et al. 2013). Individuals with biallelic pathogenic variants in ANKS6 are reported to have had polycystic kidney disease (PKD). Individuals with missense variants had PKD with normal sized kidneys, while those with splicing or truncating variants had PKD with enlarged kidneys and liver fibrosis, congenital heart defects and situs inversus (Hoff et al. 2013; Taskiran et al. 2014).

Clinical sensitivity is problematic to predict due to genetic heterogeneity of these disorders and the paucity of documented cases. Analytical sensitivity may be high because all ANKS6 mutations reported to date are expected to be detected by direct sequencing of genomic DNA.

This test provides full coverage of all coding exons of the ANKS6 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).