Nephronophthisis and Senior-Loken Syndrome via the IQCB1/NPHP5 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. Nat Genet 17:149-153, 1997; Hildebrandt et al. J Am Soc Nephrol 20:23-35, 2009). Nephronophthisis type 5 (NPH5) (OMIM# 609254) is a form of juvenile nephronophthisis with Leber congenital amaurosis known as Senior-Loken syndrome (Otto et al. Nat Genet 37:282-288, 2005; Hildebrandt et al. 2009).

NPH5 is inherited in an autosomal recessive manner. Variants in the IQCB1/NPHP5 gene cause NPH5 (Otto et al. Nat Genet 37:282-288, 2005). IQCB1 encodes a protein called nephrocystin-5, which is localized to the connecting cilia of the photoreceptor in the retina and to the primary cilia in renal cells. Nephrocystin-5 contains an IQ domain, which directly interacts with calmodulin. It is found in a complex with retinitis pigmentosa GTPase regulator (RPGR) protein, responsible for X-linked retinitis pigmentosa, and also interacts with nephrocystin-6 (product of the CEP290 gene), suggesting that nephrocystin-5 has a role in photoreceptor homeostasis (Otto et al. 2005; Schafer et al. Hum Mol Genet 17:3655-3662, 2008; Hildebrandt et al. J Am Soc Nephrol 20:23-35, 2009). A mix of nonsense, frameshift, and splicing variants has been reported in IQCB1/NPHP5 (Otto et al. 2005; Otto et al. Hum Mut 29:418-426, 2008). Nephronophthisis exhibits locus heterogeneity. Nine NPH genes have been identified (NPHP1, INVS/NPHP2, NPHP3, NPHP4, IQCB1/NPHP5, CEP260/NPHP6, GLIS2/NPHP7, RPGRIP1L/NPHP8, and NEK8/NPHP9) (Hildebrandt et al. 2009).

Variants in IQCB1/NPHP5 gene are estimated to cause approximately ~3% of NPH cases (Hildebrandt et al. J Am Soc Nephrol 20:23-35, 2009). It has been predicted that variant in the IQCB1 gene are the most frequent cause of Senior-Loken syndrome (Otto et al. Nat Genet 37:282-8, 2005).

This test provides full coverage of all coding exons of the IQCB1 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).