The Invitae Senior-Loken Syndrome Panel analyzes eight genes that are associated with Senior-Loken syndrome (SLSN), which is characterized by a combination of childhood retinal and renal disease. These genes were selected based on the available evidence to date to provide Invitae’s broadest test for SLSN.
Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant can inform recurrence-risk assessment and genetic counseling.
CEP290 INVS IQCB1 NPHP1 NPHP3 NPHP4 SDCCAG8 WDR19
CEP290 INVS IQCB1 NPHP1 NPHP3 NPHP4 SDCCAG8 WDR19
Senior-Loken syndrome is a member of a class of disorders called ciliopathies. Ciliopathies share many overlapping symptoms, often making it difficult to distinguish between them based on clinical presentation alone. Depending on the individual’s clinical and family history, the broader Invitae Ciliopathies Panel may be appropriate. It can be ordered at no additional cost.
Senior-Loken syndrome (SLSN) is a rare pediatric oculorenal disease characterized by the association of nephronophthisis (NPHP) and retinal dystrophy. It is often considered to be a Joubert syndrome related disease (JSRD) because many individuals originally diagnosed with SLSN were found to have additional clinical features that were reminiscent of JSRD, including molar tooth sign and developmental delay.
SLSN usually presents within the first two decades of life. Retinal lesions are variable, ranging from severe Leber congenital amaurosis (LCA), which can cause blindness in early infancy, to later onset retinitis pigmentosa (RP). Other ocular symptoms can include cataract, Coat’s disease, and keratoconus. Renal disease often manifests as a medullary cystic kidney disease known as nephronophthisis, whose symptoms are identical to those of isolated NPHP—polyuria, polydipsia, and impaired ability to concentrate urine. Onset of renal disease can be insidious, with a severe progression to end stage renal disease by 13 years of age. Occasionally, neurologic features that are typical of classic Joubert syndrome are present, including molar tooth sign, ataxia, hypotonia, developmental delay, nystagmus, and abnormal breathing patterns.
The precise clinical sensitivity of this panel test is unknown due to the rarity of SLSN, but it is expected to exceed 30% for individuals with both nephronopthisis and retinal dystrophy.
SLSN is inherited in an autosomal recessive manner.
There is phenotypic variability in the onset and severity of the retinal disease. End stage renal disease appears to be fully penetrant.
The prevalence of SLSN worldwide is estimated at 1 in 1,000,000 worldwide, but prevalence of the Joubert syndrome and related disorders (JSRD) has been estimated at 1 in 80,000 to 1 in 100,000. This may be an underestimate; the figures will continue to evolve as the genetic etiology of JSRD is elucidated.
Testing for SLSN should be considered in any individual presenting with visual impairment and renal failure within the first two decades of life. Additionally, any infant presenting with Leber congenital amaurosis should be tested for SLSN in order to rule out the risk of childhood renal failure.
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|
CEP290: Analysis includes the intronic variant NM_025114.3:c.2991+1655A>G.