The Invitae Coffin-Lowry Syndrome Test analyzes RPS6KA3 (also known as RSK2), a gene associated with Coffin-Lowry syndrome (CLS), an X-linked developmental disorder characterized by severe to profound intellectual disability and developmental delay in males. Heterozygous carrier females can be as severely affected as males, show mild intellectual impairment, or have no clinical phenotype.
Genetic testing of this gene may confirm a diagnosis and help guide treatment and management. Identification of a disease-causing variant can inform recurrence-risk assessment and genetic counseling.
Coffin-Lowry syndrome is an X-linked congenital disorder characterized in males by significant learning disability, distinctive dysmorphic features, progressive kyphoscoliosis and short, soft, fleshy hands with tapering, hyperextensible fingers. Other features include stimulus-induced drop attacks (SIDAs), cardiac abnormalities, short stature, microcephaly and hearing loss. There is a risk of premature death, primarily due to cardiac or respiratory complications. The presentation of this condition is variable and mutations of the RPS6KA3 gene can cause nonspecific intellectual disability without other characteristic features of Coffin-Lowry syndrome. The degree of intellectual disability and other features of Coffin-Lowry syndrome is generally milder in affected females, although it can be as severe as in males in some cases.
Approximately 25-40% of patients with a strong clinical suspicion of Coffin-Lowry syndrome have pathogenic sequence variants in RPS6KA3.
Coffin-Lowry syndrome is inherited in an X-linked manner. Most cases occur de novo.
Pathogenic variants in RPS6KA3 in males demonstrate complete penetrance with variable expressivity. Female carriers may be affected or unaffected; however, the observed phenotype in heterozygous carrier females is generally less severe than affected males.
An exact prevalence of Coffin-Lowry syndrome is not yet known but has been estimated to be 1:40,000 to 1:50,000.
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|