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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|