The Invitae Hereditary Spastic Paraplegia X-linked Panel analyzes 5 genes that cause hereditary spastic paraplegia (HSP) that is inherited in an X-linked pattern. These genes cause primarily complicated forms of HSP, including X-linked intellectual disability – Claes-Jensen type, L1 syndrome, Pelizaeus-Merzbacher disease, MCT8-specific thyroid hormone cell transporter deficiency (also known as Allan-Herndon-Dudley syndrome), and adrenoleukodystrophy.
ABCD1 KDM5C L1CAM PLP1 SLC16A2
ABCD1 KDM5C L1CAM PLP1 SLC16A2
For a broader analysis, clinicians may consider the Invitae Hereditary Spastic Paraplegia Comprehensive panel. It includes genes with dominant, recessive, and X-linked inheritance and is particularly helpful if the inheritance is unclear. This broader panel can be ordered at no additional charge.
Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurological disorders that is subdivided into complicated (i.e. syndromic) and uncomplicated forms. All forms of HSP, complicated and uncomplicated, share the primary symptom of lower-extremity spastic weakness. Individuals with complicated HSP exhibit additional neurologic features such as intellectual disability, seizures, ataxia, peripheral neuropathy, deafness, cataracts, retinal degeneration, or muscle atrophy, depending on which gene is causative.
X-linked HSP cases are primarily complicated forms of HSP. ABCD1 is associated with adrenoleukodystrophy, which is characterized by symptoms of adrenocortical insufficiency and cerebral demyelination. Adrenoleukodystrophy has been reported to present as HSP in some cases and is included in the X-linked HSP panel due to this phenotypic overlap. Pathogenic variants in L1CAM cause L1 syndrome, which encompasses a range of phenotypes, including hydrocephalus with stenosis of aqueduct of Sylvius (HSAS), MASA syndrome (intellectual disability, aphasia, spastic paraplegia, adducted thumbs), spastic paraplegia with intellectual disability, and corpus callosum agenesis. Pathogenic variants in PLP1 also cause a spectrum of phenotypes, from Pelizaeus-Merzbacher disease (PMD), an early-onset syndrome that causes serious deficits in many aspects of the nervous system, to spastic paraplegia with onset in childhood to adulthood (SPG2). SLC16A2 is associated with MCT8-specific thyroid hormone cell transporter deficiency, also known as Allan-Herndon-Dudley syndrome, which is characterized by hypotonia, intellectual disability, and spasticity. KDM5C is associated with a syndromic form of intellectual disability, termed Claes-Jensen type, which includes spasticity and variable dysmorphic features.
|Gene||Subtype||Inheritance||Clinical form||Associated syndromes and other related disorders|
|Autosomal dominant||Autosomal recessive||X-linked||Uncomplicated||Complicated|
|KDM5C||MRXSCJ||✓||✓||X-linked intellectual disability, Claes-Jensen type|
|SLC16A2||SLC16A2||✓||✓||MCT8-specific thyroid hormone cell transporter deficiency (Allan-Herndon-Dudley syndrome)|
Due to the rarity of X-linked HSP, the detection rate for the genes included in this assay is currently unknown.
This test is specific for subtypes of HSP that are inherited in X-linked pattern.
The penetrance of HSP varies depending on the causative gene and the specific pathogenic variant. Pathogenic variants in ABCD1, KDM5C, L1CAM, PLP1, and SLC16A2 are highly penetrant, although these genes are associated with a range of phenotypes. The symptoms associated with these genes typically manifest in early childhood, with the exception of some cases of SPG2 and adrenoleukodystrophy, for which onset may occur in adulthood.
The disorders associated with ABCD1, KDM5C, L1CAM, PLP1, and SLC16A2 are rare. The prevalence of adrenoleukodystrophy is 1 in 20,000, for L1 syndrome it is approximately 1 in 30,000 and for PLP1-associated disorders it is between 1 in 200,000 and 1 in 500,000. AHDS and MRXSCJ are very rare, with a prevalence estimated at less than 1 in 1,000,000.
The clinical presentation of HSP can be variable. Genetic testing may confirm a suspected diagnosis or rule out disorders with similar symptoms. A genetic diagnosis may also help predict disease progression or inform family planning.
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|