The Invitae Congenital Fiber-Type Disproportion Panel analyzes seven genes associated with congenital fiber-type disproportion (CFTD), a form of congenital myopathy. These genes were curated based on the available evidence to date to provide a comprehensive test for this condition.
Individuals with clinical signs and symptoms of CFTD may benefit from diagnostic genetic testing to confirm the diagnosis, provide anticipatory guidance, and inform recurrence risk.
ACTA1 LMNA MYH7 RYR1 SELENON TPM2 TPM3
ACTA1 LMNA MYH7 RYR1 SELENON TPM2 TPM3
For a broader analysis of genes associated with myopathies, clinicians may consider the Invitae Congenital Myopathy Panel, or the Invitae Comprehensive Myopathy Panel. These broader panels can be ordered at no additional charge.
Congenital fiber-type disproportion (CFTD) is a form of congenital myopathy that typically presents at birth or in the first year of life with hypotonia and mild-to-severe proximal or generalized muscle weakness. Most affected individuals have static, generalized muscle weakness that may improve over time; however, some affected individuals may have slowly progressive muscle weakness. Delayed motor development is common, but the majority of affected individuals are able to achieve independent ambulation. Other findings that may be observed in individuals with CFTD include respiratory issues, feeding difficulties, ophthalmoplegia, contractures, and spinal deformities. Cognitive impairment, cardiac issues, and cryptorchidism are rare features of CFTD. Initially, the core histologic finding associated with CFTD was defined as hypotrophic type 1 muscle fibers that are at least 12% smaller than type 2A or 2B muscle fiber diameters; more recent studies have suggested that the degree of disproportion between type 1 and type 2 fiber size is typically at least 40% in individuals with true CFTD.
In addition to CFTD, these seven genes have been associated with a diverse range of other neuromuscular disorders, with variable clinical and histopathologic findings.
|Gene||Proportion of CFTD cases||Inheritance||Other associated neuromuscular conditions|
|Autosomal dominant||Autosomal recessive|
|ACTA1||<6%||✓||Nemaline myopathy 3|
|LMNA||Rare||✓||Dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy type 2, limb girdle muscular dystrophy type 1B|
|MYH7||Unknown||✓||Congenital muscular dystrophy, dilated cardiomyopathy, hypertrophic cardiomyopathy, Laing distal myopathy, left ventricular noncompaction, myosin storage myopathy|
|RYR1||10%–20%||✓||Central core disease, multiminicore disease, centronuclear myopathy|
|SELENON (formerly known as SEPN1)||Rare||✓||Multiminicore disease|
|TPM2||Rare||✓||Nemaline myopathy 4|
|TPM3||20%–40%||✓||✓||Nemaline myopathy 1|
The TPM3 and RYR1 genes are the most common known causes of CFTD; together, they account for up to 60% of affected individuals. ACTA1 accounts for less than 6% of affected individuals. The LMNA, MYH7, SELENON and TPM3 genes have only been associated with CFTD in a small number of families, and the percentage of affected individuals with CFTD who have variants in these genes is currently unknown.
CFTD is inherited in either an autosomal dominant or an autosomal recessive pattern. CFTD associated with the ACTA1, LMNA, MYH7 and TPM2 genes is inherited in an autosomal dominant pattern. CFTD associated with RYR1 and SELENON is inherited in an autosomal recessive pattern. TPM3-associated CFTD can be inherited in either an autosomal dominant or an autosomal recessive pattern. ACTA1- and TPM3-associated CFTD is commonly associated with de novo variants.
Incomplete penetrance has been observed in some of the autosomal dominant forms of CFTD.
CFTD is a rare condition whose prevalence is unknown.
Fiber-type disproportion is not pathognomonic for CFTD and can be observed in other neuromuscular disorders. Genetic testing may be useful in confirming a suspected diagnosis of CFTD or ruling out other disorders with similar findings. A genetic diagnosis may also help predict disease progression and inform recurrence risk.
For management guidelines please refer to:
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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
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|
SEPN1: SELENON: Analysis includes the NM_20451.2:c.*1107T>C variant in the 3' UTR.