Table 1.

Molecular Genetic Testing Used in Congenital Fiber-Type Disproportion

Gene 1Proportion of CFTD Attributed to Mutation of GeneMethodVariants Detected 2
ACTA1 <6%% 3Sequence analysis 4Sequence variants
UnknownDeletion/duplication analysis 5Unknown; none reported 6
SELENON (SEPN1)Rare 7Sequence analysis 4Sequence variants
UnknownDeletion/duplication analysis 5Unknown; none reported 6
TPM3 ~20%-40%Sequence analysis 4, 8Sequence variants
UnknownDeletion/duplication analysis 5Unknown; none reported 6
RYR1 10%-20% 9
Likely common		Sequence analysis 4, 10Sequence variants
Deletion/duplication analysis 5Unknown; none reported 6
TPM2 RareSequence analysis 4, 11Sequence variants
Deletion/duplication analysis 5Unknown; none reported 6
MYH7 Unknown 12Sequence analysis 4Sequence variants
UnknownDeletion/duplication analysis 5Unknown; none reported 6
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants.

3.

Heterozygous pathogenic missense variants were observed in 6% of individuals with CFTD in one series [Laing et al 2004] and have been reported in at least seven families [Laing et al 2009].

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6.

No large deletions or duplications that were causative of CFTD have been reported in ACTA1, RYR1, TPM2, or TPM3.

7.

SELENON homozygous pathogenic missense variants have been reported in two sisters with CFTD [Clarke et al 2006].

8.

TPM3 heterozygous pathogenic missense variants have been reported in more than ten families with CFTD, and homozygous pathogenic variants of the stop codon were reported in one family [Clarke et al 2008, Lawlor et al 2010, Munot et al 2010]. Clarke et al [2008] identified TPM3 alterations in four families from one CFTD cohort, representing approximately 20%-25% of their cases. Lawlor et al [2010] discovered TPM3 pathogenic variants in five of 13 families in another CFTD cohort, accounting for almost 40% of their cases.

9.

Clarke et al [2010] identified recessive RYR1 alterations in four of seven families with CFTD in whom ACTA1 and TPM3 pathogenic variants had been previously excluded, suggesting that RYR1 pathogenic variants are one of the two most common causes of CFTD, along with TPM3 alterations. They estimated that RYR1 alterations are responsible for 10%-20% of cases of CFTD.

10.

RYR1 compound heterozygous pathogenic missense, nonsense, and/or splice site variants were identified in four families (5 affected individuals) with CFTD in one study [Clarke et al 2010].

11.

A TPM2 heterozygous pathogenic missense variant was reported in a small number of families with CFTD [Brandis et al 2008, Clarke et al 2012].

12.

Heterozygous MYH7 pathogenic variants have been reported in at least three families (4 affected individuals) with CFTD. All of the families had other affected family members with muscle biopsies that contained additional morphologic features that did not fit the CFTD criteria [Muelas et al 2010, Ortolano et al 2011].

From: Congenital Fiber-Type Disproportion – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY

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