Submission Details

The relationship between TPM2 and autosomal dominant TPM2-Related Myopathy was evaluated using the ClinGen Clinical Validity Framework as of 10/08/20. Variants in TPM2 were first reported in humans with Nemaline Myopathy as early as 2002 (Donner et al., PMID: 11738357), with other histologically distinct cases being reported soon after. At least 10 unique variants (e.g. missense, in-frame indel, duplication) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 12 probands in 5 publications (PMIDs: 11738357, 17434307, 23378224, 19047562, 17846275). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Although there is not a significant genotype-phenotype correlation, the mechanism for disease is variable depending on the type of mutation and the resulting calcium sensitivity. Some variants can interfere with actin-myosin interactions, while others can affect calcium sensitivity in two distinct ways. One type of variant leads to a heterozygous loss of function, with tropomyosin not responding to calcium stimulation and causing a hypocontractile phenotype generally characterized by congenital muscle weakness and hypotonia. Another, less common, type of variant leads to a heteroygous gain of function with tropomyosin increasing the response to calcium stimulation and causing a hypercontractile phenotype generally characterized by congenital muscle stiffness and later-onset weakness/hypotonia. This gene-disease association is supported by several pieces of experimental evidence including the relationship between TPM2's function and the resulting phenotypes of nemaline myopathy, the association with ACTA1, the primary expression of TPM2 in the skeletal muscle, and expression of mutant variants in human myoblast cells, mouse myoblast cells, and zebrafish with the resulting phenotypes reflecting those in humans. In summary, TPM2 is definitively associated with autosomal dominant TPM2-Related Myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Myopathy Working Group on 12/23/20 (SOP Version 7).

Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no likely difference in the inheritance patterns underlying the disease entities: (1) Arthrogryposis, distal, type 1A (MIM: 108120); (2) Arthrogryposis, distal, type 2B4 (MIM:108120); (3) CAP myopathy 2 (MIM:609285); and (4) Nemaline myopathy 4, autosomal dominant (MIM:609285). There are distinct molecular mechanisms that can vary by mutation, however without a clear genotype-phenotype correlation this evidence is not enough to classify these entities differently. There is no clear correlation outside of a shared variant between (3) and (4) (Martilla, 2014 PMID: 24692096; Li, 2018 PMID: 30285720). Recent evidence has shown that TPM2 is likely expressed and is integral during prenatal development, which may cause the phenotypes displayed in the distal arthrogryposis. The phenotypes are markedly different, with (1) and (2) displaying a set of deformities that are rarely seen in (3) and (4) such as overlapping fingers and absent flexion creases while displaying few of the muscular phenotypes such as muscle weakness, gait difficulty, or cap structures. The two types of arthrogryposis have also been separately reviewed and recommended to consider them phenotypic extremes of the same disorder (Beck, 2013 PMID: 23401156). Therefore, we have lumped the myopathies together and the two types of arthrogryposis together, but split these two resulting groups apart. Of note, there are three other entities that were asserted after the lumping and splitting process: (5) Arthrogryposis, distal, type 7 (MIM: 158300); (6) Myopathy, congenital, with fiber-type disproportion (MIM: 255310); and (7) Multiple Pterygium Syndrome, Escobar Variant (MIM: 265000). Of these, (5)/(7) should be lumped with (1)/(2) and (6) should be lumped with (3)/(4) based on L&S criteria. All of these later assertions have minimal published evidence, so it is possible this should be revisited once more evidence is available.