Digenic inheritance in patients with undiagnosed myopathies
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Abstract
Advances in genetic sequencing have allowed a specific gene-based diagnosis in many patients with a suspected genetic myopathy. However, a significant minority of patients remain in whom the specific diagnosis remains elusive. In addition to the classic forms of Mendelian inheritance including autosomal recessive, autosomal dominant and X-linked, another mechanism of genetic transmission is digenic inheritance. This occurs when there is an interaction of two genes resulting in a given phenotype. In this study, we report three patients with myopathy hypothesized to follow a digenic pattern of inheritance. All of the patients had progressive weakness due to a myopathic disorder and underwent genetic analysis of a panel of genes established to cause inherited myopathies. Variants were observed in multiple genes in this panel. The data was further analyzed by review of published reports of the variants, public databases to determine the frequency and subjected to protein modeling to assess their possible pathogenic significance. One patient had variants in the CAPN3 (c.1553A>G; pGln518Arg) and SYNE2 (c.7664C>T; p.Thr2555Met) genes that our analysis indicates are the likely cause of her myopathy. Following a similar protocol, a second patient carries genes with two variants that are in cis in the TTN gene (c.85582G>A; p.Val28528Ile and c.103292C>T; p.Thr34431Met). There is another variant in the SYNE2 gene (c.18632C>T;p.Thr6211Met) and the combination of both likely result in her myopathy. In the last patient, a previously described mutation in the COL6A2 gene, c.1970-3 C>A in intron 25 was identified. This can result in limb girdle muscular dystrophy phenotype observed in this patient. In addition, a new variant was detected in the SGCG gene, c.643 G>T, p.Ala215Ser and its role as a modifier of disease phenotype is discussed. Our study suggests that digenic inheritance should be considered in patients with suspected undiagnosed myopathies in whom next generation sequencing fails to establish a diagnosis.
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References
2. Shieh PB. Muscular dystrophies and other genetic myopathies. Neurol Clin. 2013 Nov;31(4): 1009-29. doi: 10.1016/j.ncl.2013.04.004.
3. Ten Dam L, de Visser M, Ginjaar IB, van Duyvenvoorde HA, van Koningsbruggen S, van der Kooi AJ. Elucidation of the Genetic Cause in Dutch Limb Girdle Muscular Dystrophy Families: A 27-Year's Journey. J Neuromuscul Dis. 2021;8(2):261-272. doi: 10.3233/JND-200585.
4. Harris E, Topf A, Barresi R, et al. Exome sequences versus sequential gene testing in the UK highly specialised Service for Limb Girdle Muscular Dystrophy. Orphanet J Rare Dis. 2017 Sep 6;12(1):151. doi: 10.1186/s13023-017-0699-9.
5. Haskell GT, Adams MC, Fan Z, et al. Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders. Neurol Genet. 2018 Feb 1;4(1):e212. doi: 10.1212/NXG.0000000000000212.
6. Bugiardini E, Khan AM, Phadke R, et al. Genetic and phenotypic characterisation of inherited myopathies in a tertiary neuromuscular centre. Neuromuscul Disord. 2019 Oct;29(10):747-757. doi: 10.1016/j.nmd.2019.08.003
7. Nallamilli BRR, Chakravorty S, Kesari A, et al. Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. Ann Clin Transl Neurol. 2018 Dec 1;5(12):1574-1587. doi: 10.1002/acn3.649.
8. Chakravorty S, Nallamilli BRR, Khadilkar SV, et al. Clinical and Genomic Evaluation of 207 Genetic Myopathies in the Indian Subcontinent. Front Neurol. 2020 Nov 5;11:559327. doi: 10.3389/fneur .2020.559327.
9. Töpf A, Johnson K, Bates A, et al. Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness. Genet Med. 2020 Sep;22(9):1478-1488. doi: 10.1038/s41436-020-0840-3.
10. Schäffer AA. Digenic inheritance in medical genetics. J Med Genet. 2013 Oct;50(10):641-52. doi: 10.1136/jmedgenet-2013-101713.
11. Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020 May;58 1(7809):434-443. doi: 10.1038/s41586-020-2308-7.
12. Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res. 2001 May; 11(5):863-74. doi: 10.1101/gr.176601.
13. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting damaging missense mutations. Nat Methods. 2010 Apr;7(4):248-9. doi: 10.1038/nmeth0410-248.
14. Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014 Apr;11 (4):361-2. doi: 10.1038/nmeth.2890.
15. Szklarczyk D, Kirsch R, Koutrouli M, et al.The STRING database in 2023: protein–protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023 Jan 6;51(D1): D638-646.
16. Westra D, Schouten MI, Stunnenberg BC, et al. Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service. J Neuromuscul Dis. 2019;6(2):241-258. doi: 10.3233/JND-180376. PMID: 31127727.
17. Peddareddygari LR, Oberoi K, Grewal RP. Limb Girdle Muscular Dystrophy due to Digenic Inheritance of DES and CAPN3 Mutations. Case Rep Neurol. 2018 Sep 18;10(3):272-278. doi: 10. 1159/000492664.
18. Lampe AK, Bushby KM. Collagen VI related muscle disorders. J Med Genet. 2005 Sep;42 (9):673-85. doi: 10.1136/jmg.2002.002311.
19. Tagliavini F, Sardone F, Squarzoni S, Maraldi NM, Merlini L, Faldini C, Sabatelli P. Ultrastructural changes in muscle cells of patients with collagen VI-related myopathies. Muscles Ligaments Tendons J. 2014 Feb 24;3(4):281-6.