Clinical characteristic and genetic test analysis of 2 neonates with congenital distal arthrogryposis caused by MYH3 mutation

doi:10.3969/j.issn.1673-8640.2023.02.005

Abstract

Abstract:

Objective To analyze the clinical characteristics and genetic test analysis results of 2 neonates with distal arthrogryposis （DA），and to improve the understanding of DA. Methods The clinical data of 2 neonates with DA were analyzed retrospectively，and the trio-whole-exome sequencing （Trio-WES） of the 2 neonates and their parents were sequenced. Bioinformatics prediction analysis and Sanger sequencing verification were carried out for the suspicious mutations found，and the spatial structure of mutation protein was constructed to analyze its biological hazard. Results The 2 neonates with DA showed severe hand foot joint contracture. The results of Trio-WES indicated that MYH3 mutation occurred in the 2 neonates. Case 1 was c.1106A>G（ p. Gln369Arg），and Case 2 was c.3059C>A（p. Ser1020Tyr），and the parents of 2 neonates were wild-type. The c.1106A>G（ p.Gln369Arg），which was not included in dbSNP，ExAC，1000 Genomes and gnomeAD databases. The c.3059C>A（ p.Ser1020Tyr） was only distributed in the gnomeAD database with a frequency of 0.0001. It had not been reported in HGMD database and Pubmed database. Both c.1106A>G（ p.Gln369Arg） and c.3059C>A（p.Ser1020Tyr） were rated as possibly pathogenic according to the guidelines of American College of Medical Genetics and Genomics （ACMG）. Both of the 2 mutations may lead to a decrease in the stability of protein local structure and affect the function of protein. Conclusions The 2 neonates with DA caused by MYH3 mutation show the characteristics of joint contracture. Two mutations of MYH3 have been found，which expand the variation spectrum of MYH3 and DA phenotype spectrum of Chinese population.

Key words: MYH3, Trio-whole-exome sequencing, Distal arthrogryposis

CLC Number:

R446.1

CHENG Huanhuan, ZHAO Yuwei. Clinical characteristic and genetic test analysis of 2 neonates with congenital distal arthrogryposis caused by MYH3 mutation[J]. Laboratory Medicine, 2023, 38(2): 124-129.

Figures/Tables 4

References 16

[1]	CHONG J X, BURRAGE L C, BECK A E, et al. Autosomal-dominant multiple pterygium syndrome is caused by mutations in MYH3[J]. Am J Hum Genet, 2015, 96(5):841-849. DOI PMID
[2]	WHITTLE J, JOHNSON A, DOBBS M B, et al. Models of distal arthrogryposis and lethal congenital contracture syndrome[J]. Genes (Basel), 2021, 12(6):943. DOI URL
[3]	SCHIAFFINO S, ROSSI A C, SMERDU V, et al. Developmental myosins:expression patterns and functional significance[J]. Skelet Muscle, 2015, 5:22. DOI URL
[4]	CAMERON-CHRISTIE S R, WELLS C F, SIMON M, et al. Recessive spondylocarpotarsal synostosis syndrome due to compound heterozygosity for variants in MYH3[J]. Am J Hum Genet, 2018, 102(6):1115-1125. DOI URL
[5]	TOYDEMIR R M, RUTHERFORD A, WHITBY F G, et al. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome[J]. Nat Genet, 2006, 38(5):561-565. DOI PMID
[6]	POLING M I, MORALES CORADO J A, CHAMBERLAIN R L. Findings,phenotypes,and outcomes in Freeman-Sheldon and Sheldon-Hall syndromes and distal arthrogryposis types 1 and 3:protocol for systematic review and patient-level data meta-analysis[J]. Syst Rev, 2017, 6(1):46. DOI URL
[7]	HAKONEN A H, LEHTONEN J, KIVIRIKKO S, et al. Recessive MYH3 variants cause "Contractures,pterygia,and variable skeletal fusions syndrome 1B" mimicking Escobar variant multiple pterygium syndrome[J]. Am J Med Genet A, 2020, 182(11):2605-2610. DOI URL
[8]	RICHARDS S, AZIZ N, BALE S, et al. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5):405-424.
[9]	BAMSHAD M, JORDE L B, CAREY J C. A revised and extended classification of the distal arthrogryposes[J]. Am J Med Genet, 1996, 65(4):277-281. DOI URL
[10]	STEVENSON D A, CAREY J C, PALUMBOS J, et al. Clinical characteristics and natural history of Freeman-Sheldon syndrome[J]. Pediatrics, 2006, 117(3):754-762. PMID
[11]	ZHAO S, ZHANG Y, HALLGRIMSDOTTIR S, et al. Expanding the mutation and phenotype spectrum of MYH3-associated skeletal disorders[J]. NPJ Genom Med, 2022, 7(1):11. DOI PMID
[12]	TAJSHARGHI H, OLDFORS A. Myosinopathies:pathology and mechanisms[J]. Acta Neuropathol, 2013, 125(1):3-18. DOI URL
[13]	TAJSHARGHI H, KIMBER E, KROKSMARK A K, et al. Embryonic myosin heavy-chain mutations cause distal arthrogryposis and developmental myosin myopathy that persists postnatally[J]. Arch Neurol, 2008, 65(8):1083-1090.
[14]	FITTS R H. The cross-bridge cycle and skeletal muscle fatigue[J]. J Appl Physiol (1985), 2008, 104(2):551-558. DOI URL
[15]	BOEHM S, LIMPAPHAYOM N, ALAEE F, et al. Early results of the Ponseti method for the treatment of clubfoot in distal arthrogryposis[J]. J Bone Joint Surg Am, 2008, 90(7):1501-1507. DOI PMID
[16]	WHITTLE J, ANTUNES L, HARRIS M, et al. MYH3-associated distal arthrogryposis zebrafish model is normalized with para-aminoblebbistatin[J]. EMBO Mol Med, 2020, 12(11):e12356.