Identification of a novel LFNG variant in a Chinese fetus with spondylocostal dysostosis and a systematic review.

Journal

Journal of human genetics
ISSN: 1435-232X
Titre abrégé: J Hum Genet
Pays: England
ID NLM: 9808008

Informations de publication

Date de publication:
02 Apr 2024
Historique:
received: 28 02 2024
accepted: 22 03 2024
revised: 21 03 2024
medline: 3 4 2024
pubmed: 3 4 2024
entrez: 2 4 2024
Statut: aheadofprint

Résumé

Spondylocostal dysostosis (SCDO) encompasses a group of skeletal disorders characterized by multiple segmentation defects in the vertebrae and ribs. SCDO has a complex genetic etiology. This study aimed to analyze and identify pathogenic variants in a fetus with SCDO. Copy number variant sequencing and whole exome sequencing were performed on a Chinese fetus with SCDO, followed by bioinformatics analyses, in vitro functional assays and a systematic review on the reported SCDO cases with LFNG pathogenic variants. Ultrasound examinations in utero exhibited that the fetus had vertebral malformation, scoliosis and tethered cord, but rib malformation was not evident. We found a novel homozygous variant (c.1078 C > T, p.R360C) within the last exon of LFNG. The variant was predicted to cause loss of function of LFNG by in silico prediction tools, which was confirmed by an in vitro assay of LFNG enzyme activity. The systematic review listed a total of 20 variants of LFNG in SCDO. The mutational spectrum spans across all exons of LFNG except the last one. This study reported the first Chinese case of LFNG-related SCDO, revealing the prenatal phenotypes and expanding the mutational spectrum of the disorder.

Identifiants

DOI: 10.1038/s10038-024-01248-3 PMID: 38565611
pubmed: 38565611
doi: 10.1038/s10038-024-01248-3
pii: 10.1038/s10038-024-01248-3
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 82201865

Informations de copyright

© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.

Références

Solomon L, Jimenez RB, Reiner L. Spondylothoracic dysostosis: report of two cases and review of the literature. Arch Pathol Lab Med. 1978;102:201–5.
pubmed: 350188
Gucev ZS, Tasic V, Pop-Jordanova N, Sparrow DB, Dunwoodie SL, Ellard S, et al. Autosomal dominant spondylocostal dysostosis in three generations of a Macedonian family: negative mutation analysis of DLL3, MESP2, HES7, and LFNG. Am J Med Genet A. 2010;152A:1378–82. https://doi.org/10.1002/ajmg.a.33471
doi: 10.1002/ajmg.a.33471 pubmed: 20503311
Whittock NV, Sparrow DB, Wouters MA, Sillence D, Ellard S, Dunwoodie SL, et al. Mutated MESP2 causes spondylocostal dysostosis in humans. Am J Hum Genet. 2004. https://doi.org/10.1086/421053
doi: 10.1086/421053 pubmed: 15122512 pmcid: 1182088
Sparrow DB, Chapman G, Wouters MA, Whittock NV, Ellard S, Fatkin D, et al. Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. Am J Hum Genet. 2006;78:28–37. https://doi.org/10.1086/498879
doi: 10.1086/498879 pubmed: 16385447
Sparrow DB, Guillen-Navarro E, Fatkin D, Dunwoodie SL. Mutation of Hairy-and-Enhancer-of-Split-7 in humans causes spondylocostal dysostosis. Hum Mol Genet. 2008;17:3761–6. https://doi.org/10.1093/hmg/ddn272
doi: 10.1093/hmg/ddn272 pubmed: 18775957
Umair M, Younus M, Shafiq S, Nayab A, Alfadhel M. Clinical genetics of spondylocostal dysostosis: a mini review. Front Genet. 2022;13:996364. https://doi.org/10.3389/fgene.2022.996364
doi: 10.3389/fgene.2022.996364 pubmed: 36506336 pmcid: 9732429
Wu N, Ming X, Xiao J, Wu Z, Chen X, Shinawi M, et al. TBX6 null variants and a common hypomorphic allele in congenital scoliosis. N Engl J Med. 2015;372:341–50. https://doi.org/10.1056/NEJMoa1406829
doi: 10.1056/NEJMoa1406829 pubmed: 25564734 pmcid: 4326244
McInerney-Leo AM, Sparrow DB, Harris JE, Gardiner BB, Marshall MS, O’Reilly VC, et al. Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects. Hum Mol Genet. 2015;24:1234–42. https://doi.org/10.1093/hmg/ddu534
doi: 10.1093/hmg/ddu534 pubmed: 25343988
Bulman MP, Kusumi K, Frayling TM, McKeown C, Garrett C, Lander ES, et al. Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat Genet. 2000;24:438–41. https://doi.org/10.1038/74307
doi: 10.1038/74307 pubmed: 10742114
Turnpenny PD, Whittock N, Duncan J, Dunwoodie S, Kusumi K, Ellard S. Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis. J Med Genet. 2003;40:333–9. https://doi.org/10.1136/jmg.40.5.333
doi: 10.1136/jmg.40.5.333 pubmed: 12746394 pmcid: 1735475
Zhang S, Qiao Y, Wang Z, Zhuang J, Sun Y, Shang X, et al. Identification of novel compound heterozygous variants in SLC19A2 and the genotype-phenotype associations in thiamine-responsive megaloblastic anemia. Clin Chim Acta. 2021;516:157–68. https://doi.org/10.1016/j.cca.2021.01.025
doi: 10.1016/j.cca.2021.01.025 pubmed: 33571483
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9. https://doi.org/10.1038/nmeth0410-248
doi: 10.1038/nmeth0410-248 pubmed: 20354512 pmcid: 2855889
Schwarz JM, Rodelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods. 2010;7:575–6. https://doi.org/10.1038/nmeth0810-575
doi: 10.1038/nmeth0810-575 pubmed: 20676075
Shangguan H, Su C, Ouyang Q, Cao B, Wang J, Gong C, et al. Kabuki syndrome: novel pathogenic variants, new phenotypes and review of literature. Orphanet J Rare Dis. 2019;14:255. https://doi.org/10.1186/s13023-019-1219-x
doi: 10.1186/s13023-019-1219-x pubmed: 31727177 pmcid: 6854618
Rodrigues CH, Pires DE, Ascher DB. DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability. Nucleic Acids Res. 2018;46:W350–5. https://doi.org/10.1093/nar/gky300
doi: 10.1093/nar/gky300 pubmed: 29718330 pmcid: 6031064
Mirdita M, Schütze K, Moriwaki Y, Heo L, Ovchinnikov S, Steinegger M. ColabFold: making protein folding accessible to all. Nat Methods. 2022;19:679–82. https://doi.org/10.1038/s41592-022-01488-1
doi: 10.1038/s41592-022-01488-1 pubmed: 35637307 pmcid: 9184281
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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. Genet Med Off J Am Coll Med Genet. 2015;17:405–24. https://doi.org/10.1038/gim.2015.30
doi: 10.1038/gim.2015.30
Rampal R, Li AS, Moloney DJ, Georgiou SA, Luther KB, Nita-Lazar A, et al. Lunatic fringe, manic fringe, and radical fringe recognize similar specificity determinants in O-fucosylated epidermal growth factor-like repeats. J Biol Chem. 2005;280:42454–63. https://doi.org/10.1074/jbc.M509552200
doi: 10.1074/jbc.M509552200 pubmed: 16221665
Otomo N, Mizumoto S, Lu HF, Takeda K, Campos-Xavier B, Mittaz-Crettol L, et al. Identification of novel LFNG mutations in spondylocostal dysostosis. J Hum Genet. 2019;64:261–4. https://doi.org/10.1038/s10038-018-0548-2
doi: 10.1038/s10038-018-0548-2 pubmed: 30531807
Okubo Y, Sugawara T, Abe-Koduka N, Kanno J, Kimura A, Saga Y. Lfng regulates the synchronized oscillation of the mouse segmentation clock via trans-repression of Notch signalling. Nat Commun. 2012;3:1141. https://doi.org/10.1038/ncomms2133
doi: 10.1038/ncomms2133 pubmed: 23072809
Bochter MS, Servello D, Kakuda S, D’Amico R, Ebetino MF, Haltiwanger RS, et al. Lfng and Dll3 cooperate to modulate protein interactions in cis and coordinate oscillatory Notch pathway activation in the segmentation clock. Dev Biol. 2022;487:42–56. https://doi.org/10.1016/j.ydbio.2022.04.004
doi: 10.1016/j.ydbio.2022.04.004 pubmed: 35429490 pmcid: 9923780
Matsumoto K, Kumar V, Varshney S, Nairn AV, Ito A, Pennarubia F, et al. Fringe GlcNAc-transferases differentially extend O-fucose on endogenous NOTCH1 in mouse activated T cells. J Biol Chem. 2022;298:102064. https://doi.org/10.1016/j.jbc.2022.102064
doi: 10.1016/j.jbc.2022.102064 pubmed: 35623385 pmcid: 9234238
Xu K, Nieuwenhuis E, Cohen BL, Wang W, Egan SE. Lunatic fringe-mediated Notch signaling is required for lung alveogenesis. Am J Physiol Lung Cell Mol Physiol. 2010;298:L45–56. https://doi.org/10.1152/ajplung.90550.2008
doi: 10.1152/ajplung.90550.2008 pubmed: 19897741

Auteurs

Lin Wang (L)

Center of Medical Genetics, Northwest Women's and Children's Hospital, The Affiliated Northwest Women's and Children's Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Shuji Mizumoto (S)

Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Nagoya, 468-8503, Japan.
ORCID: 0000-0002-4641-1505

Ruixue Zhang (R)

Center of Medical Genetics, Northwest Women's and Children's Hospital, The Affiliated Northwest Women's and Children's Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Yuqi Zhang (Y)

Center of Medical Genetics, Northwest Women's and Children's Hospital, The Affiliated Northwest Women's and Children's Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Yuan Liu (Y)

Center of Medical Genetics, Northwest Women's and Children's Hospital, The Affiliated Northwest Women's and Children's Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Wenjing Cheng (W)

Center of Medical Genetics, Northwest Women's and Children's Hospital, The Affiliated Northwest Women's and Children's Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Xin Li (X)

Center of Medical Genetics, Northwest Women's and Children's Hospital, The Affiliated Northwest Women's and Children's Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Min Dan (M)

Department of Ultrasound, Northwest Women's and Children's Hospital, Xi'an, 710061, China.

Chunyan Zhang (C)

Department of Ultrasound, Northwest Women's and Children's Hospital, Xi'an, 710061, China.

Xinru Gao (X)

Department of Ultrasound, Northwest Women's and Children's Hospital, Xi'an, 710061, China.

Juan Wang (J)

Department of Ultrasound, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, 710004, China.

Jiaqi Han (J)

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Lianying Jiao (L)

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Yating Wang (Y)

Center of Medical Genetics, Northwest Women's and Children's Hospital, The Affiliated Northwest Women's and Children's Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Qiujie Jin (Q)

Center of Medical Genetics, Northwest Women's and Children's Hospital, The Affiliated Northwest Women's and Children's Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Lihui Yang (L)

Center of Medical Genetics, Northwest Women's and Children's Hospital, The Affiliated Northwest Women's and Children's Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Chenxing Li (C)

Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Shuxian Li (S)

Center of Medical Genetics, Northwest Women's and Children's Hospital, The Affiliated Northwest Women's and Children's Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Jinhui Zhu (J)

Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Hai Jiang (H)

Department of Pediatric Orthopedics, Northwest Women's and Children's Hospital, Xi'an, 710061, China.

Gen Nishimura (G)

Department of Radiology, Musashino-Yowakai Hospital, Tokyo, 180-0012, Japan.

Takahiro Yamada (T)

Department of Medical Ethics and Medical Genetics, Kyoto University School of Public Health, Kyoto, 606-8501, Japan.
ORCID: 0000-0002-5370-7873

Shuhei Yamada (S)

Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Nagoya, 468-8503, Japan.

Na Cai (N)

Center of Medical Genetics, Northwest Women's and Children's Hospital, The Affiliated Northwest Women's and Children's Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.

Rong Qiang (R)

Center of Medical Genetics, Northwest Women's and Children's Hospital, The Affiliated Northwest Women's and Children's Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China. qiangrongshx@163.com.

Long Guo (L)

Center of Medical Genetics, Northwest Women's and Children's Hospital, The Affiliated Northwest Women's and Children's Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China. longguo601@gmail.com.
Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China. longguo601@gmail.com.
ORCID: 0000-0002-9660-6941

Classifications MeSH