Journal of Shandong University (Health Sciences) ›› 2024, Vol. 62 ›› Issue (4): 85-91.doi: 10.6040/j.issn.1671-7554.0.2024.0059

• Clinical Medicine • Previous Articles    

Genetic analysis of two Chinese pedigrees with 3-M syndrome caused by CUL7 compound heterozygous variants

PENG Haiying1,2,3, LIU Ailing1,2,3, JI Xiangmei1,2,3, WANG Yanyan1,2,3, HE Yinlong1,2,3, GAO Chunhai1,2,3, MA Yuhua1,2,3, LI lin1,2,3   

  1. 1. Department of Laboratory Medicine, Linyi Peoples Hospital, Linyi 276000, Shandong, China;
    2. Key Laboratory for Laboratory Medicine of Linyi City, Linyi 276000, Shandong, China;
    3. Shandong Provincial Medicine and Health Key Laboratory for Precise Diagnosis of Hereditary Rare Diseases, Linyi Peoples Hospital, Linyi 276000, Shandong, China
  • Published:2024-05-16

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Abstract: Objective To explore the clinical features and genetic etiology of two Chinese pedigrees affected with 3-M(Miller-Mukusick-Malvaux)syndrome. Methods Two Chinese pedigrees with 3-M syndrome admitted to Linyi Peoples Hospital in September 2022 and June 2023 were selected as the research objects. Clinical data of the family members was collected, and the peripheral blood was selected for whole exome sequencing(WES)after informed consent. Candidate variants were verified by Sanger sequencing and pathogenicity assessment was conducted. Prenatal diagnosis was performed for high-risk fetuses in two pedigrees. Results The proband of pedigree 1 was 18-weeks pregnant with short stature, abnormal face and congenital dislocation of the hip at birth. WES detected compound heterozygous variants of CUL7 gene: c.4333C>T(p.R1445*), c.3291_3294del(p.H1098Cfs*42), inherited from the father and mother, respectively. The younger brother of the proband carried the same variants. According to the American Society for Medical Genetics and Genomics(ACMG)guidelines, both c.4333C>T and c.3291_3294del were judged to be pathogenic variants. The fetus carried the c.4333C>T variant. The proband from pedigree 2 showed short height, special face, scoliosis, pterygous scapular bone, bilateral oblique finger, short fifth finger, etc. The proband was found to harbor c.3823del(p.R1275Vfs*34)and c.758del(p.L253Rfs*2)compound heterozygous variants of CUL7 gene, which inherited from mother and father, respectively. And they were judged to be pathogenic variants and suspected pathogenic variants. Maternal prenatal diagnosis indicated that the fetus carried the c.758 del variant. Conclusion In this study, three patients with 3-M syndrome were diagnosed in two pedigrees. Two compound heterozygous variants of CUL7 gene were probably the genetic causes of pedigree 1 and pedigree 2, respectively. Above findings expanded the variation spectrum of CUL7 gene in 3-M syndrome and provided a basis for genetic counseling and prenatal diagnosis.

Key words: 3-M syndrome, Whole exome sequencing, CUL7 gene, Compound heterozygous variants

CLC Number: 

  • R574
[1] Miller JD, McKusick VA, Malvaux P, et al. The 3-M syndrome: a heritable low birthweight dwarfifism[J]. Birth Defects Orig Artic Ser, 1975, 11(5): 39-47.
[2] 张亚男, 皮亚雷, 阎雪, 等. 3M综合征家系报道及临床分析[J]. 河北医科大学学报, 2016, 37(4): 464-466.
[3] 刘晓英, 汪希珂, 周浩, 等. 3M 综合征 1 例报告并文献复习[J]. 临床儿科杂志, 2017, 35(12): 906-908. LIU Xiaoying, WANG Xike, ZHOU Hao, et al. 3M syndrome: a case report and literature review[J]. J Clin Pediatr, 2017, 35(12): 906-908.
[4] 张晓,邓巍,张婧. 3M综合征2型新基因突变位点1例及文献复习[J].武汉大学学报(医学版), 2019, 40(3): 449-452. ZHANG Xiao, DENG Wei, ZHANG Jing. 3M syndrome type 2: a novel mutation in OBSLI in a patient and literature review[J]. Medical Journal of Wuhan University, 2019, 40(3): 449-452.
[5] Hu L, Wang XK, Jin TT, et al. Identification of two CUL7 variants in two Chinese families with 3-M syndrome by whole-exome sequencing[J]. J Clin Lab Anal, 2020, 34(7): e23265. doi:10.1002/jcla.23265.
[6] 黄燕茹, 梅利斌, 张剑, 等. 一例3-M综合征患者的临床及分子遗传学分析[J]. 中华医学遗传学杂志, 2021, 38(12): 1237-1240. HUANG Yanru, MEI Libin, ZHANG Jian, et al. Clinical and molecular genetic analysis of a patient with 3-M sundrome[J]. Chinese Journal of Medical Genetics, 2021, 38(12): 1237-1240.
[7] 庄娇容,蔡少华,林茂增,等. 3M综合征并生长激素治疗一例[J]. 新医学, 2021, 52(4): 293-295. ZHUANG Jiaorong, CAI Shaohua, LIN Maozeng, et al. A case of 3-M syndrome treated with growth hormone therapy[J]. New Medicine, 2021, 52(4): 293-295.
[8] Huber C, Dias-Santagata D, Glaser A, et al. Identification of mutations in CUL7 in 3-M syndrome[J]. Nat Genet, 2005, 37(10): 1119-1124.
[9] Hanson D, Murray PG, Sud A, et al. The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1[J]. Am J Haim Genet, 2009, 84(6): 801-806.
[10] Hanson D, Murray PG, O Sullivan J, et al. Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth [J]. Am J Hum Genet, 2011, 89(1): 148-153.
[11] Huber C, Munnich A, Cormier-Daire V. The 3M syndrome[J]. Best Pract Res Clin Endocrinol Metab, 2011, 25(1): 143-151.
[12] Hanson D, Murray PG,Coulson T, et al. Mutation in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling[J]. J Mol Endocrinol, 2012, 49(3): 267-275.
[13] 王秋菊, 沈亦平, 邬玲仟, 等. 遗传变异分类标准与指南[J]. 中国科学:生命科学, 2017, 47(6): 668-688. WANG Qiuju, SHEN Yiping, WU Lingqian, et al. Standards and guidelines for the interpretation of sequence variants [J]. Scientia Sinica(Vitae), 2017, 47(6): 668-688.
[14] Simsek-Kiper PO, Taskiran E, Kosukcu C, et al. Further expanding the mutational spectrum and investigation of genotype-phenotype correlation in 3M syndrome[J]. Am J Med Genet A, 2019, 179(7): 1157-1172.
[15] Huber C, Delezoide AL, Guimiot F, et al.A large-scale mutation search reveals genetic heterogeneity in 3M syndrome[J]. Eur J Hum Genet, 2009, 17(3): 395-400.
[16] Meazza C, Lausch E, Pagani S, et al. 3-M syndrome associated with growth hormone deffciency: 18-year follow-up of a patient[J]. Ital J Pediatr, 2013, 39: 21. doi:10.1186/1824-7288-39-21.
[17] Yan J, Yan F, Li Z, et al. The 3M complex maintains microtubule and genome integrity[J]. Mol Cell, 2014, 54(5): 791-804.
[18] Hanson D, Murray PG, Black GC, et al. The genetics of 3-M syndrome: unravelling a potential new regulatory growth pathway[J]. Horm Res Paediatr, 2011, 76(6): 369-378.
[19] Holder-Espinasse M, Irving M, Cormier-Daire V. Clinical utility gene card for: 3-M syndrome - update 2013[J]. Eur J Hum Genet, 2014, 22(4): 572-572.
[20] Akawi NA, Ali BR, Hamamy H, et al. Is autosomal recessive Silver-Russel syndrome a separate entity or is it part of the 3-M syndrome spectrum [J]. Am J Med Genet A, 2011, 155A(6): 1236-1245.
[21] Maksimova N, Hara K, Miyashia A, et al. Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia[J]. J Med Genet, 2007, 44(12): 772-778.
[22] Dias DC, Dolios G, Wang R, et al. CUL7: A DOC domain-containing cullin selectively binds Skp1.Fbx29 to form an SCF-like complex[J]. Proc Natl Acad Sci, 2002, 99(26): 16601-16606.
[23] Petroski MD, Deshaies RJ. Function and regulation of cullin-RING ubiquitin ligases[J]. Nat Rev Mol Cell Biol, 2005, 6(1): 9-20.
[24] Huber C, Dias-Santagata D, Glaser A, et al. Identification of mutations in CUL7 in 3-M syndrome[J]. Nat Genet, 2005, 37(10): 1119-1124.
[25] Al-Dosari MS, Al-Shammari M, Shaheen R, et al. 3M syndrome: an easily recognizable yet underdiagnosed cause of proportionate short stature[J]. J Pediatr, 2012, 161(1): 139-145.
[26] Takizaki N, Tsurusaki Y, Katsumata K, et al. Novel CUL7 biallelic mutations alter the skeletal phenotype of 3M syndrome[J].Hum Genome Var, 2020, 7: 1.doi: 10.1038/s41439-020-0090-6.
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