一例产前Silver-Russell综合征胎儿的基因变异分析

doi:10.12280/gjszjk.20230094

摘要/Abstract

摘要：

目的： 对1例产前B超提示骨骼系统发育异常，疑似宫内生长受限的胎儿进行基因检测及生物信息学分析以明确其致病原因。方法： 采集胎儿羊水及父母外周血，提取基因组DNA，利用高通量测序平台进行家系全外显子组测序（whole exome sequencing，WES）及拷贝数变异测序（copy number variation sequencing，CNV-seq）技术检测，可疑结果经Sanger测序进行验证。结果： 胎儿高迁移率族蛋白A2（high mobility group protein AT-Hook-2，HMGA2）基因存在c.223C>T(p.R75W)新发变异，导致氨基酸改变为p.R75W(p.Arg75Trp)，为错义突变。根据美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics，ACMG）指南评级，该变异判定为可能致病性（likely pathogenic）：PS2+PM2_Supporting+PP3+PS4_Supporting。根据其临床表型，该胎儿被确诊为常染色体显性遗传的Silver-Russell综合征5型（Silver-Russell syndrome 5，SRS5）。Sanger测序确证了其变异的真实性。结论： HMGA2基因的c.223C>T(p.R75W)杂合致病性变异可能是SRS5的遗传学致病原因，扩充了该基因的变异谱，同时为该胎儿的产前遗传咨询和后续的干预措施提供了理论依据。

关键词: Silver-Russell综合征, 高迁移率族蛋白质类, 全外显子组测序, DNA拷贝数变异, 胎儿生长迟缓

Abstract:

Objective: A fetus was suggested the developmental abnormity of skeletal system and suspected growth restriction by prenatal B-ultrasound. To clarify the cause of the disease, genetic detection and bioinformatics analysis were conducted. Methods: gDNAs were extracted from the amniotic fluid of proband and the peripheral blood of his parents, respectively. Whole exome sequencing (WES) and copy number variation sequencing (CNV-seq) technique of trio via high-throughput sequencing platforms, and Sanger sequencing were used to verify the likely pathogenic variant. Results: A denovo mutation of c.223C>T(p.R75W) in the fetal high mobility group protein AT-Hook-2(HMGA2) gene was found. It is a missense mutation, resulting in the change of amino acid to p.R75W (p.Arg75Trp). According to American College of Medical Genetics and Genomics (ACMG), the variant was assessed to be a likely pathogenic variant: PS2+PM2_Supporting+PP3+PS4_Supporting. Based on the clinical phenotype, the fetus was diagnosed with an autosomal dominant Silver-Russell syndrome 5 (SRS5). Sanger sequencing confirmed the authenticity of the mutation. Conclusions: The c.223C>T(p.R75W) of HMGA2 gene may be the genetic cause of the heterozygous pathogenic variation, which expands the variant profile of this gene and provides a theoretical basis for prenatal genetic counseling and subsequent interventions in the fetus.

Key words: Silver-Russell syndrome, High mobility group proteins, Whole exome sequencing, DNA copy number variations, Fetal growth retardation

杨玉婷, 惠玲, 陈雪, 张钏, 田芯瑗, 周秉博. 一例产前Silver-Russell综合征胎儿的基因变异分析[J]. 国际生殖健康/计划生育杂志, 2023, 42(5): 371-376.

YANG Yu-ting, HUI Ling, CHEN Xue, ZHANG Chuan, TIAN Xin-yuan, ZHOU Bing-bo. Genetic Variation Analysis of A Prenatal Fetus with Silver-Russell Syndrome[J]. Journal of International Reproductive Health/Family Planning, 2023, 42(5): 371-376.

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参考文献 25

[1]	Silver HK, Kiyasu W, George J, et al. Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins[J]. Pediatrics, 1953, 12(4):368-376. pmid: 13099907
[2]	Russell A. A syndrome of intra-uterine dwarfism recognizable at birth with cranio-facial dysostosis, disproportionately short arms, and other anomalies (5 examples)[J]. Proc R Soc Med, 1954, 47(12):1040-1044. pmid: 13237189
[3]	Alhendi A, Lim D, McKee S, et al. Whole-genome analysis as a diagnostic tool for patients referred for diagnosis of Silver-Russell syndrome: a real-world study[J]. J Med Genet, 2022, 59(6):613-622. doi: 10.1136/jmedgenet-2021-107699. doi: 10.1136/jmedgenet-2021-107699 URL
[4]	刘娟, 王媛, 董超, 等. Silver-Russell综合征1例[J/OL]. 中国临床案例成果数据库, 2022, 4(1):E07195. doi: 10.3760/cma.j.cmcr.2022.e07195. doi: 10.3760/cma.j.cmcr.2022.e07195
[5]	Ligon AH, Moore SD, Parisi MA, et al. Constitutional rearrangement of the architectural factor HMGA2: a novel human phenotype including overgrowth and lipomas[J]. Am J Hum Genet, 2005, 76(2):340-348. doi: 10.1086/427565. doi: 10.1086/427565 pmid: 15593017
[6]	Price SM, Stanhope R, Garrett C, et al. The spectrum of Silver-Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria[J]. J Med Genet, 1999, 36(11):837-842. pmid: 10544228
[7]	Wakeling EL, Brioude F, Lokulo-Sodipe O, et al. Diagnosis and management of Silver-Russell syndrome: first international consensus statement[J]. Nat Rev Endocrinol, 2017, 13(2):105-124. doi: 10.1038/nrendo.2016.138. doi: 10.1038/nrendo.2016.138 pmid: 27585961
[8]	Bruce S, Hannula-Jouppi K, Peltonen J, et al. Clinically distinct epigenetic subgroups in Silver-Russell syndrome: the degree of H19 hypomethylation associates with phenotype severity and genital and skeletal anomalies[J]. J Clin Endocrinol Metab, 2009, 94(2):579-587. doi: 10.1210/jc.2008-1805. doi: 10.1210/jc.2008-1805 URL
[9]	Vishnopolska SA, Mercogliano MF, Camilletti MA, et al. Comprehensive Identification of Pathogenic Gene Variants in Patients With Neuroendocrine Disorders[J]. J Clin Endocrinol Metab, 2021, 106(7):1956-1976. doi: 10.1210/clinem/dgab177. doi: 10.1210/clinem/dgab177 pmid: 33729509
[10]	Plachy L, Strakova V, Elblova L, et al. High Prevalence of Growth Plate Gene Variants in Children With Familial Short Stature Treated With GH[J]. J Clin Endocrinol Metab, 2019, 104(10):4273-4281. doi: 10.1210/jc.2018-02288. doi: 10.1210/jc.2018-02288 pmid: 30753492
[11]	Inoue T, Nakamura A, Iwahashi-Odano M, et al. Contribution of gene mutations to Silver-Russell syndrome phenotype: multigene sequencing analysis in 92 etiology-unknown patients[J]. Clin Epigenetics, 2020, 12(1):86. doi: 10.1186/s13148-020-00865-x. doi: 10.1186/s13148-020-00865-x pmid: 32546215
[12]	Bartholdi D, Krajewska-Walasek M, Ounap K, et al. Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS-like phenotypes[J]. J Med Genet, 2009, 46(3):192-197. doi: 10.1136/jmg.2008.061820. doi: 10.1136/jmg.2008.061820 pmid: 19066168
[13]	Monk D, Wakeling EL, Proud V, et al. Duplication of 7p11.2-p13, including GRB10, in Silver-Russell syndrome[J]. Am J Hum Genet, 2000, 66(1):36-46. doi: 10.1086/302717. doi: 10.1086/302717 pmid: 10631135
[14]	Yamoto K, Saitsu H, Nakagawa N, et al. De novo IGF2 mutation on the paternal allele in a patient with Silver-Russell syndrome and ectrodactyly[J]. Hum Mutat, 2017, 38(8):953-958. doi: 10.1002/humu.23253. doi: 10.1002/humu.23253 pmid: 28489339
[15]	Abi Habib W, Brioude F, Edouard T, et al. Genetic disruption of the oncogenic HMGA2-PLAG1-IGF2 pathway causes fetal growth restriction[J]. Genet Med, 2018, 20(2):250-258. doi: 10.1038/gim.2017.105. doi: 10.1038/gim.2017.105 pmid: 28796236
[16]	Stampone E, Caldarelli I, Zullo A, et al. Genetic and Epigenetic Control of CDKN1C Expression: Importance in Cell Commitment and Differentiation, Tissue Homeostasis and Human Diseases[J]. Int J Mol Sci, 2018, 19(4):1055. doi: 10.3390/ijms19041055. doi: 10.3390/ijms19041055 URL
[17]	高龙, 王萍, 吕玲, 等. HMGA2基因变异致身材矮小一例[J]. 中华医学遗传学杂志, 2022, 39(9):1051. doi: 10.3760/cma.j.cn51137420210823-00688. doi: 10.3760/cma.j.cn51137420210823-00688
[18]	Stagi S, Lapi E, Pantaleo M, et al. A new case of de novo 6q24.2-q25.2 deletion on paternal chromosome 6 with growth hormone deficiency: a twelve-year follow-up and literature review[J]. BMC Med Genet, 2015, 16:69. doi: 10.1186/s12881-015-0212-z. doi: 10.1186/s12881-015-0212-z pmid: 26297663
[19]	郭子显, 霍竞, 全宇璐, 等. Silver-Russell综合征致病基因的研究进展[J]. 中国优生与遗传杂志, 2022, 30(12):2287-2292. doi:10.13404/j.cnki.cjbhh.2022.12.033. doi: 10.13404/j.cnki.cjbhh.2022.12.033
[20]	Gorbenko del Blanco D, de Graaff LC, Posthouwer D, et al. Isolated GH deficiency: mutation screening and copy number analysis of HMGA2 and CDK6 genes[J]. Eur J Endocrinol, 2011, 165(4):537-544. doi: 10.1530/EJE-11-0478. doi: 10.1530/EJE-11-0478 pmid: 21803798
[21]	De Crescenzo A, Citro V, Freschi A, et al. A splicing mutation of the HMGA2 gene is associated with Silver-Russell syndrome phenotype[J]. J Hum Genet, 2015, 60(6):287-293. doi: 10.1038/jhg.2015.29. doi: 10.1038/jhg.2015.29 pmid: 25809938
[22]	Costain G, Jobling R, Walker S, et al. Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing[J]. Eur J Hum Genet, 2018, 26(5):740-744. doi: 10.1038/s41431-018-0114-6. doi: 10.1038/s41431-018-0114-6 pmid: 29453418
[23]	Leszinski GS, Warncke K, Hoefele J, et al. A case report and review of the literature indicate that HMGA2 should be added as a disease gene for Silver-Russell syndrome[J]. Gene, 2018, 663:110-114. doi: 10.1016/j.gene.2018.04.027. doi: S0378-1119(18)30395-0 pmid: 29655892
[24]	Hübner CT, Meyer R, Kenawy A, et al. HMGA2 Variants in Silver-Russell Syndrome: Homozygous and Heterozygous Occurrence[J]. J Clin Endocrinol Metab, 2020, 105(7):dgaa273. doi: 10.1210/clinem/dgaa273. doi: 10.1210/clinem/dgaa273
[25]	Spiteri BS, Stafrace Y, Calleja-Agius J. Silver-Russell Syndrome: A Review[J]. Neonatal Netw, 2017, 36(4):206-212. doi: 10.1891/0730-0832.36.4.206. doi: 10.1891/0730-0832.36.4.206 pmid: 28764823

病例	转录本	变异信息	疾病	临床表型	作者	发表时间
1	NM_003483	c.250-29_250-10delAAA ATATATCTTTTTCTTTT	生长激素缺乏症	成比例的身材矮小、生长迟缓、骨成熟延迟、躯干肥胖、高音调和青春期延迟	Gorbenko del Blanco等^[20]	2011年
2	NM_003483	c.283-6_283delTTCCAGG	SRS	婴儿期生长迟缓，身材矮小，造骨症和智力低下	De Crescenzo等^[21]	2015年
3	NM_003483	c.189delA	SRS	三角脸、前额突出、喂养困难、相对巨头畸形、身体不对称	Abi Habib等^[15]	2018年
4	NM_003483	c.193C>T	SRS	体质量减轻、身材矮小、前额突出、相对巨头畸形	Abi Habib等^[15]	2018年
5	NM_003483	c.303delC	-	小于胎龄儿、身材矮小、学习困难	Costain等^[22]	2018年
6	NM_003483	c.1644_198+2797del7258	SRS	小于胎龄儿、生长迟缓、体质量轻、身材矮小、头围稍大	Leszinski等^[23]	2018年
7	NM_003483	c.239C>T	SRS	小于胎龄儿、产后生长迟缓、前额突出、喂养困难	Hübner等^[24]	2020年
8	NM_003483	c.111+1G>T	SRS	小于胎龄儿、产后生长迟缓、前额突出、喂养困难	Hübner等^[24]	2020年

病例	转录本	变异信息	疾病	临床表型	作者	发表时间
1	NM_003483	c.250-29_250-10delAAA ATATATCTTTTTCTTTT	生长激素缺乏症	成比例的身材矮小、生长迟缓、骨成熟延迟、躯干肥胖、高音调和青春期延迟	Gorbenko del Blanco等^[20]	2011年
2	NM_003483	c.283-6_283delTTCCAGG	SRS	婴儿期生长迟缓，身材矮小，造骨症和智力低下	De Crescenzo等^[21]	2015年
3	NM_003483	c.189delA	SRS	三角脸、前额突出、喂养困难、相对巨头畸形、身体不对称	Abi Habib等^[15]	2018年
4	NM_003483	c.193C>T	SRS	体质量减轻、身材矮小、前额突出、相对巨头畸形	Abi Habib等^[15]	2018年
5	NM_003483	c.303delC	-	小于胎龄儿、身材矮小、学习困难	Costain等^[22]	2018年
6	NM_003483	c.1644_198+2797del7258	SRS	小于胎龄儿、生长迟缓、体质量轻、身材矮小、头围稍大	Leszinski等^[23]	2018年
7	NM_003483	c.239C>T	SRS	小于胎龄儿、产后生长迟缓、前额突出、喂养困难	Hübner等^[24]	2020年
8	NM_003483	c.111+1G>T	SRS	小于胎龄儿、产后生长迟缓、前额突出、喂养困难	Hübner等^[24]	2020年