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Epigenotype, Genotype, and Phenotype Analysis of Taiwanese Patients with Silver–Russell Syndrome

Background: Silver–Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder characterized by severe intrauterine growth retardation, poor postnatal growth, characteristic facial features, and body asymmetry. Hypomethylation of the imprinted genes of the chromosome 11p15.5 imprin...

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Autores principales: Lin, Hsiang-Yu, Lee, Chung-Lin, Fran, Sisca, Tu, Ru-Yi, Chang, Ya-Hui, Niu, Dau-Ming, Chang, Chia-Ying, Chiu, Pao-Chin, Chou, Yen-Yin, Hsiao, Hui-Pin, Tsai, Meng-Che, Chao, Mei-Chyn, Tsai, Li-Ping, Yang, Chia-Feng, Su, Pen-Hua, Pan, Yu-Wen, Lee, Chen-Hao, Chu, Tzu-Hung, Chuang, Chih-Kuang, Lin, Shuan-Pei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624617/
https://www.ncbi.nlm.nih.gov/pubmed/34834549
http://dx.doi.org/10.3390/jpm11111197
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author Lin, Hsiang-Yu
Lee, Chung-Lin
Fran, Sisca
Tu, Ru-Yi
Chang, Ya-Hui
Niu, Dau-Ming
Chang, Chia-Ying
Chiu, Pao-Chin
Chou, Yen-Yin
Hsiao, Hui-Pin
Tsai, Meng-Che
Chao, Mei-Chyn
Tsai, Li-Ping
Yang, Chia-Feng
Su, Pen-Hua
Pan, Yu-Wen
Lee, Chen-Hao
Chu, Tzu-Hung
Chuang, Chih-Kuang
Lin, Shuan-Pei
author_facet Lin, Hsiang-Yu
Lee, Chung-Lin
Fran, Sisca
Tu, Ru-Yi
Chang, Ya-Hui
Niu, Dau-Ming
Chang, Chia-Ying
Chiu, Pao-Chin
Chou, Yen-Yin
Hsiao, Hui-Pin
Tsai, Meng-Che
Chao, Mei-Chyn
Tsai, Li-Ping
Yang, Chia-Feng
Su, Pen-Hua
Pan, Yu-Wen
Lee, Chen-Hao
Chu, Tzu-Hung
Chuang, Chih-Kuang
Lin, Shuan-Pei
author_sort Lin, Hsiang-Yu
collection PubMed
description Background: Silver–Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder characterized by severe intrauterine growth retardation, poor postnatal growth, characteristic facial features, and body asymmetry. Hypomethylation of the imprinted genes of the chromosome 11p15.5 imprinting gene cluster and maternal uniparental disomy of chromosome 7 (mUPD7) are the major epigenetic disturbances. The aim of this study was to characterize the epigenotype, genotype, and phenotype of these patients in Taiwan. Methods: Two hundred and six subjects with clinically suspected SRS were referred for diagnostic testing, which was performed by profiling the methylation of H19-associated imprinting center (IC) 1 and the imprinted PEG1/MEST region using methylation-specific multiplex ligation-dependent probe amplification and high-resolution melting analysis with a methylation-specific polymerase chain reaction assay. We also applied a whole genome strategy to detect copy number changes and loss of heterozygosity. Clinical manifestations were recorded and analyzed according to the SRS scoring system proposed by Bartholdi et al. Results: Among the 206 referred subjects, 100 were classified as having a clinical diagnosis of SRS (score ≥ 8, maximum = 15) and 106 had an SRS score ≤ 7. Molecular lesions were detected in 45% (45/100) of the subjects with a clinical diagnosis of SRS, compared to 5% (5/106) of those with an SRS score ≤ 7. Thirty-seven subjects had IC1 hypomethylation, ten subjects had mUPD7, and three subjects had microdeletions. Several clinical features were found to be statistically different (p < 0.05) between the “IC1 hypomethylation” and “mUPD7” groups, including relative macrocephaly at birth (89% vs. 50%), triangular shaped face (89% vs. 50%), clinodactyly of the fifth finger (68% vs. 20%), and SRS score (11.4 ± 2.2 vs. 8.3 ± 2.5). Conclusions: The SRS score was positively correlated with the molecular diagnosis rate (p < 0.001). The SRS subjects with mUPD7 seemed to have fewer typical features and lower SRS scores than those with IC1 hypomethylation. Careful clinical observation and timely molecular confirmation are important to allow for an early diagnosis and multidisciplinary management of these patients.
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spelling pubmed-86246172021-11-27 Epigenotype, Genotype, and Phenotype Analysis of Taiwanese Patients with Silver–Russell Syndrome Lin, Hsiang-Yu Lee, Chung-Lin Fran, Sisca Tu, Ru-Yi Chang, Ya-Hui Niu, Dau-Ming Chang, Chia-Ying Chiu, Pao-Chin Chou, Yen-Yin Hsiao, Hui-Pin Tsai, Meng-Che Chao, Mei-Chyn Tsai, Li-Ping Yang, Chia-Feng Su, Pen-Hua Pan, Yu-Wen Lee, Chen-Hao Chu, Tzu-Hung Chuang, Chih-Kuang Lin, Shuan-Pei J Pers Med Article Background: Silver–Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder characterized by severe intrauterine growth retardation, poor postnatal growth, characteristic facial features, and body asymmetry. Hypomethylation of the imprinted genes of the chromosome 11p15.5 imprinting gene cluster and maternal uniparental disomy of chromosome 7 (mUPD7) are the major epigenetic disturbances. The aim of this study was to characterize the epigenotype, genotype, and phenotype of these patients in Taiwan. Methods: Two hundred and six subjects with clinically suspected SRS were referred for diagnostic testing, which was performed by profiling the methylation of H19-associated imprinting center (IC) 1 and the imprinted PEG1/MEST region using methylation-specific multiplex ligation-dependent probe amplification and high-resolution melting analysis with a methylation-specific polymerase chain reaction assay. We also applied a whole genome strategy to detect copy number changes and loss of heterozygosity. Clinical manifestations were recorded and analyzed according to the SRS scoring system proposed by Bartholdi et al. Results: Among the 206 referred subjects, 100 were classified as having a clinical diagnosis of SRS (score ≥ 8, maximum = 15) and 106 had an SRS score ≤ 7. Molecular lesions were detected in 45% (45/100) of the subjects with a clinical diagnosis of SRS, compared to 5% (5/106) of those with an SRS score ≤ 7. Thirty-seven subjects had IC1 hypomethylation, ten subjects had mUPD7, and three subjects had microdeletions. Several clinical features were found to be statistically different (p < 0.05) between the “IC1 hypomethylation” and “mUPD7” groups, including relative macrocephaly at birth (89% vs. 50%), triangular shaped face (89% vs. 50%), clinodactyly of the fifth finger (68% vs. 20%), and SRS score (11.4 ± 2.2 vs. 8.3 ± 2.5). Conclusions: The SRS score was positively correlated with the molecular diagnosis rate (p < 0.001). The SRS subjects with mUPD7 seemed to have fewer typical features and lower SRS scores than those with IC1 hypomethylation. Careful clinical observation and timely molecular confirmation are important to allow for an early diagnosis and multidisciplinary management of these patients. MDPI 2021-11-13 /pmc/articles/PMC8624617/ /pubmed/34834549 http://dx.doi.org/10.3390/jpm11111197 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lin, Hsiang-Yu
Lee, Chung-Lin
Fran, Sisca
Tu, Ru-Yi
Chang, Ya-Hui
Niu, Dau-Ming
Chang, Chia-Ying
Chiu, Pao-Chin
Chou, Yen-Yin
Hsiao, Hui-Pin
Tsai, Meng-Che
Chao, Mei-Chyn
Tsai, Li-Ping
Yang, Chia-Feng
Su, Pen-Hua
Pan, Yu-Wen
Lee, Chen-Hao
Chu, Tzu-Hung
Chuang, Chih-Kuang
Lin, Shuan-Pei
Epigenotype, Genotype, and Phenotype Analysis of Taiwanese Patients with Silver–Russell Syndrome
title Epigenotype, Genotype, and Phenotype Analysis of Taiwanese Patients with Silver–Russell Syndrome
title_full Epigenotype, Genotype, and Phenotype Analysis of Taiwanese Patients with Silver–Russell Syndrome
title_fullStr Epigenotype, Genotype, and Phenotype Analysis of Taiwanese Patients with Silver–Russell Syndrome
title_full_unstemmed Epigenotype, Genotype, and Phenotype Analysis of Taiwanese Patients with Silver–Russell Syndrome
title_short Epigenotype, Genotype, and Phenotype Analysis of Taiwanese Patients with Silver–Russell Syndrome
title_sort epigenotype, genotype, and phenotype analysis of taiwanese patients with silver–russell syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624617/
https://www.ncbi.nlm.nih.gov/pubmed/34834549
http://dx.doi.org/10.3390/jpm11111197
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