Clinical Application of Sequential Epigenetic Analysis for Diagnosis of Silver–Russell Syndrome
10.3343/alm.2021.41.4.401
- Author:
Soo Yeon KIM
1
;
Chang Ho SHIN
;
Young Ah LEE
;
Choong Ho SHIN
;
Sei Won YANG
;
Tae-Joon CHO
;
Jung Min KO
Author Information
1. Pediatric Clinical Neuroscience Center, Department of Pediatrics, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul, Korea
- Publication Type:Original Article
- From:Annals of Laboratory Medicine
2021;41(4):401-408
- CountryRepublic of Korea
- Language:English
-
Abstract:
Background:Silver-Russell syndrome (SRS) is a pre- or post-natal growth retardation disorder caused by (epi)genetic alterations. We evaluated the molecular basis and clinical value of sequential epigenetic analysis in pediatric patients with SRS.
Methods:Twenty-eight patients who met ≥ 3 Netchine-Harbison clinical scoring system (NH-CSS) criteria for SRS were enrolled;26 (92.9%) were born small for gestational age, and 25 (89.3%) showed postnatal growth failure. Relative macrocephaly, body asymmetry, and feeding difficulty were noted in 18 (64.3%), 13 (46.4%), and 9 (32.1%) patients, respectively. Methylation-specific multiplex ligation-dependent probe amplification (MSMLPA) on chromosome 11p15 was performed as the first diagnostic step. Subsequently, bisulfite pyrosequencing (BP) for imprinting center 1 and 2 (IC1 and IC2) at chromosome 11p15, MEST on chromosome 7q32.2, and MEG3 on chromosome 14q32.2 was performed.
Results:. Seventeen (60.7%) patients exhibited methylation defects, including loss of IC1 methylation (N = 14; 11 detected by MS-MLPA and three detected by BP) and maternal uniparental disomy 7 (N = 3). The diagnostic yield was comparable between patients who met three or four of the NH-CSS criteria (53.8% vs 50.0%). Patients with methylation defects responded better to growth hormone treatment.
Conclusions:NH-CSS is a powerful tool for SRS screening. However, in practice, genetic analysis should be considered even in patients with a low NH-CSS score. BP analysis detected additional methylation defects that were missed by MS-MLPA and might be considered as a first-line diagnostic tool for SRS.
