Ann Lab Med.  2021 Jul;41(4):401-408. 10.3343/alm.2021.41.4.401.

Clinical Application of Sequential Epigenetic Analysis for Diagnosis of Silver–Russell Syndrome

Affiliations
  • 1Pediatric Clinical Neuroscience Center, Department of Pediatrics, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul, Korea
  • 2Division of Pediatric Orthopedics, Department of Orthopaedic Surgery, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul, Korea
  • 3Division of Endocrinology, Department Pediatrics, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul, Korea
  • 4Division of Clinical Genetics, Department of Pediatrics, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul, Korea

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.

Keyword

Silver–Russell syndrome; Netchine-Harbison clinical scoring system (NHCSS); Epigenetic analysis; Methylation defects; Bisulfite pyrosequencing
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