Epigenotype-phenotype correlations in Silver-Russell syndrome

Emma L Wakeling (1) , Sayeda Abu Amero (2) , Marielle Alders (3) , Jet Bliek (3) , Elizabeth Forsythe (1) , Shraddha Kumar (1) , Derek H Lim (4) , Fiona Macdonald (5) , Deborah J Mackay (6) , Eamonn R Maher (4) , Gudrun E Moore (2) , Rebecca L Poole (6) , Susan M Price (7) , Trine Tangeraas (8) , Claire Ls Turner (9) , Mieke M van Haelst (10) , Catherine Willowby (11) , Karen I Temple (9) , Jan Maarten Cobben (12)

1 North West Thames Regional Genetic Service, North West London Hospitals NHS Trust, Harrow
2 Institute of Child Health [London]
3 Department of Clinical Genetics, Academic Medical Centre, Amsterdam
4 Centre for Rare Diseases and Personalised Medicine and School of Clinical and Experimental Medicine,
5 Department of Medical and Molecular Genetics, University of Birmingham and West Midlands Genetics S
6 Salisbury District Hospital
7 Department of Clinical Genetics, Northampton General Hospital, Northampton
8 Division of Pediatrics, Oslo University Hospital , Rikshospitalet, Oslo
9 University of Southampton
10 University Medical Center [Utrecht]
11 DNA Laboratory, Medical Genetics Unit, St Georges Hospital, London
12 Department of Pediatric Genetics, Emma Kinderziekenhuis AMC, Amsterdam

Background: Silver-Russell syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face and asymmetry. Maternal uniparental disomy (mUPD) of chromosome 7 and hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 are found in around 5-10% and up to 60% of patients with SRS, respectively. As many features are non-specific, diagnosis of SRS remains difficult. Studies of patients in whom the molecular diagnosis is confirmed therefore provide valuable clinical information regarding the condition. Methods: We undertook a detailed, prospective study of 64 patients with mUPD7 (n=20) or ICR1 hypomethylation (n=44). Results and conclusions: The considerable overlap in clinical phenotype makes it difficult to distinguish these two molecular subgroups reliably. ICR1 hypomethylation patients were more likely to be scored as ¡®classical¡¯ SRS. Asymmetry, fifth finger clinodactyly and congenital anomalies were more commonly seen with ICR1 hypomethylation, whereas learning difficulties and referral for speech therapy were more likely with mUPD7. Myoclonus-dystonia has been reported previously in one mUPD7 patient. We report mild movement disorders in three further cases. No correlation was found between clinical severity and level of ICR1 hypomethylation. Use of assisted reproductive technology in association with ICR1 hypomethylation seems increased compared with the general population. ICR1 hypomethylation was also observed in affected siblings though recurrence risk remains low in the majority of cases. Overall, a wide range in severity was observed, particularly with ICR1 hypomethylation. We therefore recommend a low threshold for investigation of patients with features suggestive, but not typical, of SRS.

Mots clés: Clinical genetics

Emma L Wakeling, Sayeda Abu Amero, Marielle Alders, Jet Bliek, Elizabeth Forsythe, et al.. Epigenotype-phenotype correlations in Silver-Russell syndrome. Journal of Medical Genetics, 2010, 47 (11), pp.760. ⟨10.1136/jmg.2010.079111⟩. ⟨hal-00557400⟩