title: Clinically distinct epigenetic subgroups in Silver-Russell syndrome: the degree of H19 hypomethylation associates with phenotype severity and genital and skeletal anomalies.
abstract: BACKGROUND
  The H19 imprinting control region (ICR), located on chromosome 11p15.5, has been reported hypomethylated in 20-65% of Silver-Russell syndrome (SRS) patients.
  
  
  OBJECTIVE
  We investigated the methylation status of 11p15.5 ICRs in SRS patients and children born small for gestational age (SGA) to clarify the relationship between phenotype and H19 methylation status.
  
  
  METHODS
  We performed methylation screens of the H19 and KCNQ1OT1 ICRs in 42 SRS patients, including seven maternal uniparental disomy of chromosome 7 patients, and 90 SGA children without SRS. Clinical data were evaluated from patient records, and seven hypomethylated patients were clinically and radiologically reexamined.
  
  
  RESULTS
  H19 ICR hypomethylation was found in 62% of SRS patients but in no SGA children. A clinical severity score demonstrated strong correlation between hypomethylation level and phenotype severity. Hypomethylation related to a more severe SRS phenotype, in which especially asymmetry and micrognathia were significantly more common. Extremely hypomethylated patients had abnormally high lumbar vertebrae, lumbar hypomobility, elbow subluxations, and distinct hand and foot anomalies. They also presented with congenital aplasia of the uterus and upper vagina, equivalent to the Mayer-Rokitansky-Küster-Hauser syndrome in females, and cryptorchidism and testicular agenesis in males.
  
  
  CONCLUSIONS
  We found a dose-response relationship between the degree of H19 hypomethylation and phenotype severity in SRS. We report for the first time the association of specific anomalies of the spine, elbows, hands and feet, and genital defects in SRS with severe H19 hypomethylation. Classical SRS features were found in H19 hypomethylation and milder symptoms in maternal uniparental disomy of chromosome 7, thus distinguishing two separate clinical and etiological subgroups.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Bruce
authors.forename: Katariina
authors.initials: K
authors.lastname: Hannula-Jouppi
authors.forename: Jari
authors.initials: J
authors.lastname: Peltonen
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Marita
authors.initials: M
authors.lastname: Lipsanen-Nyman
mesh_terms: D000015:Abnormalities, Multiple / Q000145:classification / Q000235:genetics*; D001846:Bone Development / Q000235:genetics; D001842:Bone and Bones / Q000002:abnormalities*; D002657:Child Development / Q000502:physiology; D019175:DNA Methylation / Q000502:physiology; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D005835:Genitalia / Q000002:abnormalities* / Q000254:growth & development; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D008297:Male; D010641:Phenotype; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D012720:Severity of Illness Index; D013577:Syndrome
chemical_list: C094335:H19 long non-coding RNA; C485621:KCNQ1OT1 long non-coding RNA, human; D024642:Potassium Channels, Voltage-Gated; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated