Description
Silver Russell syndrome inclusion criteria (37556)
A.	All 4 core features of Silver-Russell syndrome (SRS) present and no cause found
B.	3 or more features present and family history of SRS or other imprinting disorder; or recurrent fetal loss with IUGR
C.	3 or more features present and multilocus imprinting defect
D.	Isolated/single locus 11p15 methylation defect (H19 loss of methylation) with a family history of Silver-Russell syndrome.

Recruitment of relatives in these families should follow standard guidance.

OR

E.	Isolated/single locus 11p15 methylation defect (H19 loss of methylation) without a family history of Silver-Russell syndrome.

Recruitment to families in group D should occur only as proband-mother-father trios.
Core clinical features of Silver-Russell syndrome:
1.	small for gestational age (birth weight and/or length <-2SDS) +- history of intrauterine growth retardation; 
2.	post-natal short stature (<-2 SDS )
3.	body asymmetry
4.	marked feeding difficulties in infancy / childhood +/- BMI 1.5 SDS relative to birth weight / length).

Silver Russell syndrome exclusion criteria (37556)
•	Other known short stature syndrome
•	Causative UPD (including UPD7, UPD14, UPD16, UPD20)
•	Causative chromosome rearrangement
•	Isolated methylation defect other than in familial cases

Prior genetic testing guidance (37556)
- Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. 
- Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.  

PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established. It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.

Silver Russell syndrome prior genetic testing genes (37556)
UPD7 testing and 11p15 methylation testing are required PRIOR TO RECRUITMENT as molecular diagnosis determines eligibility and methylation abnormalities cannot be detected on WGS. 

Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

- Multi-locus methylation testing

Closing statement (37556)
These requirements will be kept under continual review during the main programme and may be subject to change.

6 reviewers

  • Ellen McDonagh (Genomics England Curator)

    Group: other
    Workplace: other

  • Sarah Leigh (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Deborah Mackay (university of southampton)

    Group: GeCIP domain
    Workplace: Research lab

  • Rebecca Foulger (Genomics England curator)

    Group: Other
    Workplace: Other

  • Anna de Burca (Genomics England Curator)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS clinical service

  • Ivone Leong (Genomics England Curator)

    Group: Other
    Workplace: Other

9 Entities

9 reviewed, 5 green

List Entity Reviews Mode of inheritance Details
9 Entitiess
Green Green List (high evidence)
HMGA2
3 reviews
2 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • SRS
  • Silver-Russell syndrome
Tags
Green Green List (high evidence)
IGF1
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert list
  • Illumina TruGenome Clinical Sequencing Services
  • Literature
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Growth retardation with deafness and mental retardation due to IGF1 deficiency 608747
Tags
Green Green List (high evidence)
IGF1R
2 reviews
1 green
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert list
  • Illumina TruGenome Clinical Sequencing Services
  • Literature
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Insulin-like growth factor I, resistance to 270450
Tags
Green Green List (high evidence)
IGF2
4 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Sources
  • Expert Review Green
  • UKGTN
Phenotypes
  • Silver Russell syndrome, 180860
Tags
Green Green List (high evidence)
PLAG1
3 reviews
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • SRS
  • Silver-Russell syndrome
Tags
Red Red List (low evidence)
CDKN1C
4 reviews
2 green
MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Sources
  • Emory Genetics Laboratory
  • Expert list
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Beckwith-Wiedemann syndrome, 130650
  • IMAGE syndrome, 614732
Tags
Red Red List (low evidence)
H19
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Sources
  • Emory Genetics Laboratory
  • Expert Review Red
  • Literature
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Silver-Russell syndrome 180860
Tags
  • locus-type-rna-long-non-coding
Red Red List (low evidence)
IGFBP1
1 review
Unknown
Sources
  • Literature
Phenotypes
  • Silver-Russell Syndrome
Tags
Red Red List (low evidence)
IGFBP3
1 review
Unknown
Sources
  • Literature
Phenotypes
  • Silver Russell Syndrome
Tags

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