Description
Craniosynostosis syndromes phenotypes eligibility statement:

Craniosynotosis inclusion criteria (29699)
- Any combination of more than one major cranial vault suture fused at original presentation (from metopic, sagittal, left coronal, right coronal, left lambdoid, right lambdoid)
- Single suture synostosis accompanied by either (a) dysmorphic features or at least one major extracranial abnormality; (b) significant learning disability; (c) first or second degree relative with craniosynostosis, or offspring of consanguineous union

Craniosynotosis exclusion criteria (29699)
- Evidence of likely secondary cause. This is most likely to comprise (a) extreme prematurity <28 weeks’ gestation; (b) complications of severe perinatal asphyxia; (c) teratogenic exposure, most commonly sodium valproate; (d) compelling history of intrauterine growth restriction; (e) documented rickets (genetic or acquired)

Prior genetic testing guidance (29699)
- 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.

Craniosynostosis prior genetic testing genes (29699)
Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:
 - Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray) 
  - DNA sequencing of FGFR3-P250R, FGFR2 exons IIIa (8) and IIIc (10), TWIST1 exon 1 in all cases
  - Additional tests available for other genes as clinically indicated (nationally commissioned testing). These tests will most commonly include the EFNB1, ERF and TCF12 genes (mutations in each of these genes contribute >=1% of craniosynostosis overall), and MLPA of TWIST1. Additional testing is currently offered for FGFR1, FGFR2 (extended screen), IL11RA, POR, RAB23 and ZIC1.

Closing statement (29699)
These requirements will be kept under continual review during the main programme and may be subject to change.

5 reviewers

  • Ellen McDonagh (Genomics England Curator)

    Group: other
    Workplace: other

  • Andrew Wilkie (University of Oxford)

    Group: GeCIP domain
    Workplace: Research lab

  • Richard Scott (Genomics England Curator)

    Group: Other
    Workplace: Genomics England

  • Rebecca Foulger (Genomics England curator)

    Group: Other
    Workplace: Other

  • Louise Daugherty (Genomics England Curator)

    Group: Other
    Workplace: Other

65 Entities

64 reviewed, 40 green

List Entity Reviews Mode of inheritance Details
65 Entitiess
Green Green List (high evidence)
11p11.2 (Potocki-Shaffer syndrome) region (includes ALX4, EXT2) Loss
ISCA-37441-Loss
Region
0 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • ClinGen
  • Expert Review Green
Phenotypes
  • Potocki-Shaffer syndrome
  • multiple exostoses
  • biparietal foramina
  • intellectual disability
  • strabismus
  • minor craniofacial anomalies
  • myopia
  • ophthalmologic anomalies
  • 601224
  • mental retardation
  • enlarged anterior fontanel
  • genital abnormalities in males
  • parietal foramina
  • developmental delay
Tags
Green Green List (high evidence)
ALPL
2 reviews
1 green
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • hypophosphatasia
Tags
Green Green List (high evidence)
ALX4
2 reviews
1 green 1 red
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • Parietal foramina
  • Parietal foramina 2, (AD), 609597
  • Frontonasal dysplasia 2, (AR), 613451
Tags
Green Green List (high evidence)
ASXL1
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • Bohring-Opitz syndrome, 605039
  • Metopic synostosis frequently associated with Bohring-Opitz syndrome
Tags
Green Green List (high evidence)
CDC45
3 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • Coronal synostosis
  • Meier-Gorlin syndrome 7, 617063
Tags
Green Green List (high evidence)
COLEC11
1 review
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 265050
Tags
Green Green List (high evidence)
CTSK
1 review
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 265800
Tags
Green Green List (high evidence)
EFNB1
2 reviews
1 green
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Expert list
Phenotypes
  • 304110
Tags
  • x-linked-over-dominance
Green Green List (high evidence)
ERF
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Expert list
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Craniosynostosis 4, 600775
  • Craniosynostosis 4
Tags
Green Green List (high evidence)
FGFR1
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Expert list
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • Craniosynostosis
Tags
Green Green List (high evidence)
FGFR2
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Expert list
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Crouzon syndrome, 123500
  • Jackson-Weiss syndrome, 123150
  • Beare-Stevenson cutis gyrata syndrome, 123790
  • Pfeiffer syndrome, 101600
  • Apert syndrome, 101200
  • Saethre-Chotzen
  • Craniosynostosis, nonspecific syndrome, 101400
  • Gastric cance
  • Craniosynostosis
Tags
Green Green List (high evidence)
FGFR3
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Expert list
Phenotypes
  • Muenke syndrome
  • Crouzon syndrome with acanthosis nigricans
Tags
Green Green List (high evidence)
FLNA
2 reviews
1 green
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • frontometaphyseal dysplasia
  • oto-palato-digital syndromes
  • melnick-needles syndrome
Tags
Green Green List (high evidence)
GLI3
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 175700
Tags
Green Green List (high evidence)
GNPTAB
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 252500
Tags
Green Green List (high evidence)
IDS
2 reviews
1 green
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 309900
Tags
Green Green List (high evidence)
IDUA
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 607014
  • 607016
Tags
Green Green List (high evidence)
IHH
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 185900
Tags
Green Green List (high evidence)
IL11RA
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Expert list
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Craniosynostosis and dental anomalies, 614188
  • Craniosynostosis And Dental Anomalies
Tags
Green Green List (high evidence)
KAT6A
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • Mental retardation (with Craniosynostosis), 616268
Tags
Green Green List (high evidence)
KMT2D
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 147920
Tags
Green Green List (high evidence)
KRAS
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 609942
  • 615278
Tags
Green Green List (high evidence)
MEGF8
1 review
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 614976
Tags
Green Green List (high evidence)
MSX2
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Expert list
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Craniosynostosis, type 2, 604757
  • Parietal foramina 1, 168500
  • Parietal foramina with cleidocranial dysplasia, 168550
  • Craniosynostosis
  • MSX2-related craniosynostosis
Tags
Green Green List (high evidence)
PHEX
2 reviews
1 green
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • X-linked hypophosphataemic rickets
Tags
Green Green List (high evidence)
POR
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Expert list
Phenotypes
  • 201750
Tags
Green Green List (high evidence)
RAB23
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Expert list
Phenotypes
  • 201000
Tags
Green Green List (high evidence)
RECQL4
1 review
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 218600
Tags
Green Green List (high evidence)
RUNX2
2 reviews
1 green 1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 156510
Tags
  • gene-duplication
Green Green List (high evidence)
SKI
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 182212
Tags
Green Green List (high evidence)
SMAD6
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • metopic synostosis
  • sagittal synostosis
  • {Craniosynostosis 7, susceptibility to} 617439
Tags
  • curated-variant-list
  • polygenic
Green Green List (high evidence)
SMO
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Curry-Jones syndrome, somatic mosaic, 601707
Tags
  • mosaicism
  • somatic
Green Green List (high evidence)
STAT3
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 147060
Tags
Green Green List (high evidence)
TCF12
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Expert list
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Craniosynostosis 3, 615314
  • Craniosynostosis 3
Tags
Green Green List (high evidence)
TGFBR1
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 609192
Tags
Green Green List (high evidence)
TGFBR2
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 610168
Tags
Green Green List (high evidence)
TLK2
1 review
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Literature
Tags
Green Green List (high evidence)
TWIST1
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Expert list
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Saethre-Chotzen syndrome, 101400
  • Saethre-Chotzen syndrome with eyelid anomalies, 101400
  • Craniosynostosis, type 1, 123100
  • Robinow-Sorauf syndrome, 180750
Tags
Green Green List (high evidence)
WDR35
1 review
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • 613610
Tags
Green Green List (high evidence)
ZEB2
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • 235730
Tags
Green Green List (high evidence)
ZIC1
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Expert list
Phenotypes
  • 616602
Tags
Red Red List (low evidence)
ADAMTSL4
1 review
1 red
Not set
Sources
  • Expert Review Red
  • Expert list
Tags
Red Red List (low evidence)
ATR
1 review
1 red
Not set
Sources
  • Expert Review Red
  • Expert list
Tags
Red Red List (low evidence)
CYP26B1
1 review
1 red
Not set
Sources
  • Expert Review Red
  • Expert list
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Craniosynostosis with radiohumeral fusions and other skeletal and craniofacial anomalies, 614416
Tags
Red Red List (low evidence)
DHRS3
1 review
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
Phenotypes
  • coronal craniosynostosis, septal heart defects
Tags
Red Red List (low evidence)
EFNA4
1 review
1 red
Not set
Sources
  • Expert Review Red
  • Expert list
Tags
Red Red List (low evidence)
ESCO2
1 review
1 red
Not set
Sources
  • Expert Review Red
  • Expert list
Tags
Red Red List (low evidence)
FAM20C
1 review
1 red
Not set
Sources
  • Expert Review Red
  • Expert list
Tags
Red Red List (low evidence)
FBN1
1 review
1 red
Not set
Sources
  • Expert Review Red
  • Expert list
Tags
Red Red List (low evidence)
FREM1
1 review
1 red
Not set
Sources
  • Expert Review Red
  • Expert list
Tags
Red Red List (low evidence)
GNAS
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Sources
  • Expert Review
  • Expert Review Red
Phenotypes
  • pseudohypoparathyroidism type 1a
  • 103580
Tags
Red Red List (low evidence)
GPC3
1 review
1 red
Not set
Sources
  • Expert Review Red
  • Expert list
Tags
Red Red List (low evidence)
HUWE1
1 review
1 green
Not set
Sources
  • Expert Review Red
  • Expert list
Tags
Red Red List (low evidence)
IFT122
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Red
Phenotypes
  • cranioectodermal dysplasia
Tags
Red Red List (low evidence)
IRX5
1 review
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Red
Phenotypes
  • Hamamy syndrome
Tags
Red Red List (low evidence)
JAG1
1 review
1 red
Not set
Sources
  • Expert Review Red
  • Expert list
Tags
Red Red List (low evidence)
LMX1B
1 review
1 red
Not set
Sources
  • Expert Review Red
  • Expert list
Tags
Red Red List (low evidence)
LRP5
1 review
1 red
Not set
Sources
  • Expert Review Red
  • Expert list
Tags
Red Red List (low evidence)
PRRX1
1 review
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
Phenotypes
  • craniosynostosis, various combinations of sutures
Tags
Red Red List (low evidence)
SCARF2
1 review
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Red
Tags
Red Red List (low evidence)
SH3PXD2B
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Expert list
Phenotypes
  • 249420
Tags
Red Red List (low evidence)
SIX1
1 review
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
Phenotypes
  • sagittal synostosis, multi-suture synostosis
Tags
Red Red List (low evidence)
SPECC1L
1 review
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Red
Tags
Red Red List (low evidence)
TICRR
1 review
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
Phenotypes
  • coronal craniosynostosis, cardiomyopathy
Tags
Red Red List (low evidence)
TMCO1
1 review
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Red
Tags

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