Description
Early onset familial premature ovarian insufficiency inclusion criteria (36874)
•	4 consecutive months of amenorrhoea (primary or secondary), AND
•	Elevated serum FSH of >30IU/L on two separate occasions at least 6 weeks apart, AND
•	Age of onset is <30 years, AND
•	At least one other close family member (sister, mother, aunt or first cousin) with POF, AND
•	Availability of at least 1 additional affected family member to take part in the project

No male relatives should be recruited to this disorder. Unaffected female relatives should only be recruited if they are aged over 45 years, AND menstruation ceased after the age of 45 years.

Early onset familial premature ovarian insufficiency exclusion criteria (36874)
•	X chromosome abnormality such as Turner syndrome
•	Presence of FMR1 premutation
•	Iatrogenic cause (bilateral oophorectomy, chemotherapy, radiotherapy or any other iatrogenic cause)
•	Presence of thyroid or adrenal auto-antibodies

Prior genetic testing guidance (36874)
- 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.

Early onset familial premature ovarian insufficiency prior genetic testing genes (36874)
Testing for fragile X premutation and chromosome abnormalities is strongly recommended PRIOR TO RECRUITMENT as these may not be reliably detected by WGS using current analysis techniques.

Closing statement (36874)
These requirements will be kept under continual review during the main programme and may be subject to change.

7 reviewers

  • Ellen McDonagh (Genomics England Curator)

    Group: other
    Workplace: other

  • Helen Savage (Congenica Ltd)

    Group: Other biotech or pharmaceutical
    Workplace: Other clinical service

  • Louise IZATT (GSTT Clinical Genetics Service)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS clinical service

  • Sarah Leigh (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Alice Gardham (Genomics England)

    Group: Other
    Workplace: Other

  • Louise Daugherty (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Arianna Tucci (Genomics England Curator)

    Group: Other
    Workplace: Other

56 genes

56 reviewed, 22 green

List Gene Reviews Mode of inheritance Details
56 genes
Green Green List (high evidence)
TWNK
2 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Perrault syndrome 5, 616138
Green Green List (high evidence)
AARS2
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Leukoencephalopathy, progressive, with ovarian failure 615889
Green Green List (high evidence)
BMP15
3 reviews
2 green
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • Expert list
  • Expert Review Green
  • Other
Phenotypes
  • premature ovarian failure
  • Ovarian dysgenesis 2,300510
  • Premature ovarian failure 4300510
  • Ovarian Dysgenesis
Green Green List (high evidence)
CLPP
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Perrault syndrome 3 614129
Green Green List (high evidence)
CYP17A1
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • 17-alpha-hydroxylase, 17,20-lyase deficiency 202110
Green Green List (high evidence)
CYP19A1
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Aromatase deficiency 613546
Green Green List (high evidence)
EIF2B5
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Ovarioleukodystrophy 603896
Green Green List (high evidence)
FOXL2
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert list
  • Expert Review Green
  • Other
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • BPES, premature ovarian failure
  • Premature ovarian failure 3,608996
  • Blepharophimosis,epicanthus inversus and ptosis,type 1 and 2,110100
Green Green List (high evidence)
FSHB
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Hypogonadotropic hypogonadism 24 without anosmia 229070
Green Green List (high evidence)
FSHR
3 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Other
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Ovarian dysgenesis 1 233300
  • Ovarian response to FSH stimulation 276400
Green Green List (high evidence)
GALT
2 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Galactosemia, 230400
Green Green List (high evidence)
HFM1
3 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert list
  • Expert Review Green
  • Other
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • premature ovarian failure
  • Premature ovarian failure 9,615724
Green Green List (high evidence)
HSD17B4
2 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Perrault syndrome 1 233400
Green Green List (high evidence)
LARS2
2 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Perrault syndrome 4 615300
Green Green List (high evidence)
MCM8
3 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Other
  • Expert list
Phenotypes
  • premature ovarian failure
Green Green List (high evidence)
MCM9
2 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Literature
  • Expert Review Green
Phenotypes
  • Ovarian dysgenesis 4, 616185
Green Green List (high evidence)
NOBOX
3 reviews
2 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Other
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Premature ovarian failure 5,611548
  • Premature Ovarian Failure
Green Green List (high evidence)
NR5A1
3 reviews
2 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Other
  • Radboud University Medical Center, Nijmegen
  • Expert list
Phenotypes
  • premature ovarian failure, spermatogenic failure, adenocotical insufficiecny, 46 XY sex reversal
  • 46XY sex reversal 3,612965
  • Premature ovarian failure 7,612964
  • Spermatogenic failure 8,613957
Green Green List (high evidence)
PMM2
2 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Congenital disorder of glycosylation, type Ia 212065
Green Green List (high evidence)
POLG
2 reviews
2 green
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Progressive external ophthalmoplegia, autosomal dominant 1 157640
  • Progressive external ophthalmoplegia, autosomal recessive 1 258450
Green Green List (high evidence)
SOHLH1
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Primary ovarian insufficiency
Green Green List (high evidence)
STAG3
3 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • premature ovarian failure
Amber Amber List (moderate evidence)
BMPR1B
2 reviews
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
Phenotypes
  • Premature Ovarian Insufficiency
Amber Amber List (moderate evidence)
DACH2
1 review
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • premature ovarian insufficiency
Amber Amber List (moderate evidence)
DIAPH2
1 review
Not set
Sources
  • Expert Review Amber
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Premature ovarian failure,300511
Amber Amber List (moderate evidence)
EIF2B4
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Ovarioleukodystrophy 603896
Amber Amber List (moderate evidence)
EIF4ENIF1
1 review
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Literature
  • Expert Review Amber
  • Expert list
Phenotypes
  • premature ovarian failure
  • Primary ovarian insufficiency
Amber Amber List (moderate evidence)
FIGLA
2 reviews
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Radboud University Medical Center, Nijmegen
  • Expert Review Amber
  • Other
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • Premature ovarian failure,612310
  • Premature Ovarian Failure
Amber Amber List (moderate evidence)
GDF9
1 review
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Primary ovarian insufficiency
Amber Amber List (moderate evidence)
HARS2
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Perrault syndrome 2, 614926
Amber Amber List (moderate evidence)
LMNA
2 reviews
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Other
Amber Amber List (moderate evidence)
NANOS3
2 reviews
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Primary ovarian insufficiency
Amber Amber List (moderate evidence)
NOG
1 review
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Primary ovarian insufficiency
Amber Amber List (moderate evidence)
NUP107
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Gonadal dysgenesis
Amber Amber List (moderate evidence)
PGRMC1
2 reviews
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Literature
  • Expert Review Amber
Phenotypes
  • premature ovarian insufficiency
Amber Amber List (moderate evidence)
POF1B
1 review
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Amber
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • Expert list
Phenotypes
  • premature ovarian failure
  • Premature ovarian failure 2B,300604
  • Premature Ovarian Failure 2B
Amber Amber List (moderate evidence)
POU5F1
1 review
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Primary ovarian insufficiency
Amber Amber List (moderate evidence)
PSMC3IP
2 reviews
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Other
  • Radboud University Medical Center, Nijmegen
  • Expert list
Phenotypes
  • premature ovarian failure
  • Ovarian dysgenesis 3,614324
Amber Amber List (moderate evidence)
RCBTB1
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Retinal dystrophy with or without extraocular anomalies 617175
Amber Amber List (moderate evidence)
SGO2
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • PERRAULT SYNDROME
Amber Amber List (moderate evidence)
SOHLH2
1 review
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Primary ovarian insufficiency
Amber Amber List (moderate evidence)
SYCE1
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Premature ovarian failure 12616947
Red Red List (low evidence)
ATM
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Ataxia-telangiectasia 208900
Red Red List (low evidence)
BLM
2 reviews
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Bloom syndrome 210900
Red Red List (low evidence)
EIF2B2
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Ovarioleukodystrophy 603896
Red Red List (low evidence)
ERAL1
1 review
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Literature
Phenotypes
  • Perrault syndrome 6 617565
Red Red List (low evidence)
FANCA
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Fanconi anemia, complementation group A 227650
Red Red List (low evidence)
FANCC
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Fanconi anemia, complementation group C 227645
Red Red List (low evidence)
FANCG
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Fanconi anemia, complementation group G 614082
Red Red List (low evidence)
FMR1
3 reviews
1 green 1 red
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Expert Review Red
  • Emory Genetics Laboratory
  • Radboud University Medical Center, Nijmegen
  • Eligibility statement exclusion criteria
Phenotypes
  • Fragile X syndrome, 300624
  • Fragile X tremor ataxia syndrome, 300623
  • Premature ovarian failure 1, 311360
  • Premature Ovarian Insufficiency
Tags
  • currently-ngs-unreportable
  • nucleotide-repeat-expansion
Red Red List (low evidence)
FOXO4
2 reviews
2 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • premature ovarian insufficiency
Red Red List (low evidence)
MSH5
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Other
Phenotypes
  • ?Premature ovarian failure 13 617442
Red Red List (low evidence)
NBN
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Nijmegen breakage syndrome 251260
Red Red List (low evidence)
RECQL4
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Rothmund-Thomson syndrome 268400
Red Red List (low evidence)
WRN
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Werner syndrome 277700
No list No list
BMPR1B-AS1
3 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Removed
  • Literature
Phenotypes
  • premature ovarian insufficiency

1 STR

1 reviewed, 0 green

List STR Reviews Mode of inheritance Details
1 STRs
Red Red List (low evidence)
FMR1_CGG
1 review
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 list
Phenotypes
  • Fragile X syndrome 300624
Tags
  • STR

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