Description
Idiopathic hypogonadotropic hypogonadism inclusion criteria 
Delayed or absent puberty with low or suppressed gonadotropins (including primary amenorrhoea, oligo/azoospermia with low testosterone. Bilateral cryptorchidism with micophallus is suggestive of congenital IHH) AND at least one of the following, 
Parental consanguinity, OR 
One or more similarly affected first, second or third degree relative, OR
Syndromic features such as anosmia, cleft lip or palate, deafness, renal agenesis, neurological disorders 

Individuals with severe or syndromic disease should be recruited according to standard guidance, typically as trios. Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease. 

In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs. 

Idiopathic hypogonadotropic hypogonadism exclusion criteria 
Acquired structural hypothalamo-pituitary disease 
History of anabolic steroid use, recent history of glucocorticoid or opiate use 
Severe intercurrent illness, anorexia, or other forms of undernourishment
Evidence of primary hypogonadism 
Co-existent pituitary hormone deficiency 
Features of Bardet Biedl, CHARGE syndromes, or other complex syndromes for which UKGTN testing exists 

Prior genetic testing guidance 
- 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.

Idiopathic hypogonadotropic hypogonadism prior genetic testing genes Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: 
No genes specified 

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

11 reviewers

  • Ellen McDonagh (Genomics England Curator)

    Group: other
    Workplace: other

  • Mehul Dattani (UCL Institute of Child Health)

    Group: GeCIP domain
    Workplace: Research lab

  • Louise IZATT (GSTT Clinical Genetics Service)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS clinical service

  • Richard Scott (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Sarah Leigh (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Richard Quinton (Newcastle University)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS clinical service

  • Louise Daugherty (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Eleanor Williams (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

  • Martina Owens (Exeter Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS diagnostic lab

46 Entities

46 reviewed, 30 green

List Entity Reviews Mode of inheritance Details
46 Entitiess
Green Green List (high evidence)
ANOS1
7 reviews
3 green
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert list
  • Expert Review Green
  • OMIM
  • Other
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1) 308700
Tags
Green Green List (high evidence)
CHD7
3 reviews
2 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • OMIM
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Hypogonadotropic hypogonadism 5 with or without anosmia,612370
  • CHARGE syndrome, 214800
  • Scoliosis, idiopathic 3, 608765
Tags
Green Green List (high evidence)
CUL4B
2 reviews
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Mental retardation, X-linked, syndromic 15 (Cabezas type), 300354
  • XLMR with Short Stature, Small Testes, Muscle Wasting, and Tremor panel
Tags
Green Green List (high evidence)
DCAF17
4 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Woodhouse-Sakati syndrome 241080
Tags
Green Green List (high evidence)
FEZF1
4 reviews
3 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • OMIM
Phenotypes
  • Hypogonadotropic hypogonadism 22, with or without anosmia, 616030
Tags
Green Green List (high evidence)
FGF8
5 reviews
3 green
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • OMIM
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 6 with or without anosmia, 612702
  • Endocrine Disorders including conditions such as hypogonadotropic hypogonadism (with or without anosmia): Sequencing Panel (Emory)
Tags
Green Green List (high evidence)
FGFR1
4 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • OMIM
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Hypogonadotropic hypogonadism 2 with or without anosmia, 147950
  • Beare-Stevenson Cutis Gyrata Syndrome, 123790
  • Crouzon Syndrome, 123500
  • Pfeiffer Syndrome, 101600
  • Endocrine Disorders including conditions such as hypogonadotropic hypogonadism (with or without anosmia): Sequencing Panel (Emory)
  • Pfeiffer syndrome, 101600
  • Jackson-Weiss syndrome, 123150
  • Osteoglophonic dysplasia, 166250
  • Trigonocephaly 1, 190440
  • Hartsfield syndrome, 615465
  • Nonsyndromic Trigonocephaly
Tags
  • monogenic-polygenic
Green Green List (high evidence)
FSHB
3 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • OMIM
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 24 without anosmia 229070
  • Isolated Follicle-Stimulating Hormone Deficiency
Tags
Green Green List (high evidence)
GLI2
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
Phenotypes
  • Culler-Jones syndrome, (includes hypogonadotropic hypogonadism) 615849
  • Holoprosencephaly-9, 610829
Tags
Green Green List (high evidence)
GNRH1
3 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • OMIM
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 12 with or without anosmia 614841
  • Endocrine Disorders including conditions such as hypogonadotropic hypogonadism (with or without anosmia): Sequencing Panel
  • Isolated GnRH Deficiency
Tags
Green Green List (high evidence)
GNRHR
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • OMIM
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 7 without anosmia, 146110
  • Endocrine Disorders including conditions such as hypogonadotropic hypogonadism (with or without anosmia): Sequencing Panel
  • Isolated GnRH Deficiency
Tags
Green Green List (high evidence)
HAMP
1 review
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • Hemochromatosis, type 2B 613313
Tags
Green Green List (high evidence)
HFE
1 review
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • Hemochromatosis, 235200
Tags
Green Green List (high evidence)
IL17RD
6 reviews
3 green 1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
  • Other
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 18 with or without anosmia 615267
Tags
  • monogenic-polygenic
Green Green List (high evidence)
KISS1R
4 reviews
3 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert list
  • Expert Review Green
  • Other
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 8 with or without anosmia, 614837
  • Precocious puberty, central, 1, (AD), 176400
Tags
  • monogenic-polygenic
Green Green List (high evidence)
LHB
3 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • OMIM
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 23 with or without anosmia, 228300
Tags
Green Green List (high evidence)
LHX4
3 reviews
2 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Pituitary hormone deficiency, combined, 4, 262700
Tags
Green Green List (high evidence)
NR0B1
1 review
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Literature
  • OMIM
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Adrenal hypoplasia, congenital, with hypogonadotropic hypogonadism 300200
Tags
Green Green List (high evidence)
NSMF
5 reviews
3 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • OMIM
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 9 with or without anosmia, 614838
  • Endocrine Disorders including conditions such as hypogonadotropic hypogonadism (with or without anosmia): Sequencing Panel (Emory)
Tags
  • monogenic-polygenic
Green Green List (high evidence)
PROK2
4 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • OMIM
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 4 with or without anosmia, 610628
  • Endocrine Disorders including conditions such as hypogonadotropic hypogonadism (with or without anosmia): Sequencing Panel
Tags
  • monogenic-polygenic
Green Green List (high evidence)
PROKR2
4 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • OMIM
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 3 with or without anosmia, 244200
  • Endocrine Disorders including conditions such as hypogonadotropic hypogonadism (with or without anosmia): Sequencing Panel (Emory)
  • Kallmann Syndrome
Tags
  • monogenic-polygenic
Green Green List (high evidence)
PROP1
4 reviews
3 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • UKGTN
Phenotypes
  • Pituitary hormone deficiency, combined, 2, 262600
  • Proportionate Short Stature/Small for Gestational Age
  • Combined Pituitary Hormone Deficiency, Recessive
Tags
Green Green List (high evidence)
SLC29A3
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Histiocytosis-lymphadenopathy plus syndrome, 602782
Tags
Green Green List (high evidence)
SLC40A1
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • Hemochromatosis, type 4 606069
Tags
Green Green List (high evidence)
SOX10
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Literature
  • Other
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Waardenburg syndrome, type 4C 613266
Tags
Green Green List (high evidence)
SOX2
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Emory Genetics Laboratory
  • Expert list
  • Expert Review Green
  • Other
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Microphthalmia syndromic type 3, Optic nerve hypoplasia and abnormalities of the central nervous system, 206900
Tags
Green Green List (high evidence)
TAC3
4 reviews
3 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • OMIM
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 10 with or without anosmia 614839
  • Endocrine Disorders including conditions such as hypogonadotropic hypogonadism (with or without anosmia): Sequencing Panel
Tags
Green Green List (high evidence)
TACR3
3 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • OMIM
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 11 with or without anosmia, 614840
  • Endocrine Disorders including conditions such as hypogonadotropic hypogonadism (with or without anosmia): Sequencing Panel (Emory)
  • Isolated GnRH Deficiency
Tags
Green Green List (high evidence)
TFR2
1 review
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Green
Phenotypes
  • Hemochromatosis, type 3 604250
Tags
Green Green List (high evidence)
WDR11
4 reviews
3 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Literature
  • OMIM
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 14 with or without anosmia, 614858
Tags
Amber Amber List (moderate evidence)
CCDC141
3 reviews
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Normosmic IHH (no OMIM)
Tags
Red Red List (low evidence)
DUSP6
5 reviews
3 green 1 red
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Red
  • OMIM
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 19 with or without anosmia, 615269
Tags
  • monogenic-polygenic
Red Red List (low evidence)
FGF17
1 review
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Red
  • Other
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 20 with or without anosmia 615270
Tags
  • monogenic-polygenic
Red Red List (low evidence)
FLRT3
5 reviews
3 green 1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • OMIM
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 21 with anosmia, 615271
Tags
Red Red List (low evidence)
HESX1
3 reviews
2 green
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Red
Phenotypes
  • Pituitary hormone deficiency, combined, 5, Growth hormone deficiency with pituitary anomalies, Septooptic dysplasia, 182230
Tags
Red Red List (low evidence)
HFE2
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
Phenotypes
  • Hemochromatosis 235200
Tags
  • new-gene-name
Red Red List (low evidence)
HS6ST1
4 reviews
3 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • OMIM
Phenotypes
  • Hypogonadotropic hypogonadism 15 with or without anosmia, 614880
Tags
  • polygenic
Red Red List (low evidence)
KISS1
5 reviews
3 green 1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Red
  • OMIM
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 13 with or without anosmia, 614842
  • Endocrine Disorders including conditions such as hypogonadotropic hypogonadism (with or without anosmia): Sequencing Panel (Emory)
Tags
Red Red List (low evidence)
KLB
1 review
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert list
Phenotypes
  • Congenital hypogonadotropic hypogonadism
Tags
Red Red List (low evidence)
LHCGR
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Red
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Leydig cell hypoplasia with hypergonadotropic hypogonadism, Leydig cell hypoplasia with pseudohermaphroditism, Luteinizing hormone resistance,female, 238320
  • Endocrine Disorders including conditions such as hypogonadotropic hypogonadism (with or without anosmia): Sequencing Panel
  • Leydig cell adenoma,somatic,with precocious puberty,176410
Tags
Red Red List (low evidence)
LHX3
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Pituitary hormone deficiency, combined, 3 221750
Tags
Red Red List (low evidence)
SEMA3A
5 reviews
3 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert list
  • Expert Review Red
  • Literature
  • OMIM
  • Other
Phenotypes
  • Hypogonadotropic hypogonadism 16 with or without anosmia, 614897
Tags
  • monogenic-polygenic
Red Red List (low evidence)
SEMA3E
3 reviews
2 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Literature
  • Other
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • CHARGE syndrome, 214800
Tags
Red Red List (low evidence)
SEMA7A
1 review
Unknown
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Congenital hypogonadotropic hypogonadism
Tags
  • polygenic
Red Red List (low evidence)
SOX3
1 review
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert list
Phenotypes
  • Panhypopituitarism, X-linked
Tags
Red Red List (low evidence)
SPRY4
5 reviews
3 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert list
  • Expert Review Red
  • Literature
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypogonadotropic hypogonadism 17 with or without anosmia 615266
Tags
  • monogenic-polygenic

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