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Hypogonadotropic hypogonadism (GMS) v5.2 PROKR2 Ida Ertmanska commented on gene: PROKR2: Comment on mode of inheritance: The majority (up to 90%) of cases reported in literature with Hypogonadotropic hypogonadism and PROKR2 variants are heterozygotes. There are at least 22 patients with HH and biallelic PROKR2 variants - mostly biallelic missense. Hence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel.
Hypogonadotropic hypogonadism (GMS) v5.2 PROKR2 Ida Ertmanska Publications for gene: PROKR2 were set to 36694982
Hypogonadotropic hypogonadism (GMS) v5.1 PROKR2 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: PROKR2.
Hypogonadotropic hypogonadism (GMS) v5.1 PROKR2 Ida Ertmanska changed review comment from: PMID: 36843573 Martinez-Mayer and Perez-Millan, 2023
Literature review of 435 cases with PROKR2 variants, 108 with hypogonadotropic hypogonadism (HH) and 236 with Kallmann syndrome (KS). 90% of cases are heterozygous, 7% homozygous and 3% comp het.

Biallelic case examples:
PMID: 18682503 Abreu et al., 2008
PROKR2 p.Y140X change was identified in the homozygous state in an anosmic boy with micropenis, bilateral cryptorchidism, and high-arched palate. His asymptomatic parents were heterozygous.

PMID: 35236788 Sugisawa et al., 2022
We describe the case of a 31-year-old man with normosmic-CHH, who also had obesity, type 2 diabetes and intellectual disability. Diagnosed with sexual immaturity at 20 yrs old. He was comp het for PROKR2 variants p.Trp178Ser and p.Trp212*.

PROKR2 is associated with AD,AR Hypogonadotropic hypogonadism 3 with or without anosmia, OMIM:244200 (accessed 20th May 2026).; to: PMID: 36843573 Martinez-Mayer and Perez-Millan, 2023
Literature review of 435 cases with PROKR2 variants, 108 with hypogonadotropic hypogonadism (HH) and 236 with Kallmann syndrome (KS). 90% of cases are heterozygous, 7% homozygous and 3% comp het.

Biallelic case examples:
PMID: 18682503 Abreu et al., 2008
PROKR2 p.Y140X change was identified in the homozygous state in an anosmic boy with micropenis, bilateral cryptorchidism, and high-arched palate. His asymptomatic parents were heterozygous.

PMID: 35236788 Sugisawa et al., 2022
Report of a case of a 31-year-old Japanese man with normosmic-CHH, who also had obesity, type 2 diabetes and intellectual disability. Diagnosed with sexual immaturity at 20 yrs old. He was comp het for PROKR2 variants p.Trp178Ser and p.Trp212*.
Literature review in same article found 21 other patients from 17 families with biallelic PROKR2 variants and CHH (86% diagnosed with KS). 17/22 patients had missense variants on both alleles; only 1 had biallelic truncating variants.

PROKR2 is associated with AD,AR Hypogonadotropic hypogonadism 3 with or without anosmia, OMIM:244200 (accessed 20th May 2026).
Hypogonadotropic hypogonadism (GMS) v5.1 PROKR2 Ida Ertmanska reviewed gene: PROKR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18682503, 35236788, 36843573; Phenotypes: Hypogonadotropic hypogonadism 3 with or without anosmia, OMIM:244200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hypogonadotropic hypogonadism (GMS) v4.4 PROKR2 Ida Ertmanska Phenotypes for gene: PROKR2 were changed from Hypogonadotropic hypogonadism type 3 (OMIM 244200) to Hypogonadotropic hypogonadism 3 with or without anosmia, OMIM:244200
Hypogonadotropic hypogonadism (GMS) v3.2 PROKR2 Achchuthan Shanmugasundram Publications for gene: PROKR2 were set to
Hypogonadotropic hypogonadism (GMS) v1.15 CCDC141 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 251920460 describes 2 affected siblings from a consanguineous family with anosmic HH, who had homozygous variant in FEZF1 (Amber gene on this panel) and also homozyous for variant in CCDC141.

PMID: 28324054 describes the above case and also 3 new cases (all had normal sense of smell and HH). Family 2: compound het for CCDC141 and heterozygous for DMXL2 variant. Family 3: heterozygous for CCDC141 variant and heterozygous for variants in 3 other genes (NR5A2, FSHB - Green on HH panel, IGSF10). Family 4: affected patient was heterozygous for CCDC141 variant, which the father also carried but father was unaffected.

PMID: 32520725 describes a large Chinese cohort with congenital HH looking at the contribution of CCDC141 to the disease. 12 probands had variants CCDC141 and 9 of these probands had variants in other HH-related genes (inluding PCSK1, ANOS1, PROKR2, AXL, SOX10, HS6ST1, PNPLA6 and FGFR1). The authors concluded that CCDC141 variants alone is not sufficient to cause HH.

PMID: 27014940 talks about a ccdc141 knockdown mouse model reduces GnRH neuronal migration.

After discussing with the Genomics England Clinical Team, it was decided that this gene should have an Amber rating as variants. Helen Brittain (Genomics England):
"...variants in this gene may be seen as a risk allele (either with other known contributory genetic factors, or unexplained variable penetrance)."
Hypogonadotropic hypogonadism (GMS) v0.18 PROKR2 Ivone Leong Classified gene: PROKR2 as Green List (high evidence)
Hypogonadotropic hypogonadism (GMS) v0.18 PROKR2 Ivone Leong Gene: prokr2 has been classified as Green List (High Evidence).
Hypogonadotropic hypogonadism (GMS) v0.7 PROKR2 Simon Thomas reviewed gene: PROKR2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hypogonadotropic hypogonadism (GMS) v0.6 PROKR2 Ivone Leong Source Wessex and West Midlands GLH was added to PROKR2.
Hypogonadotropic hypogonadism (GMS) v0.5 PROKR2 Martina Owens reviewed gene: PROKR2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hypogonadotropic hypogonadism (GMS) v0.4 PROKR2 Ivone Leong Added phenotypes Hypogonadotropic hypogonadism type 3 (OMIM 244200) for gene: PROKR2
Hypogonadotropic hypogonadism (GMS) v0.3 PROKR2 Ivone Leong gene: PROKR2 was added
gene: PROKR2 was added to Hypogonadotropic hypogonadism idiopathic. Sources: South West GLH,NHS GMS
Mode of inheritance for gene: PROKR2 was set to BIALLELIC, autosomal or pseudoautosomal