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07 Oct 2026	Hypogonadotropic hypogonadism (GMS) v5.4	FGF8	Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Hypogonadotropic hypogonadism. There are also at 5 individuals reported in literature with biallelic FGF8 variants. However, three of them presented with holoprosencephaly, diabetes insipidus, and pituitary insufficiency, rather than hypogonadotropic hypogonadism. Another individual with biallelic FGF8 variants and IHH described in PMID: 18596921 harboured additional FGFR1 variants. Hence, there is little robust evidence for the association between biallelic FGF8 variants and HH, and the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal on this panel.; to: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Hypogonadotropic hypogonadism. There are also at 5 individuals reported in literature with biallelic FGF8 variants. However, three of them presented with holoprosencephaly, diabetes insipidus, and pituitary insufficiency, rather than hypogonadotropic hypogonadism. An individual with biallelic FGF8 variants and IHH, described in PMID: 18596921, harboured additional FGFR1 variants. Hence, there is little robust evidence for the association between biallelic FGF8 variants and HH, and the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal on this panel.
07 Oct 2026	Hypogonadotropic hypogonadism (GMS) v5.4	FGF8	Ida Ertmanska edited their review of gene: FGF8: Added comment: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Hypogonadotropic hypogonadism. There are also at 5 individuals reported in literature with biallelic FGF8 variants. However, three of them presented with holoprosencephaly, diabetes insipidus, and pituitary insufficiency, rather than hypogonadotropic hypogonadism. Another individual with biallelic FGF8 variants and IHH described in PMID: 18596921 harboured additional FGFR1 variants. Hence, there is little robust evidence for the association between biallelic FGF8 variants and HH, and the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal on this panel.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
07 Oct 2026	Hypogonadotropic hypogonadism (GMS) v5.4	FGF8	Ida Ertmanska changed review comment from: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured het variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Case 3 - homozygous for FGF8 p.Phe40Leu variant. Other cases had het FGF8 variants. Additional FGFR1 mutations were detected in cases 3 and 4. Functional: mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).; to: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured het variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Case 3 - homozygous for FGF8 p.Phe40Leu variant. Other cases had het FGF8 variants. Additional FGFR1 mutations were detected in cases 3 and 4. Functional: mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).
07 Oct 2026	Hypogonadotropic hypogonadism (GMS) v5.4	FGF8	Ida Ertmanska changed review comment from: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Case 3 - homozygous for FGF8 p.Phe40Leu variant. Other cases had het FGF8 variants. Additional FGFR1 mutations were detected in cases 3 and 4. Functional: mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).; to: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured het variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Case 3 - homozygous for FGF8 p.Phe40Leu variant. Other cases had het FGF8 variants. Additional FGFR1 mutations were detected in cases 3 and 4. Functional: mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).
07 Oct 2026	Hypogonadotropic hypogonadism (GMS) v5.4	FGF8	Ida Ertmanska changed review comment from: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Additional FGFR1 mutations were detected in cases 3 and 4. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).; to: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Case 3 - homozygous for FGF8 p.Phe40Leu variant. Other cases had het FGF8 variants. Additional FGFR1 mutations were detected in cases 3 and 4. Functional: mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).
07 Oct 2026	Hypogonadotropic hypogonadism (GMS) v5.4	FGF8	Ida Ertmanska changed review comment from: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Additional FGFR1 mutations were detected in cases 3 and 4. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).; to: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Additional FGFR1 mutations were detected in cases 3 and 4. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).
07 Oct 2026	Hypogonadotropic hypogonadism (GMS) v5.4	FGF8	Ida Ertmanska changed review comment from: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Additional FGFR1 mutations were detected in cases 3 and 4. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).; to: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Additional FGFR1 mutations were detected in cases 3 and 4. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).
07 Oct 2026	Hypogonadotropic hypogonadism (GMS) v5.4	FGF8	Ida Ertmanska changed review comment from: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).; to: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Additional FGFR1 mutations were detected in cases 3 and 4. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).
27 Feb 2026	Hypogonadotropic hypogonadism (GMS) v4.7	FGFR1	Ida Ertmanska changed review comment from: PMID: 27055092 Mazen et al., 2016 Male patient with congenital heart disease (CHD) and ambiguous genitalia, referred at 15 months. Consanguineous parents, positive family history for CHD. Trio WES revealed a homozygous FGFR1 c.1418G>A variant (hg38: c.1424G>A, p.Arg475Gln - rs747333248, 34 total alleles in gnomAD v4.1.0, no homozygotes). Patient also homozygous for a STARD3 p.Ala247Val mutation, no disease association reported for this gene. Ambiguous genitalia highlighted as unusual presentation in FGFR1-related disease. PMID: 25394172 Villanueva et al., 2015 7 individuals with Congenital hypogonadotropic hypogonadism (CHH), 3/7 with anosmia, and 7/7 with split hand/foot malformation. The patients harboured FGFR1 variants - 6 heterozygous and 1 homozygous. P1: male, homozygous for c.1286T>A, p.V429E. Heterozygous sister and parents. Sister has hyposmia, otherwise no phenotype reported in heterozygous family members. In the 6 heterozygous pedigrees, CHH was an autosomal dominant trait with incomplete penetrance. PMID: 23812909 Simonis et al., 2013 6 patients with Hartsfield syndrome and 1 female fetus with similar symptoms. FGFR1 variants were detected in the extracellular binding domain (two patients with homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Patients presented with holoprosencephaly 7/7 (lobar, alobar, or semilobar), corpus callosum agenesis 5/7 (full or partial), ectrodactyly 7/7 (hands and/or feet affected), growth retardation 6/6, genital anomalies 3/6 (micropenis, cryptorchidism), DD/ID 6/6 (mild to severe). P1 was homozygous for L165S, heterozygous parents unaffected. P2 was homozygous for L191S, parents not available for testing. PMID: 23154428 Jarzabek et al., 2012 5 Kallmann syndrome (KS) patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Patients 1-4 harboured de novo heterozygous FGFR1 mutations, while P5 was homozygous for the c.499G>T, p.Ala167Ser variant - his parents are sister are heterozygous and unaffected. All 5 patients had absent puberty, as well as hyposmia or anosmia. 3/5 patients presented with skeletal abnormalities and lip/palate malformations. P5 (previously described in PMID: 12627230) had KS, cleft palate, corpus callosum agenesis, vertebral anomalies, unilateral fusion of fourth and fifth metacarpal bones, and bilateral oligodactyly of feet (four digits). FGFR1 is associated with multiple dominant conditions in OMIM, including AD Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950 and AD Hartsfield syndrome, OMIM:615465.; to: PMID: 27055092 Mazen et al., 2016 Male patient with congenital heart disease (CHD) and ambiguous genitalia, referred at 15 months. Consanguineous parents, positive family history for CHD. Trio WES revealed a homozygous FGFR1 c.1418G>A variant (hg38: c.1424G>A, p.Arg475Gln - rs747333248, 34 total alleles in gnomAD v4.1.0, no homozygotes). Patient also homozygous for a STARD3 p.Ala247Val mutation, no disease association reported for this gene. Ambiguous genitalia highlighted as unusual presentation in FGFR1-related disease. PMID: 25394172 Villanueva et al., 2015 7 individuals with Congenital hypogonadotropic hypogonadism (CHH), 3/7 with anosmia, and 7/7 with split hand/foot malformation. The patients harboured FGFR1 variants - 6 heterozygous and 1 homozygous. P1: male, homozygous for c.1286T>A, p.V429E. Heterozygous sister and parents. Sister has hyposmia, otherwise no phenotype reported in heterozygous family members. In the 6 heterozygous pedigrees, CHH was an autosomal dominant trait with incomplete penetrance. PMID: 23812909 Simonis et al., 2013 6 patients with Hartsfield syndrome and 1 female fetus with similar symptoms. FGFR1 variants were detected in the extracellular binding domain (two patients with homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Patients presented with holoprosencephaly 7/7 (lobar, alobar, or semilobar), corpus callosum agenesis 5/7 (full or partial), ectrodactyly 7/7 (hands and/or feet affected), growth retardation 6/6, genital anomalies 3/6 (micropenis, cryptorchidism), DD/ID 6/6 (mild to severe). P1 was homozygous for L165S, heterozygous parents unaffected. P2 was homozygous for L191S, parents not available for testing. PMID: 23154428 Jarzabek et al., 2012 5 Kallmann syndrome (KS) patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Patients 1-4 harboured de novo heterozygous FGFR1 mutations, while P5 was homozygous for the c.499G>T, p.Ala167Ser variant - his parents are sister are heterozygous and unaffected. All 5 patients had absent puberty, as well as hyposmia or anosmia. 3/5 patients presented with skeletal abnormalities and lip/palate malformations. P5 (previously described in PMID: 12627230) had KS, cleft palate, corpus callosum agenesis, vertebral anomalies, unilateral fusion of fourth and fifth metacarpal bones, and bilateral oligodactyly of feet (four digits). FGFR1 is associated with multiple dominant conditions in OMIM, including AD Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950 and AD Hartsfield syndrome, OMIM:615465 (accessed 27th Feb 2026).
27 Feb 2026	Hypogonadotropic hypogonadism (GMS) v4.7	FGFR1	Ida Ertmanska Phenotypes for gene: FGFR1 were changed from Hypogonadotropic hypogonadism type 2(OMIM 147950) to Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950; Hartsfield syndrome, OMIM:615465
27 Feb 2026	Hypogonadotropic hypogonadism (GMS) v4.6	FGFR1	Ida Ertmanska Publications for gene: FGFR1 were set to
27 Feb 2026	Hypogonadotropic hypogonadism (GMS) v4.5	FGFR1	Ida Ertmanska Tag Q1_26_MOI tag was added to gene: FGFR1.
27 Feb 2026	Hypogonadotropic hypogonadism (GMS) v4.5	FGFR1	Ida Ertmanska commented on gene: FGFR1: Comment on mode of inheritance: There are more than 3 unrelated cases reported for both dominant and recessive FGFR1-related hypogonadotropic hypogonadism. The condition is usually caused by heterozygous kinase domain variants or homozygous extracellular domain mutations, but there are exceptions to this genotype-phenotype pattern (e.g. PMID: 27790375). Based on available evidence, the MOI for Hypogonadotropic hypogonadism (GMS) should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
27 Feb 2026	Hypogonadotropic hypogonadism (GMS) v4.5	FGFR1	Ida Ertmanska reviewed gene: FGFR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23154428, 23812909, 25394172, 27055092; Phenotypes: Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950, Hartsfield syndrome, OMIM:615465; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
30 Nov 2023	Hypogonadotropic hypogonadism (GMS) v3.14	NSMF	Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from biallelic to monoallelic as only heterozygous variants in this gene have been reported in association with IHH, even though this is only partially explains the phenotype due to possible oligogenic variants in other genes such as FGFR1 and HS6ST1.
01 Apr 2021	Hypogonadotropic hypogonadism (GMS) v1.42	DUSP6	Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. PMID: 23643382 - 5 cases with variants in DUSP6 (3 of these cases have variants in other genes FGFR1 and SPRY4). PMID: 32389901 - 6 cases with variants in DUSP6 (1 case also has variants in CCDC141). Based on the available evidence this gene has been given an Amber rating and will be reviewed by the GMS specialist group.
01 Apr 2021	Hypogonadotropic hypogonadism (GMS) v1.41	FGF17	Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. PMID: 23643382 identfied 3 cases with variants in the FGF17 gene. However, 1 of these cases have variants in other genes as well (FLRT3, HS6ST1 and FGFR1). Based on the available evidence variants in this gene contribute to disease with variable penetrance. This gene has been given an Amber rating until further evidence is available.
24 Mar 2021	Hypogonadotropic hypogonadism (GMS) v1.30	KLB	Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is not associated with a phenotype in OMIM or Gene2Phenotype. This gene is Green on the Hypogonadotropic hypogonadism (Version 1.29) panel and have the following review: "Rachel Jones (GSTT) Green List (high evidence) Publication by Pitteloud et al: "Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21." They also included functional analysis and showed decreased activity in response to FGF21 and FGF8 KLB is an obligate coreceptor for FGF21 alongside FGFR1 Created: 10 Mar 2020, 10:55 a.m. \| Last Modified: 10 Mar 2020, 10:55 a.m. Panel Version: 1.27 Mode of inheritance MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes hypogonadotrophic hypogonadism Publications PMID: 28754744 Created: 10 Mar 2020, 10:55 a.m. Last Modified: 10 Mar 2020, 10:55 a.m. Panel version: 1.27" There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
23 Mar 2021	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)."
15 Jul 2020	Hypogonadotropic hypogonadism (GMS) v1.8	DUSP6	Zornitza Stark gene: DUSP6 was added gene: DUSP6 was added to Hypogonadotropic hypogonadism idiopathic. Sources: Expert list Mode of inheritance for gene: DUSP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DUSP6 were set to 23643382; 32389901 Phenotypes for gene: DUSP6 were set to Hypogonadotropic hypogonadism 19 with or without anosmia, MIM# 615269 Review for gene: DUSP6 was set to GREEN gene: DUSP6 was marked as current diagnostic Added comment: PMID: 23643382 - 5 individuals with congenital hypogonadotrophic hypogonadism (CHH) (3 carry additional variants in FGFR1, SPRY4) PMID: 32389901 - 6 individuals with isolated HH, 3 also had cryptorchidism. Sources: Expert list
22 Mar 2019	Hypogonadotropic hypogonadism (GMS) v0.11	FGFR1	Ivone Leong Classified gene: FGFR1 as Green List (high evidence)
22 Mar 2019	Hypogonadotropic hypogonadism (GMS) v0.11	FGFR1	Ivone Leong Gene: fgfr1 has been classified as Green List (High Evidence).
22 Mar 2019	Hypogonadotropic hypogonadism (GMS) v0.7	FGFR1	Simon Thomas reviewed gene: FGFR1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
22 Mar 2019	Hypogonadotropic hypogonadism (GMS) v0.6	FGFR1	Ivone Leong Source Wessex and West Midlands GLH was added to FGFR1.
15 Mar 2019	Hypogonadotropic hypogonadism (GMS) v0.5	FGFR1	Martina Owens reviewed gene: FGFR1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
15 Mar 2019	Hypogonadotropic hypogonadism (GMS) v0.4	FGFR1	Ivone Leong Added phenotypes Hypogonadotropic hypogonadism type 2(OMIM 147950) for gene: FGFR1
15 Mar 2019	Hypogonadotropic hypogonadism (GMS) v0.3	FGFR1	Ivone Leong gene: FGFR1 was added gene: FGFR1 was added to Hypogonadotropic hypogonadism idiopathic. Sources: South West GLH,NHS GMS Mode of inheritance for gene: FGFR1 was set to BIALLELIC, autosomal or pseudoautosomal