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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).
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).; 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. 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 Cohort of patients with holoprosencephaly. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary 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.; 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. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026).
31 Jan 2023	Hypogonadotropic hypogonadism (GMS) v2.5	IL17RD	Catherine Snow Tag Q2_21_expert_review was removed from gene: IL17RD. Tag Q2_21_MOI was removed from gene: IL17RD.
31 Jan 2023	Hypogonadotropic hypogonadism (GMS) v2.5	IL17RD	Catherine Snow changed review comment from: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed and remains XX. The additional comments from GLH's is "Possiblity of digenic/oligogenic inheritance."; to: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed and remains BIALLELIC, autosomal or pseudoautosomal. The additional comments from GLH's is "Possiblity of digenic/oligogenic inheritance."
31 Jan 2023	Hypogonadotropic hypogonadism (GMS) v2.5	IL17RD	Catherine Snow commented on gene: IL17RD
01 Apr 2021	Hypogonadotropic hypogonadism (GMS) v1.42	IL17RD	Ivone Leong edited their review of gene: IL17RD: Added comment: In addition to the review by Zornitza Stark (Australian Genomics), PMID: 23643382 states the following: "Collectively, these data indicate that IL17RD mutations are strongly associated with KS and hearing loss; however, one allelic defect is most likely not sufficient, meaning that additional affected alleles in the same and/or other genes must be present to create the phenotype of KS with hearing loss."; Changed rating: AMBER
01 Apr 2021	Hypogonadotropic hypogonadism (GMS) v1.42	IL17RD	Ivone Leong Tag Q2_21_expert_review tag was added to gene: IL17RD.
29 Mar 2021	Hypogonadotropic hypogonadism (GMS) v1.40	IL17RD	Ivone Leong reviewed gene: IL17RD: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
29 Mar 2021	Hypogonadotropic hypogonadism (GMS) v1.40	IL17RD	Ivone Leong Tag Q2_21_MOI tag was added to gene: IL17RD.
29 Mar 2021	Hypogonadotropic hypogonadism (GMS) v1.40	IL17RD	Ivone Leong Phenotypes for gene: IL17RD were changed from Hypogonadotropic hypogonadism type 18 (OMIM 615267) to Hypogonadotropic hypogonadism 18 with or without anosmia, OMIM:615267
29 Mar 2021	Hypogonadotropic hypogonadism (GMS) v1.39	IL17RD	Ivone Leong Publications for gene: IL17RD were set to
18 Jul 2020	Hypogonadotropic hypogonadism (GMS) v1.8	IL17RD	Zornitza Stark reviewed gene: IL17RD: Rating: AMBER; Mode of pathogenicity: None; Publications: 23643382, 32389901; Phenotypes: Hypogonadotropic hypogonadism 18 with or without anosmia, MIM# 615267; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
22 Mar 2019	Hypogonadotropic hypogonadism (GMS) v0.14	IL17RD	Ivone Leong Classified gene: IL17RD as Green List (high evidence)
22 Mar 2019	Hypogonadotropic hypogonadism (GMS) v0.14	IL17RD	Ivone Leong Gene: il17rd has been classified as Green List (High Evidence).
22 Mar 2019	Hypogonadotropic hypogonadism (GMS) v0.7	IL17RD	Simon Thomas reviewed gene: IL17RD: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
22 Mar 2019	Hypogonadotropic hypogonadism (GMS) v0.6	IL17RD	Ivone Leong Source Wessex and West Midlands GLH was added to IL17RD.
15 Mar 2019	Hypogonadotropic hypogonadism (GMS) v0.5	IL17RD	Martina Owens reviewed gene: IL17RD: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
15 Mar 2019	Hypogonadotropic hypogonadism (GMS) v0.4	IL17RD	Ivone Leong Added phenotypes Hypogonadotropic hypogonadism type 18 (OMIM 615267) for gene: IL17RD
15 Mar 2019	Hypogonadotropic hypogonadism (GMS) v0.3	IL17RD	Ivone Leong gene: IL17RD was added gene: IL17RD was added to Hypogonadotropic hypogonadism idiopathic. Sources: South West GLH,NHS GMS Mode of inheritance for gene: IL17RD was set to BIALLELIC, autosomal or pseudoautosomal