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| Holoprosencephaly v6.4 | FGF8 |
Ida Ertmanska changed review comment from: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 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 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. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). No pituitary deficiency reported for these patients. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026).; to: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 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 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: 31748124 - IHH Proband 15, male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 18596921 - Case 3 - IHH proband homozygous for FGF8 p.Phe40Leu variant. Additional FGFR1 mutations were also detected. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). No pituitary deficiency reported for these patients. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). |
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| Holoprosencephaly v6.4 | FGF8 |
Ida Ertmanska changed review comment from: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 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 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. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). No pituitary deficiency reported for these patients. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921.; to: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 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 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. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). No pituitary deficiency reported for these patients. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). |
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| Holoprosencephaly v6.4 | FGF8 |
Ida Ertmanska changed review comment from: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 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 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. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921.; to: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 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 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. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). No pituitary deficiency reported for these patients. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. |
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| Holoprosencephaly v6.4 | FGF8 |
Ida Ertmanska changed review comment from: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 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: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). PMID: 21832120 McCabe et al., 2011 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: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921.; to: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 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 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. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. |
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| Holoprosencephaly v6.4 | FGF8 |
Ida Ertmanska changed review comment from: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 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 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: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921.; to: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 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: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). PMID: 21832120 McCabe et al., 2011 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: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. |
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| Holoprosencephaly v6.4 | FGF8 |
Ida Ertmanska changed review comment from: 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.; to: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 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 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: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. |
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| Holoprosencephaly v5.3 | DISP1 |
Ida Ertmanska changed review comment from: PMID: 38529886 Lavillaureix et al., 2024 25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7). As 5 out of 9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1. This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).; to: PMID: 38529886 Lavillaureix et al., 2024 25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1. This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025). |
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| Holoprosencephaly v5.3 | DISP1 |
Ida Ertmanska changed review comment from: PMID: 38529886 Lavillaureix et al., 2024 25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7). As 5 out of 9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1. This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).; to: PMID: 38529886 Lavillaureix et al., 2024 25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7). As 5 out of 9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1. This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025). |
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| Holoprosencephaly v1.21 | SHH | Louise Daugherty Source NHS GMS was added to SHH. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly v1.20 | SHH | Louise Daugherty commented on gene: SHH | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly | SHH | Helen Brittain marked SHH as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly | SHH | Helen Brittain commented on SHH | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly | SHH | Helen Brittain classified SHH as green | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly | SHH | Lara Menzies reviewed SHH | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||