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| Clefting v6.17 | PRKCI |
Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants. Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort). Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios). Variants confirmed as de novo (7 probands): c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84. c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91. c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48. Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter). c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher). Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4). In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ? Functional evidence: 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). ; to: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants. Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios). Variants confirmed as de novo (7 probands): c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84. c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); lower lip pits + hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91. c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48. Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter). c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher). Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4). In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ? Functional evidence: 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). |
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| Clefting v6.17 | PRKCI |
Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants. Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort). Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios). Variants confirmed as de novo (7 probands): c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84. c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91. c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48. Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter). c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher). Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4). In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ? 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). ; to: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants. Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort). Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios). Variants confirmed as de novo (7 probands): c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84. c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91. c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48. Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter). c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher). Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4). In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ? Functional evidence: 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). |
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| Clefting v6.17 | PRKCI |
Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants). Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios). Variants confirmed as de novo (7 probands): c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84. c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual in gnomAD v.4.1.0; Revel score = 0.91. c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48. Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter). c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher). In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ? Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4). 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not LoF intolerant! pLI score for this gene = 0.01 - not predicted to be loss-of-function intolerant. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). ; to: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants. Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort). Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios). Variants confirmed as de novo (7 probands): c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84. c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91. c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48. Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter). c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher). Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4). In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ? 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). |
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| Clefting v6.17 | PRKCI |
Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts and peridermopathies. Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by trio WGS. Vairant c.1148A>G (p.Asn383Ser) was found de novo in five unrelated individuals, indicating a hotspot mutation. 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). Sources: Other; to: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants). Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios). Variants confirmed as de novo (7 probands): c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84. c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual in gnomAD v.4.1.0; Revel score = 0.91. c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48. Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter). c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher). In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ? Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4). 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not LoF intolerant! pLI score for this gene = 0.01 - not predicted to be loss-of-function intolerant. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). |
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| Clefting v6.16 | PRKCI |
Ida Ertmanska gene: PRKCI was added gene: PRKCI was added to Clefting. Sources: Other Q4_25_promote_green tags were added to gene: PRKCI. Mode of inheritance for gene: PRKCI was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PRKCI were set to 40902599 Phenotypes for gene: PRKCI were set to van der Woude syndrome, MONDO:0019508 Review for gene: PRKCI was set to GREEN Added comment: PMID: 40902599 Robinson et al., 2025 Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts and peridermopathies. Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by trio WGS. Vairant c.1148A>G (p.Asn383Ser) was found de novo in five unrelated individuals, indicating a hotspot mutation. 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF. This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). Sources: Other |
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| Clefting v6.8 | MED16 |
Achchuthan Shanmugasundram gene: MED16 was added gene: MED16 was added to Clefting. Sources: Literature Q3_25_promote_green tags were added to gene: MED16. Mode of inheritance for gene: MED16 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MED16 were set to 40081376 Phenotypes for gene: MED16 were set to Guillouet-Gordon syndrome, OMIM:621220 Review for gene: MED16 was set to GREEN Added comment: PMID:40081376 (2025) reported 25 patients from 18 families with biallelic MED16 variants and multiple congenital anomalies (MCAs)-intellectual disability syndrome. Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot). Visual impairment, deafness, and magnetic resonance imaging (MRI) abnormalities were also frequent. There were a total of 8 predicted protein-truncating and 18 missense or in-frame duplication variants identified from these patients. Clefting was reported in eight patients from seven different families. This gene has been associated with relevant phenotypes in OMIM (MIM #621220), but not yet in Gene2Phenotype. Sources: Literature |
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| Clefting | SON | Helen Brittain reviewed SON | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||