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| Clefting v7.10 | PAX3 |
Ida Ertmanska changed review comment from: PMID: 34918979 Liang et al., 2021 Report of a Chinese pedigree with nonsyndromic cleft lip with or without palate. PAX3 missense variant detected: c.92C>G, p.(Thr31Ser). PMID: 27081571 Yoshida et al., 2016 Report of a 10 mo Japanese boy with pigmentation abnormalities of the right iris, ocular hypertelorism (W index: 2.00), right-sided congenital hearing loss, synophrys, incomplete left cleft lip, and cryptorchidism. Family history of iris pigmentation abnormality and hearing loss on mother's side. Proband was het for PAX3: c.1107C>G, p.(Ser369Arg), parents not tested. Variant not in gnomAD v4.1.1. PMID: 18483623 Wu et al., 2008 - mouse model Persistent expression of Pax3 in cranial neural crest cells resulted in cleft palate, ocular defects, malformation of the sphenoid bone, and perinatal lethality in mice.; to: PMID: 34918979 Liang et al., 2021 Report of a Chinese pedigree with nonsyndromic cleft lip with or without palate. Son (proband, 11yo male) and his father affected. Both affected individuals were het for a PAX3 missense variant: c.92C>G, p.(Thr31Ser). Method: Trio WES. Variant was absent in the healthy mother, as well as 113 unrelated healthy controls. PMID: 27081571 Yoshida et al., 2016 Report of a 10 mo Japanese boy with pigmentation abnormalities of the right iris, ocular hypertelorism (W index: 2.00), right-sided congenital hearing loss, synophrys, incomplete left cleft lip, and cryptorchidism. Family history of iris pigmentation abnormality and hearing loss on mother's side. Proband was het for PAX3: c.1107C>G, p.(Ser369Arg), parents not tested. Variant not in gnomAD v4.1.1. PMID: 18483623 Wu et al., 2008 - mouse model Persistent expression of Pax3 in cranial neural crest cells resulted in cleft palate, ocular defects, malformation of the sphenoid bone, and perinatal lethality in mice. |
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| Clefting v7.9 | RIC1 |
Luke Stuart gene: RIC1 was added gene: RIC1 was added to Clefting. Sources: Literature Mode of inheritance for gene: RIC1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: RIC1 were set to 27878435; 31932796; 36493769 Phenotypes for gene: RIC1 were set to CATIFA syndrome, OMIM:618761; Catifa syndrome, MONDO:0032901 Review for gene: RIC1 was set to AMBER Added comment: RIC1 is associated with autosomal recessive CATIFA syndrome (OMIM #618761; accessed 08/2026). Patel et al., 2017 (PMID 27878435) reported two unrelated males from consanguineous families who were homozygous for the same founder variant, RIC1 p.Arg1265Pro (R1265P), within a shared autozygous interval. Both had syndromic cataracts with global developmental delay, microcephaly, and structural brain anomalies detectable on MRI, with variable cleft lip and palate. Unlu et al., 2020 (PMID 31932796) described eight additional affected individuals from the same extended familes, all homozygous for RIC1 p.Arg1265Pro (affecting the final coding residue of exon 24). Phenotypes included global developmental delay, intellectual disability, motor, speech and cognitive impairment, hypotonia with clumsy gait, variable craniofacial dysmorphism, tooth eruption/alignment abnormalities, and cleft lip and/or palate in 5/8 individuals. Behavioural abnormalities and ADHD were reported in all seven affected males. In zebrafish, ric1−/− animals showed intracellular collagen retention, defective cartilage matrix formation, craniofacial malformations, tooth defects, tendon and muscle attachment abnormalities, impaired locomotion, and reduced forebrain and cerebellar structures. Wild-type human RIC1 rescued collagen secretion and craniofacial defects, whereas RIC1 p.Arg1265Pro failed to do so effectively. cDNA analysis of patient fibroblasts identified two distinct transcripts: one correctly spliced transcript encoding the p.Arg1265Pro variant, and a second transcript with intron 24 retention, introducing a premature stop codon at position 1266 and predicted to undergo NMD. Fibroblasts from CATIFA patients also had reduced levels of RIC1 transcript (<50% of control cells), supporting a hypomorphic splicing defect. Landson et al., 2023 (PMID 36493769) reported three individuals with non-syndromic cleft lip/palate carrying a deletion encompassing the RIC1 5′UTR and exons 1–2. Inheritance data were available for two individuals: one deletion occurred de novo and one was inherited from an affected mother. In Xenopus (splice-blocking morpholino knockdown and F0 CRISPR knockout) and zebrafish (F0 CRISPR knockout), loss of ric1 caused cleft-like midfacial defects and hypoplastic jaw cartilages. Sequencing was not performed, thus the presence of a second pathogenic hit on the non-deleted allele cannot be excluded. Summary: Homozygosity for the founder variant p.Arg1265Pro segregated with CATIFA syndrome in a large consanguineous family. Functional studies in zebrafish and Xenopus support a role for RIC1 in craniofacial development and clefting. Additional evidence suggests a possible association between heterozygous loss of RIC1 (haploinsufficiency) and non-syndromic cleft lip/palate. An amber rating with BOTH monoallelic and biallelic inheritance is recommended for clefting. Sources: Literature |
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| Clefting v7.2 | LOXL3 |
Ida Ertmanska gene: LOXL3 was added gene: LOXL3 was added to Clefting. Sources: Literature Mode of inheritance for gene: LOXL3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LOXL3 were set to 25663169; 30362103; 36610533; 36917121; 38957076; 41052910 Phenotypes for gene: LOXL3 were set to Myopia 28, autosomal recessive, OMIM:619781; Stickler syndrome, MONDO:0019354 Review for gene: LOXL3 was set to GREEN Added comment: PMID: 41052910 Sanchez et al., 2026 3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3). PMID: 38957076 Klejnotowska et al., 2024 4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2. PMID: 36917121 Jiang et al., 2023 9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though. PMID: 30362103 Chan et al., 2019 Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss. PMID: 25663169 Alzahrani et al., 2015 Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering). Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration. Sources: Literature |
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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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||