Cleft Lip/Palate

Complex MONDO:0016044 Pathograph 4 Show in embeddings browser Orofacial Cleft Disorder of Development or Morphogenesis

Cleft lip and/or palate (orofacial clefting) is one of the most common congenital malformations, arising from failure of the embryonic facial prominences and/or palatal shelves to fuse during the fourth to ninth weeks of development. Cleft lip results from incomplete fusion of the medial nasal and maxillary prominences forming the upper lip and primary palate; cleft palate results from failure of the paired secondary palatal shelves to elevate, appose, and fuse at the midline. Clefts may be unilateral or bilateral, complete or incomplete, and may involve the lip alone, the palate alone, or both. The great majority of cases are nonsyndromic (isolated) and multifactorial, reflecting the combined action of common and rare risk variants at loci such as IRF6, GRHL3, and the 8q24 region together with environmental exposures including maternal smoking, alcohol, folate status, and teratogenic anticonvulsants; a substantial minority occur as part of recognized Mendelian syndromes (e.g., Van der Woude syndrome). Clefting causes feeding difficulty, speech and language impairment, recurrent otitis media with conductive hearing loss, and dental and midfacial growth anomalies, and is managed by staged surgical repair and multidisciplinary team care.

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1
Inheritance
3
Pathophys.
7
Phenotypes
4
Pathograph
6
Genes
5
Medical Actions
2
Subtypes
1
References
1
Deep Research
👪

Inheritance

1
Polygenic/multifactorial inheritance HP:0010982
Nonsyndromic CL/P is a complex trait resulting from multiple genetic risk variants interacting with environmental exposures, departing from simple Mendelian inheritance.
Polygenic inheritance
Show evidence (1 reference)
PMID:21331089 SUPPORT Human Clinical
"Clefts of the lip and/or palate (CLP) are common birth defects of complex aetiology."
Establishes the complex (multifactorial) etiology underlying nonsyndromic clefting.
◆

Subtypes

2
Nonsyndromic (isolated) cleft lip with or without cleft palate
Cleft lip with or without cleft palate occurring in isolation, without other major malformations or a recognized syndrome. Etiology is multifactorial, with common and rare variants at multiple loci interacting with environmental exposures. Accounts for roughly 70% of cleft lip +/- palate cases. Note: cleft lip with or without cleft palate (CL/P) and isolated cleft palate only (CPO) are partly distinct developmental and genetic entities (they arise in different embryonic windows and some loci, e.g., the IRF6 rs642961 enhancer variant, associate with cleft lip but not isolated cleft palate); this entry (MONDO:0016044) centers on the CL/P axis.
Show evidence (1 reference)
PMID:21331089 SUPPORT Human Clinical
"approximately 70% of cases of CLP occur as isolated entities with no other apparent cognitive or structural abnormalities"
About 70% of clefts are isolated/nonsyndromic, defining this subtype.
Syndromic cleft lip/palate
Orofacial clefting occurring as one feature of a recognized Mendelian or chromosomal syndrome (e.g., Van der Woude syndrome [IRF6], 22q11.2 deletion, ectrodactyly-ectodermal dysplasia-clefting [TP63]). A single major gene or chromosomal lesion drives the phenotype.
Show evidence (1 reference)
PMID:20301581 SUPPORT Human Clinical
"Most commonly, IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS) at the mild end to popliteal pterygium syndrome (PPS) at the more severe end."
Van der Woude syndrome is the prototypical Mendelian (IRF6) syndromic cause of cleft lip/palate.
⚙

Pathophysiology

3
Failure of Lip and Primary Palate Fusion
During weeks 4-7 of development, cranial neural crest-derived mesenchyme populates the frontonasal prominence and paired maxillary prominences. Formation of the upper lip and primary palate requires the medial nasal prominences to merge with each other and with the maxillary prominences. Deficient neural crest cell migration, proliferation, or survival, or failure of epithelial seam breakdown at the sites of contact, prevents fusion and produces a cleft of the lip (with or without the alveolus), which may be unilateral or bilateral.
cranial neural crest cell CL:0011012
neural crest cell migration GO:0001755 primary palate development GO:1903929 cell population proliferation GO:0008283
Show evidence (1 reference)
PMID:21331089 SUPPORT Human Clinical
"The common forms of CLP involve disruption of tissue planes above the lip extending into the nares and/or the palate (hard and/or soft)"
Describes the anatomical disruption of lip and palate structures that defines clefting.
Failure of Secondary Palatal Shelf Elevation and Fusion
Between weeks 6 and 9, the paired secondary palatal shelves grow vertically beside the tongue, elevate to a horizontal position above the descending tongue, grow toward the midline, and fuse. Fusion requires apposition of the medial edge epithelia, formation of a midline epithelial seam, and subsequent removal of the seam by epithelial apoptosis and/or epithelial-mesenchymal transition, allowing mesenchymal confluence. Disruption of shelf growth, delayed or failed elevation, impaired seam formation, or persistence of the medial edge epithelium yields a cleft of the secondary palate.
palatal shelf mesenchyme (cranial neural crest-derived) CL:0011012
secondary palate development GO:0062009 epithelial cell apoptosis in palatal shelf fusion GO:1990134 roof of mouth development GO:0060021
Show evidence (2 references)
PMID:22186724 SUPPORT Other
"the embryonic primary and secondary palatal shelves develop as outgrowths from the medial nasal and maxillary prominences, respectively, remodel and fuse to form the intact roof of the oral cavity."
Describes the palatal shelf outgrowth, remodeling, and midline fusion whose failure produces cleft palate.
PMID:7493021 SUPPORT Model Organism
"The defect appears to result from impaired adhesion of the apposing medial edge epithelia of the palatal shelves and subsequent elimination of the mid-line epithelial seam."
Tgfb3-null mice show that failed medial edge epithelial adhesion and seam removal cause cleft palate, mechanistically linking this node to palatal fusion failure.
Disruption of the Orofacial Developmental Gene Regulatory Network
Lip and palate morphogenesis is governed by a conserved gene regulatory network in which transcription factors and signaling pathways (IRF6-GRHL3 in the periderm/oral epithelium; SHH, BMP4, FGF, and WNT signaling; MSX1, FOXE1, PAX7, TP63) coordinate epithelial-mesenchymal interactions. Pathogenic variants and common risk alleles at these loci perturb the network, reducing the developmental robustness of fusion and increasing cleft susceptibility. IRF6 is the single most important locus, contributing to both syndromic (Van der Woude) and nonsyndromic clefting.
oral periderm cell CL:0000078
IRF6 hgnc:6121
roof of mouth development GO:0060021
Downstream
Failure of Lip and Primary Palate Fusion Perturbation of the IRF6-GRHL3 periderm/epithelial network reduces the developmental robustness of medial nasal-maxillary prominence fusion, predisposing to cleft lip and primary palate.
Failure of Secondary Palatal Shelf Elevation and Fusion The same epithelial gene regulatory network (and TGF-beta signaling) governs medial edge epithelial adhesion and seam removal, so its disruption predisposes to failed secondary palatal shelf fusion.
Show evidence (3 references)
PMID:18836445 SUPPORT Human Clinical
"The A allele is significantly overtransmitted (P = 1 x 10(-11)) in families with NSCL/P, in particular those with cleft lip but not cleft palate."
A common regulatory variant in an IRF6 enhancer perturbs the network and increases cleft-lip risk.
PMID:18836445 SUPPORT Model Organism
"expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures"
In vivo mouse expression analysis places the IRF6 enhancer activity in developing craniofacial structures, supporting its role in the orofacial gene regulatory network.
PMID:20436469 SUPPORT Human Clinical
"two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance"
GWAS confirms multiple risk loci (8q24, IRF6, MAFB, ABCA4) contributing to the gene regulatory network underlying nonsyndromic CL/P.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cleft Lip/Palate Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Digestive 1
Feeding difficulties in infancy Feeding difficulties in infancy HP:0008872
Show evidence (1 reference)
PMID:21331089 SUPPORT Human Clinical
"Individuals with CLP may experience problems with feeding, speaking, hearing and social integration"
Feeding difficulty is a recognized complication of clefting.
Ear 2
Otitis media Otitis media HP:0000388
Show evidence (1 reference)
PMID:25287451 SUPPORT Human Clinical
"Compared with conservative forms of management (eg, watchful waiting), VTI has been shown to be beneficial to the recovery of hearing in children with cleft palate and OME."
Otitis media with effusion and associated hearing loss are common in children with cleft palate and are managed with ventilation tubes.
Conductive hearing impairment Conductive hearing impairment HP:0000405
Show evidence (1 reference)
PMID:25287451 SUPPORT Human Clinical
"Compared with conservative forms of management (eg, watchful waiting), VTI has been shown to be beneficial to the recovery of hearing in children with cleft palate and OME."
Otitis media with effusion in cleft palate causes hearing loss recoverable with ventilation tubes, consistent with a conductive mechanism.
Head and Neck 3
Cleft lip Cleft lip HP:0410030
Show evidence (1 reference)
PMID:19747722 SUPPORT Human Clinical
"Clefts of the lip and palate are generally divided into two groups, isolated cleft palate and cleft lip with or without cleft palate, representing a heterogeneous group of disorders affecting the lips and oral cavity."
Defines cleft lip with or without cleft palate as a core clinical group.
Cleft palate Cleft palate HP:0000175
Show evidence (1 reference)
PMID:19747722 SUPPORT Human Clinical
"Clefts of the lip and palate are generally divided into two groups, isolated cleft palate and cleft lip with or without cleft palate, representing a heterogeneous group of disorders affecting the lips and oral cavity."
Cleft palate is one of the two principal cleft groups.
Dental anomalies Abnormality of the dentition HP:0000164
Show evidence (1 reference)
PMID:10742093 SUPPORT Human Clinical
"MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans."
MSX1 links clefting to tooth agenesis, illustrating the dental anomalies that co-occur with orofacial clefting.
Nervous System 1
Delayed speech and language development Delayed speech and language development HP:0000750
Show evidence (1 reference)
PMID:21331089 SUPPORT Human Clinical
"Individuals with CLP may experience problems with feeding, speaking, hearing and social integration"
Speech/language problems are a recognized functional consequence of clefting.
🧬

Genetic Associations

6
IRF6 (Risk Factor)
Gene: IRF6 hgnc:6121
Show evidence (2 references)
PMID:15317890 SUPPORT Human Clinical
"Strong evidence of overtransmission of the valine (V) allele was found in the entire population data set (P<10(-9))"
IRF6 coding variation is significantly associated with isolated cleft lip or palate across populations.
PMID:15317890 SUPPORT Human Clinical
"We identified the gene that encodes interferon regulatory factor 6"
IRF6 was identified as a candidate through its role in Van der Woude syndrome.
GRHL3 (Risk Factor)
Gene: GRHL3 hgnc:25839
Show evidence (1 reference)
PMID:24360809 SUPPORT Human Clinical
"In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3)."
GRHL3 coding mutations cause Van der Woude syndrome in families without IRF6 mutations.
MSX1 (Risk Factor)
Gene: MSX1 hgnc:7391
Show evidence (1 reference)
PMID:10742093 SUPPORT Human Clinical
"MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans."
MSX1 mutation links orofacial clefting with tooth agenesis in humans.
FOXE1 (Risk Factor)
Gene: FOXE1 hgnc:3806
Show evidence (1 reference)
PMID:19779022 SUPPORT Human Clinical
"These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies."
Fine-mapping and replication across multiple populations established FOXE1 as a major gene for cleft lip +/- palate and isolated cleft palate.
TP63 (Risk Factor)
Gene: TP63 hgnc:15979
Show evidence (1 reference)
PMID:10535733 SUPPORT Human Clinical
"EEC syndrome is an autosomal dominant disorder characterized by ectrodactyly, ectodermal dysplasia, and facial clefts."
TP63 (p63) germline mutations cause EEC syndrome, a Mendelian syndromic cause of facial clefting.
TGFB3 (Risk Factor)
Gene: TGFB3 hgnc:11769
Show evidence (1 reference)
PMID:7493021 SUPPORT Model Organism
"Mice lacking TGF-beta 3 exhibit an incompletely penetrant failure of the palatal shelves to fuse leading to cleft palate."
Tgfb3-null mice develop cleft palate, establishing TGF-beta 3 as an intrinsic regulator of palatal shelf fusion.
💊

Medical Actions

5
Primary Surgical Cleft Lip Repair (Cheiloplasty)
Action: surgical procedure MAXO:0000004
Staged surgical repair of the cleft lip, typically performed in the first months of life, to restore lip continuity, muscle function, and nasal symmetry.
Show evidence (1 reference)
PMID:21331089 SUPPORT Human Clinical
"can be corrected to varying degrees by surgery, dental treatment, speech therapy and psychosocial intervention"
Surgery is a mainstay of cleft management.
Surgical Cleft Palate Repair (Palatoplasty)
Action: surgical procedure MAXO:0000004
Surgical closure of the cleft palate, generally performed around 9-18 months of age, to separate the oral and nasal cavities and enable normal speech development.
Show evidence (1 reference)
PMID:20301581 SUPPORT Human Clinical
"Supportive/symptomatic treatment of VWS and PPS may include surgical treatment of lip pits and cleft lip and palate pediatric dentistry, orthodontia, speech therapy, feeding therapy, timely treatment of otitis media due to eustachian tube dysfunction to prevent secondary hearing loss"
GeneReviews management guidance confirms surgical repair of cleft lip and palate as standard treatment.
Speech and Language Therapy
Action: speech therapy MAXO:0000930
Assessment and management of velopharyngeal insufficiency and speech-sound disorders associated with palatal clefting.
Show evidence (1 reference)
PMID:21331089 SUPPORT Human Clinical
"can be corrected to varying degrees by surgery, dental treatment, speech therapy and psychosocial intervention"
Speech therapy is part of standard multidisciplinary cleft care.
Feeding Support
Action: supportive care MAXO:0000950
Specialized bottles, nipples, and feeding techniques to ensure adequate nutrition in infants before cleft repair.
Show evidence (1 reference)
PMID:20301581 SUPPORT Human Clinical
"weekly assessment of nutritional intake and weight gain during the first month of life"
GeneReviews surveillance guidance recommends weekly nutritional and weight monitoring in the first month, supporting feeding support as standard early care.
Multidisciplinary Team Care
Action: supportive care MAXO:0000950
Coordinated care from birth to adulthood involving surgery, dentistry, speech therapy, audiology, and psychosocial support.
Show evidence (1 reference)
PMID:19747722 SUPPORT Human Clinical
"children with these disorders need multidisciplinary care from birth to adulthood"
Multidisciplinary, lifelong team care is the standard management model.
🌍

Environmental Factors

4
Maternal Tobacco Smoking
Maternal cigarette smoking during the periconceptional period increases the risk of orofacial clefting in offspring, with a dose-response relationship.
Show evidence (1 reference)
PMID:15112010 SUPPORT Human Clinical
"Consistent, moderate and statistically significant associations were found between maternal smoking and cleft lip, with or without cleft palate (relative risk 1.34, 95% confidence interval 1.25-1.44) and between maternal smoking and cleft palate (relative risk 1.22, 95% confidence interval 1.10-1.35)."
Meta-analysis of 24 studies confirms maternal smoking raises the risk of both cleft lip +/- palate and cleft palate.
Maternal Folate Status
Low maternal folate intake is associated with increased cleft risk; periconceptional folic acid supplementation may reduce risk.
Show evidence (1 reference)
PMID:17259187 SUPPORT Human Clinical
"Folic acid supplementation during early pregnancy (> or =400 microg/day) was associated with a reduced risk of isolated cleft lip with or without cleft palate after adjustment for multivitamins, smoking, and other potential confounding factors"
Population-based case-control study shows periconceptional folic acid supplementation reduces the risk of isolated cleft lip +/- palate.
Maternal Alcohol Consumption
Prenatal alcohol exposure is associated with increased risk of orofacial clefts.
Show evidence (1 reference)
PMID:20810466 SUPPORT Human Clinical
"Heavy maternal alcohol consumption during early pregnancy increases the risk of oral clefts, but little is known about how genetic variation in alcohol metabolism affects this association."
Population-based case-control study links heavy early-pregnancy maternal alcohol consumption to increased oral cleft risk.
Anticonvulsant Exposure
In utero exposure to certain antiepileptic drugs, particularly valproate and phenytoin/topiramate, increases the risk of orofacial clefting.
Show evidence (1 reference)
PMID:20558369 SUPPORT Human Clinical
"The use of valproic acid monotherapy in the first trimester was associated with significantly increased risks of several congenital malformations, as compared with no use of antiepileptic drugs or with use of other antiepileptic drugs."
First-trimester valproate monotherapy was significantly associated with several malformations, including cleft palate (odds ratio 5.2, 95% CI 2.8-9.9).
{ }

Source YAML

click to show 
name: Cleft Lip/Palate
creation_date: "2026-07-01T00:00:00Z"
description: >-
  Cleft lip and/or palate (orofacial clefting) is one of the most common
  congenital malformations, arising from failure of the embryonic facial
  prominences and/or palatal shelves to fuse during the fourth to ninth weeks
  of development. Cleft lip results from incomplete fusion of the medial nasal
  and maxillary prominences forming the upper lip and primary palate; cleft
  palate results from failure of the paired secondary palatal shelves to
  elevate, appose, and fuse at the midline. Clefts may be unilateral or
  bilateral, complete or incomplete, and may involve the lip alone, the palate
  alone, or both. The great majority of cases are nonsyndromic (isolated) and
  multifactorial, reflecting the combined action of common and rare risk
  variants at loci such as IRF6, GRHL3, and the 8q24 region together with
  environmental exposures including maternal smoking, alcohol, folate status,
  and teratogenic anticonvulsants; a substantial minority occur as part of
  recognized Mendelian syndromes (e.g., Van der Woude syndrome). Clefting
  causes feeding difficulty, speech and language impairment, recurrent otitis
  media with conductive hearing loss, and dental and midfacial growth
  anomalies, and is managed by staged surgical repair and multidisciplinary
  team care.
category: Complex
parents:
- Orofacial Cleft
- Disorder of Development or Morphogenesis
disease_term:
  preferred_term: cleft lip/palate
  term:
    id: MONDO:0016044
    label: cleft lip/palate

references:
- reference: PMID:20301581
  title: "IRF6-Related Disorders."
  tags:
  - GeneReviews

prevalence:
- population: General
  percentage: 0.17
  notes: Approximately 1.7 affected births per 1000 live births, with ethnic and geographic variation.
  evidence:
  - reference: PMID:19747722
    reference_title: "Cleft lip and palate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These defects arise in about 1.7 per 1000 liveborn babies, with ethnic and geographic variation."
    explanation: Lancet seminar reports the birth prevalence of cleft lip and palate.

inheritance:
- name: Polygenic/multifactorial inheritance
  description: >-
    Nonsyndromic CL/P is a complex trait resulting from multiple genetic risk
    variants interacting with environmental exposures, departing from simple
    Mendelian inheritance.
  inheritance_term:
    preferred_term: Polygenic inheritance
    term:
      id: HP:0010982
      label: Polygenic inheritance
  evidence:
  - reference: PMID:21331089
    reference_title: "Cleft lip and palate: understanding genetic and environmental influences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clefts of the lip and/or palate (CLP) are common birth defects of complex aetiology."
    explanation: Establishes the complex (multifactorial) etiology underlying nonsyndromic clefting.

has_subtypes:
- name: Nonsyndromic CL/P
  display_name: Nonsyndromic (isolated) cleft lip with or without cleft palate
  description: >-
    Cleft lip with or without cleft palate occurring in isolation, without other
    major malformations or a recognized syndrome. Etiology is multifactorial,
    with common and rare variants at multiple loci interacting with environmental
    exposures. Accounts for roughly 70% of cleft lip +/- palate cases.
    Note: cleft lip with or without cleft palate (CL/P) and isolated cleft palate
    only (CPO) are partly distinct developmental and genetic entities (they arise
    in different embryonic windows and some loci, e.g., the IRF6 rs642961 enhancer
    variant, associate with cleft lip but not isolated cleft palate); this entry
    (MONDO:0016044) centers on the CL/P axis.
  evidence:
  - reference: PMID:21331089
    reference_title: "Cleft lip and palate: understanding genetic and environmental influences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "approximately 70% of cases of CLP occur as isolated entities with no other apparent cognitive or structural abnormalities"
    explanation: About 70% of clefts are isolated/nonsyndromic, defining this subtype.
- name: Syndromic CL/P
  display_name: Syndromic cleft lip/palate
  description: >-
    Orofacial clefting occurring as one feature of a recognized Mendelian or
    chromosomal syndrome (e.g., Van der Woude syndrome [IRF6], 22q11.2 deletion,
    ectrodactyly-ectodermal dysplasia-clefting [TP63]). A single major gene or
    chromosomal lesion drives the phenotype.
  evidence:
  - reference: PMID:20301581
    reference_title: "IRF6-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most commonly, IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS) at the mild end to popliteal pterygium syndrome (PPS) at the more severe end."
    explanation: Van der Woude syndrome is the prototypical Mendelian (IRF6) syndromic cause of cleft lip/palate.

pathophysiology:
- name: Failure of Lip and Primary Palate Fusion
  description: >-
    During weeks 4-7 of development, cranial neural crest-derived mesenchyme
    populates the frontonasal prominence and paired maxillary prominences.
    Formation of the upper lip and primary palate requires the medial nasal
    prominences to merge with each other and with the maxillary prominences.
    Deficient neural crest cell migration, proliferation, or survival, or
    failure of epithelial seam breakdown at the sites of contact, prevents
    fusion and produces a cleft of the lip (with or without the alveolus),
    which may be unilateral or bilateral.
  cell_types:
  - preferred_term: cranial neural crest cell
    term:
      id: CL:0011012
      label: neural crest cell
  biological_processes:
  - preferred_term: neural crest cell migration
    term:
      id: GO:0001755
      label: neural crest cell migration
  - preferred_term: primary palate development
    term:
      id: GO:1903929
      label: primary palate development
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:21331089
    reference_title: "Cleft lip and palate: understanding genetic and environmental influences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The common forms of CLP involve disruption of tissue planes above the lip extending into the nares and/or the palate (hard and/or soft)"
    explanation: Describes the anatomical disruption of lip and palate structures that defines clefting.
- name: Failure of Secondary Palatal Shelf Elevation and Fusion
  description: >-
    Between weeks 6 and 9, the paired secondary palatal shelves grow vertically
    beside the tongue, elevate to a horizontal position above the descending
    tongue, grow toward the midline, and fuse. Fusion requires apposition of the
    medial edge epithelia, formation of a midline epithelial seam, and
    subsequent removal of the seam by epithelial apoptosis and/or
    epithelial-mesenchymal transition, allowing mesenchymal confluence.
    Disruption of shelf growth, delayed or failed elevation, impaired seam
    formation, or persistence of the medial edge epithelium yields a cleft of
    the secondary palate.
  cell_types:
  - preferred_term: palatal shelf mesenchyme (cranial neural crest-derived)
    term:
      id: CL:0011012
      label: neural crest cell
  biological_processes:
  - preferred_term: secondary palate development
    term:
      id: GO:0062009
      label: secondary palate development
  - preferred_term: epithelial cell apoptosis in palatal shelf fusion
    term:
      id: GO:1990134
      label: epithelial cell apoptotic process involved in palatal shelf morphogenesis
  - preferred_term: roof of mouth development
    term:
      id: GO:0060021
      label: roof of mouth development
  evidence:
  - reference: PMID:22186724
    reference_title: "Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the embryonic primary and secondary palatal shelves develop as outgrowths from the medial nasal and maxillary prominences, respectively, remodel and fuse to form the intact roof of the oral cavity."
    explanation: Describes the palatal shelf outgrowth, remodeling, and midline fusion whose failure produces cleft palate.
  - reference: PMID:7493021
    reference_title: "Transforming growth factor-beta 3 is required for secondary palate fusion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The defect appears to result from impaired adhesion of the apposing medial edge epithelia of the palatal shelves and subsequent elimination of the mid-line epithelial seam."
    explanation: Tgfb3-null mice show that failed medial edge epithelial adhesion and seam removal cause cleft palate, mechanistically linking this node to palatal fusion failure.
- name: Disruption of the Orofacial Developmental Gene Regulatory Network
  description: >-
    Lip and palate morphogenesis is governed by a conserved gene regulatory
    network in which transcription factors and signaling pathways (IRF6-GRHL3
    in the periderm/oral epithelium; SHH, BMP4, FGF, and WNT signaling; MSX1,
    FOXE1, PAX7, TP63) coordinate epithelial-mesenchymal interactions.
    Pathogenic variants and common risk alleles at these loci perturb the
    network, reducing the developmental robustness of fusion and increasing
    cleft susceptibility. IRF6 is the single most important locus, contributing
    to both syndromic (Van der Woude) and nonsyndromic clefting.
  gene:
    preferred_term: IRF6
    term:
      id: hgnc:6121
      label: IRF6
  cell_types:
  - preferred_term: oral periderm cell
    term:
      id: CL:0000078
      label: peridermal cell
  biological_processes:
  - preferred_term: roof of mouth development
    term:
      id: GO:0060021
      label: roof of mouth development
  downstream:
  - target: Failure of Lip and Primary Palate Fusion
    causal_link_type: DIRECT
    description: >-
      Perturbation of the IRF6-GRHL3 periderm/epithelial network reduces the
      developmental robustness of medial nasal-maxillary prominence fusion,
      predisposing to cleft lip and primary palate.
  - target: Failure of Secondary Palatal Shelf Elevation and Fusion
    causal_link_type: DIRECT
    description: >-
      The same epithelial gene regulatory network (and TGF-beta signaling)
      governs medial edge epithelial adhesion and seam removal, so its
      disruption predisposes to failed secondary palatal shelf fusion.
  evidence:
  - reference: PMID:18836445
    reference_title: "Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The A allele is significantly overtransmitted (P = 1 x 10(-11)) in families with NSCL/P, in particular those with cleft lip but not cleft palate."
    explanation: A common regulatory variant in an IRF6 enhancer perturbs the network and increases cleft-lip risk.
  - reference: PMID:18836445
    reference_title: "Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures"
    explanation: In vivo mouse expression analysis places the IRF6 enhancer activity in developing craniofacial structures, supporting its role in the orofacial gene regulatory network.
  - reference: PMID:20436469
    reference_title: "A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance"
    explanation: GWAS confirms multiple risk loci (8q24, IRF6, MAFB, ABCA4) contributing to the gene regulatory network underlying nonsyndromic CL/P.

phenotypes:
- category: Craniofacial
  name: Cleft lip
  description: >-
    A fissure of the upper lip resulting from failure of fusion of the medial
    nasal and maxillary prominences, ranging from a minor notch to a complete
    cleft extending into the nostril; may be unilateral or bilateral.
  phenotype_term:
    preferred_term: Cleft lip
    term:
      id: HP:0410030
      label: Cleft lip
  evidence:
  - reference: PMID:19747722
    reference_title: "Cleft lip and palate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clefts of the lip and palate are generally divided into two groups, isolated cleft palate and cleft lip with or without cleft palate, representing a heterogeneous group of disorders affecting the lips and oral cavity."
    explanation: Defines cleft lip with or without cleft palate as a core clinical group.
- category: Craniofacial
  name: Cleft palate
  description: >-
    A midline opening in the roof of the mouth from failed fusion of the
    secondary palatal shelves, involving the hard and/or soft palate.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:19747722
    reference_title: "Cleft lip and palate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clefts of the lip and palate are generally divided into two groups, isolated cleft palate and cleft lip with or without cleft palate, representing a heterogeneous group of disorders affecting the lips and oral cavity."
    explanation: Cleft palate is one of the two principal cleft groups.
- category: Feeding
  name: Feeding difficulties in infancy
  description: >-
    Impaired ability to generate suction and inefficient feeding due to the
    oronasal communication, a common early complication requiring specialized
    feeding techniques.
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  evidence:
  - reference: PMID:21331089
    reference_title: "Cleft lip and palate: understanding genetic and environmental influences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with CLP may experience problems with feeding, speaking, hearing and social integration"
    explanation: Feeding difficulty is a recognized complication of clefting.
- category: Otologic
  name: Otitis media
  description: >-
    Recurrent middle ear effusion, especially with cleft palate, due to
    dysfunction of the tensor veli palatini and Eustachian tube, commonly
    causing conductive hearing loss.
  phenotype_term:
    preferred_term: Otitis media
    term:
      id: HP:0000388
      label: Otitis media
  evidence:
  - reference: PMID:25287451
    reference_title: "Grommets for otitis media with effusion in children with cleft palate: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with conservative forms of management (eg, watchful waiting), VTI has been shown to be beneficial to the recovery of hearing in children with cleft palate and OME."
    explanation: Otitis media with effusion and associated hearing loss are common in children with cleft palate and are managed with ventilation tubes.
- category: Otologic
  name: Conductive hearing impairment
  description: >-
    Conductive hearing loss secondary to chronic middle ear effusion from
    Eustachian tube dysfunction, particularly in children with cleft palate.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:25287451
    reference_title: "Grommets for otitis media with effusion in children with cleft palate: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with conservative forms of management (eg, watchful waiting), VTI has been shown to be beneficial to the recovery of hearing in children with cleft palate and OME."
    explanation: Otitis media with effusion in cleft palate causes hearing loss recoverable with ventilation tubes, consistent with a conductive mechanism.
- category: Neurodevelopmental
  name: Delayed speech and language development
  description: >-
    Speech and language delay and velopharyngeal insufficiency, related to
    palatal dysfunction and hearing loss.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:21331089
    reference_title: "Cleft lip and palate: understanding genetic and environmental influences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with CLP may experience problems with feeding, speaking, hearing and social integration"
    explanation: Speech/language problems are a recognized functional consequence of clefting.
- category: Dental
  name: Dental anomalies
  description: >-
    Abnormalities of tooth number, shape, and position, particularly in the
    region of the alveolar cleft.
  phenotype_term:
    preferred_term: Abnormality of the dentition
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  evidence:
  - reference: PMID:10742093
    reference_title: "MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans."
    explanation: MSX1 links clefting to tooth agenesis, illustrating the dental anomalies that co-occur with orofacial clefting.

genetic:
- name: IRF6
  association: Risk Factor
  gene_term:
    preferred_term: IRF6
    term:
      id: hgnc:6121
      label: IRF6
  notes: >-
    Interferon regulatory factor 6. Loss-of-function variants cause Van der
    Woude syndrome (the most common syndromic cleft); common variants (e.g.,
    rs642961) are a major susceptibility factor for nonsyndromic CL/P.
  evidence:
  - reference: PMID:15317890
    reference_title: "Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strong evidence of overtransmission of the valine (V) allele was found in the entire population data set (P<10(-9))"
    explanation: IRF6 coding variation is significantly associated with isolated cleft lip or palate across populations.
  - reference: PMID:15317890
    reference_title: "Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified the gene that encodes interferon regulatory factor 6"
    explanation: IRF6 was identified as a candidate through its role in Van der Woude syndrome.
- name: GRHL3
  association: Risk Factor
  gene_term:
    preferred_term: GRHL3
    term:
      id: hgnc:25839
      label: GRHL3
  notes: >-
    Grainyhead-like 3, acts downstream of IRF6 in the periderm; dominant
    variants cause Van der Woude syndrome (type 2).
  evidence:
  - reference: PMID:24360809
    reference_title: "Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3)."
    explanation: GRHL3 coding mutations cause Van der Woude syndrome in families without IRF6 mutations.
- name: MSX1
  association: Risk Factor
  gene_term:
    preferred_term: MSX1
    term:
      id: hgnc:7391
      label: MSX1
  notes: Msh homeobox 1; variants associated with clefting and tooth agenesis.
  evidence:
  - reference: PMID:10742093
    reference_title: "MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans."
    explanation: MSX1 mutation links orofacial clefting with tooth agenesis in humans.
- name: FOXE1
  association: Risk Factor
  gene_term:
    preferred_term: FOXE1
    term:
      id: hgnc:3806
      label: FOXE1
  notes: Forkhead box E1; risk locus for nonsyndromic CL/P.
  evidence:
  - reference: PMID:19779022
    reference_title: "FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies."
    explanation: Fine-mapping and replication across multiple populations established FOXE1 as a major gene for cleft lip +/- palate and isolated cleft palate.
- name: TP63
  association: Risk Factor
  gene_term:
    preferred_term: TP63
    term:
      id: hgnc:15979
      label: TP63
  notes: >-
    Tumor protein p63; variants cause ectodermal dysplasia syndromes with
    clefting and act upstream of IRF6.
  evidence:
  - reference: PMID:10535733
    reference_title: "Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EEC syndrome is an autosomal dominant disorder characterized by ectrodactyly, ectodermal dysplasia, and facial clefts."
    explanation: TP63 (p63) germline mutations cause EEC syndrome, a Mendelian syndromic cause of facial clefting.
- name: TGFB3
  association: Risk Factor
  gene_term:
    preferred_term: TGFB3
    term:
      id: hgnc:11769
      label: TGFB3
  notes: >-
    Transforming growth factor beta 3; key regulator of palatal shelf adhesion
    and midline epithelial seam breakdown, and a nonsyndromic cleft
    susceptibility and gene-environment (smoking) interaction locus.
  evidence:
  - reference: PMID:7493021
    reference_title: "Transforming growth factor-beta 3 is required for secondary palate fusion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice lacking TGF-beta 3 exhibit an incompletely penetrant failure of the palatal shelves to fuse leading to cleft palate."
    explanation: Tgfb3-null mice develop cleft palate, establishing TGF-beta 3 as an intrinsic regulator of palatal shelf fusion.

environmental:
- name: Maternal Tobacco Smoking
  description: >-
    Maternal cigarette smoking during the periconceptional period increases the
    risk of orofacial clefting in offspring, with a dose-response relationship.
  evidence:
  - reference: PMID:15112010
    reference_title: "Tobacco smoking and oral clefts: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent, moderate and statistically significant associations were found between maternal smoking and cleft lip, with or without cleft palate (relative risk 1.34, 95% confidence interval 1.25-1.44) and between maternal smoking and cleft palate (relative risk 1.22, 95% confidence interval 1.10-1.35)."
    explanation: Meta-analysis of 24 studies confirms maternal smoking raises the risk of both cleft lip +/- palate and cleft palate.
- name: Maternal Folate Status
  description: >-
    Low maternal folate intake is associated with increased cleft risk;
    periconceptional folic acid supplementation may reduce risk.
  evidence:
  - reference: PMID:17259187
    reference_title: "Folic acid supplements and risk of facial clefts: national population based case-control study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Folic acid supplementation during early pregnancy (> or =400 microg/day) was associated with a reduced risk of isolated cleft lip with or without cleft palate after adjustment for multivitamins, smoking, and other potential confounding factors"
    explanation: Population-based case-control study shows periconceptional folic acid supplementation reduces the risk of isolated cleft lip +/- palate.
- name: Maternal Alcohol Consumption
  description: >-
    Prenatal alcohol exposure is associated with increased risk of orofacial
    clefts.
  evidence:
  - reference: PMID:20810466
    reference_title: "Maternal alcohol consumption, alcohol metabolism genes, and the risk of oral clefts: a population-based case-control study in Norway, 1996-2001."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heavy maternal alcohol consumption during early pregnancy increases the risk of oral clefts, but little is known about how genetic variation in alcohol metabolism affects this association."
    explanation: Population-based case-control study links heavy early-pregnancy maternal alcohol consumption to increased oral cleft risk.
- name: Anticonvulsant Exposure
  description: >-
    In utero exposure to certain antiepileptic drugs, particularly valproate
    and phenytoin/topiramate, increases the risk of orofacial clefting.
  evidence:
  - reference: PMID:20558369
    reference_title: "Valproic acid monotherapy in pregnancy and major congenital malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The use of valproic acid monotherapy in the first trimester was associated with significantly increased risks of several congenital malformations, as compared with no use of antiepileptic drugs or with use of other antiepileptic drugs."
    explanation: First-trimester valproate monotherapy was significantly associated with several malformations, including cleft palate (odds ratio 5.2, 95% CI 2.8-9.9).

treatments:
- name: Primary Surgical Cleft Lip Repair (Cheiloplasty)
  description: >-
    Staged surgical repair of the cleft lip, typically performed in the first
    months of life, to restore lip continuity, muscle function, and nasal
    symmetry.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:21331089
    reference_title: "Cleft lip and palate: understanding genetic and environmental influences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "can be corrected to varying degrees by surgery, dental treatment, speech therapy and psychosocial intervention"
    explanation: Surgery is a mainstay of cleft management.
- name: Surgical Cleft Palate Repair (Palatoplasty)
  description: >-
    Surgical closure of the cleft palate, generally performed around 9-18 months
    of age, to separate the oral and nasal cavities and enable normal speech
    development.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:20301581
    reference_title: "IRF6-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Supportive/symptomatic treatment of VWS and PPS may include surgical treatment of lip pits and cleft lip and palate pediatric dentistry, orthodontia, speech therapy, feeding therapy, timely treatment of otitis media due to eustachian tube dysfunction to prevent secondary hearing loss"
    explanation: GeneReviews management guidance confirms surgical repair of cleft lip and palate as standard treatment.
- name: Speech and Language Therapy
  description: >-
    Assessment and management of velopharyngeal insufficiency and
    speech-sound disorders associated with palatal clefting.
  treatment_term:
    preferred_term: speech therapy
    term:
      id: MAXO:0000930
      label: speech therapy
  evidence:
  - reference: PMID:21331089
    reference_title: "Cleft lip and palate: understanding genetic and environmental influences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "can be corrected to varying degrees by surgery, dental treatment, speech therapy and psychosocial intervention"
    explanation: Speech therapy is part of standard multidisciplinary cleft care.
- name: Feeding Support
  description: >-
    Specialized bottles, nipples, and feeding techniques to ensure adequate
    nutrition in infants before cleft repair.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301581
    reference_title: "IRF6-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "weekly assessment of nutritional intake and weight gain during the first month of life"
    explanation: GeneReviews surveillance guidance recommends weekly nutritional and weight monitoring in the first month, supporting feeding support as standard early care.
- name: Multidisciplinary Team Care
  description: >-
    Coordinated care from birth to adulthood involving surgery, dentistry,
    speech therapy, audiology, and psychosocial support.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:19747722
    reference_title: "Cleft lip and palate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "children with these disorders need multidisciplinary care from birth to adulthood"
    explanation: Multidisciplinary, lifelong team care is the standard management model.
📚

References & Deep Research

References

1
PMID:20301581
IRF6-Related Disorders.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 59 citations 2026-07-01T19:23:22.027976

1. Disease Information

Overview

Cleft lip and/or palate (CL/P) represents the most common congenital craniofacial malformation worldwide, affecting approximately 1 in 700 live births (ma2025burdenoforofacial pages 1-2, im2025molecularregulationof pages 5-6). The condition results from failure of fusion of the facial processes during embryogenesis, leading to structural discontinuity of the lip, alveolus, and/or palate (won2023generegulatorynetworks pages 1-2). Craniofacial development relies on proper growth and fusion of initially distinct collections of mesenchyme derived from the cranial neural crest, covered by epithelium of ectodermal origin (won2023generegulatorynetworks pages 1-2). Perturbation of the coordinated morphogenetic events underlying these processes—including cell migration, survival, proliferation, death, patterning, adhesion, and differentiation—can lead to orofacial cleft phenotypes (won2023generegulatorynetworks pages 1-2).

Key Identifiers

  • MONDO: MONDO:0016044 (cleft lip/palate)
  • OMIM: Multiple entries including #119530 (CL/P nonsyndromic), #119300 (Van der Woude syndrome with IRF6)
  • ICD-10: Q35 (Cleft palate), Q36 (Cleft lip), Q37 (Cleft palate with cleft lip)
  • ICD-11: LA20.0 (Cleft lip), LA20.1 (Cleft palate), LA20.2 (Cleft lip with cleft palate)
  • MeSH: D002971 (Cleft Lip), D002972 (Cleft Palate)
  • Orphanet: ORPHA:199306 (Cleft lip/palate)

Synonyms and Alternative Names

Common synonyms include: orofacial cleft (OFC), harelip (archaic), cheiloschisis (cleft lip), palatoschisis (cleft palate), CL/P, NSCL/P (nonsyndromic cleft lip with or without palate), CLP (cleft lip with cleft palate), CPO (cleft palate only). The condition is classified into three main subtypes: cleft lip only (CL), cleft palate only (CP), and cleft lip with cleft palate (CLP) (jaruga2022orofacialcleftand pages 3-5).

Data Sources

The information herein is derived from aggregated disease-level resources including population-based epidemiological studies (Global Burden of Disease), molecular genetic research (GWAS, WES, WGS), curated disease-gene databases (OpenTargets, ClinVar, OMIM), clinical trial registries, and primary research literature.

2. Etiology

Disease Causal Factors

CL/P has a complex, multifactorial etiology involving interactions between genetic susceptibility and environmental exposures. Approximately 93–97% of cases are nonsyndromic (NSCLP), arising from cumulative effects of multiple genetic alterations with modest effect sizes interacting with environmental factors (im2025molecularregulationof pages 5-6). The remaining 5–7% are syndromic, associated with over 400 genetic syndromes following Mendelian inheritance patterns (jaruga2022orofacialcleftand pages 3-5).

Genetic Risk Factors

Major susceptibility genes identified through GWAS, linkage studies, and sequencing include IRF6, MSX1, ARHGAP29, CTNND1, PAX7, TP63, CDH1, BMP4, NTN1, NECTIN1, FOXE1, TGFB3, GRHL3, and others (OpenTargets Search: cleft lip,cleft palate, jaruga2022orofacialcleftand pages 5-6, cheng2023geneticinheritancemodels pages 2-5, im2025molecularregulationof pages 5-6). IRF6 is the most extensively validated susceptibility gene, with heterozygous pathogenic mutations causing Van der Woude syndrome (the most common syndromic form, affecting ~15% of patients) and common regulatory variants contributing to nonsyndromic risk (cheng2023geneticinheritancemodels pages 2-5, rahimov2024highincidenceand pages 1-4). MSX1 and IRF6 are the only two genes in which rare mutations contribute to both syndromic and nonsyndromic forms of CL/P and CP (rahimov2024highincidenceand pages 1-4). Linkage analysis has identified over 20 chromosomal regions linked to NSCLP, including 1p36, 2p21, 3p11.1, 8q21.3, 8q24, 13q31.1, and 15q22 (cheng2023geneticinheritancemodels pages 5-6, im2025molecularregulationof pages 6-8). Patients with a positive family history have up to a 32-fold increased risk, with an estimated recurrence risk of 4–10% (im2025molecularregulationof pages 5-6, jaruga2022orofacialcleftand pages 5-6).

The following table summarizes the key genes implicated in CL/P with their functions and association evidence:

Gene symbol Full name OMIM ID (if known) Associated syndrome / phenotype Gene function relevant to CL/P Typical variant type(s) reported OpenTargets association score Key evidence
IRF6 Interferon regulatory factor 6 607199 Van der Woude syndrome; popliteal pterygium syndrome; syndromic and non-syndromic cleft lip/palate; regulatory variant associated with cleft palate in Finland Periderm differentiation; epithelial integrity; palatal fusion transcriptional regulator Heterozygous pathogenic variants; common risk SNPs; regulatory/enhancer variants 0.57 (cleft lip); 0.42 (cleft lip/palate) (OpenTargets Search: cleft lip,cleft palate, cheng2023geneticinheritancemodels pages 2-5, rahimov2024highincidenceand pages 1-4, im2025molecularregulationof pages 5-6, im2025molecularregulationof pages 16-18)
MSX1 Msh homeobox 1 142983 Non-syndromic CL/P; tooth agenesis; rare syndromic and non-syndromic cleft palate/lip-palate Homeobox transcription factor in craniofacial patterning; regulates epithelial-mesenchymal signaling during palate development Rare pathogenic coding variants; common susceptibility variants; null alleles in models 0.47 (cleft lip); 0.77 (cleft lip/palate) (OpenTargets Search: cleft lip,cleft palate, cheng2023geneticinheritancemodels pages 2-5, rahimov2024highincidenceand pages 1-4, cheng2023geneticinheritancemodels pages 11-12, won2023generegulatorynetworks pages 13-14)
BMP4 Bone morphogenetic protein 4 112262 Cleft lip/palate susceptibility; craniofacial malformations BMP pathway ligand controlling proliferation, differentiation, apoptosis, and palatal mesenchyme growth Susceptibility SNPs; missense/duplication evidence in broader craniofacial anomaly literature 0.74 (cleft lip/palate) (OpenTargets Search: cleft lip,cleft palate, im2025molecularregulationof pages 36-37, im2025molecularregulationof pages 12-13, won2023generegulatorynetworks pages 13-14)
TP63 Tumor protein p63 603273 EEC syndrome; Hay-Wells syndrome; Rapp-Hodgkin syndrome; CL/P susceptibility Epithelial development, adhesion, and palatal seam biology; upstream regulator of epithelial differentiation Rare pathogenic missense / truncating variants; GWAS SNP rs76479869 association 0.42 (cleft lip); 0.49 (cleft lip/palate) (OpenTargets Search: cleft lip,cleft palate, jaruga2022orofacialcleftand pages 5-6, cheng2023geneticinheritancemodels pages 5-6, won2023generegulatorynetworks pages 8-10)
ARHGAP29 Rho GTPase activating protein 29 610496 Non-syndromic cleft lip / palate susceptibility Cytoskeletal / Rho signaling regulator implicated in craniofacial morphogenesis Rare pathogenic variants; susceptibility variants from sequencing/GWAS-supported studies 0.61 (cleft lip) (OpenTargets Search: cleft lip,cleft palate, jaruga2022orofacialcleftand pages 5-6)
CTNND1 Catenin delta 1 601045 Non-syndromic CL/P; epithelial adhesion-related cleft phenotypes Cadherin–catenin complex component regulating epithelial adhesion and integrity Pathogenic/likely pathogenic variants; splice-related dysregulation via ESRP1/2 0.51 (cleft lip) (OpenTargets Search: cleft lip,cleft palate, cheng2023geneticinheritancemodels pages 5-6, im2025molecularregulationof pages 15-16)
PAX7 Paired box 7 167410 Non-syndromic cleft lip susceptibility; frontonasal patterning-related phenotypes Transcription factor involved in craniofacial/frontonasal mesenchyme development Common susceptibility variants/SNPs 0.49 (cleft lip) (OpenTargets Search: cleft lip,cleft palate, jaruga2022orofacialcleftand pages 5-6, im2025molecularregulationof pages 24-26)
CDH1 Cadherin 1 192090 Blepharocheilodontic syndrome; cleft lip susceptibility Cell-cell adhesion protein essential for epithelial integrity Heterozygous pathogenic variants; likely loss-of-function / missense variants 0.39 (cleft lip) (OpenTargets Search: cleft lip,cleft palate, cheng2023geneticinheritancemodels pages 2-5, cheng2023geneticinheritancemodels pages 12-14)
NECTIN1 Nectin cell adhesion molecule 1 600644 Cleft lip/palate-ectodermal dysplasia syndrome; cleft lip susceptibility Cell adhesion molecule contributing to epithelial fusion processes Pathogenic variants in syndromic clefting; curated gene-disease evidence 0.48 (cleft lip); 0.85 (cleft lip/palate-ectodermal dysplasia syndrome) (OpenTargets Search: cleft lip,cleft palate)
NTN1 Netrin 1 601614 Non-syndromic cleft lip susceptibility Guidance cue involved in tissue morphogenesis and craniofacial developmental signaling Common susceptibility variants; sequencing-supported variants 0.47 (cleft lip) (OpenTargets Search: cleft lip,cleft palate, cheng2023geneticinheritancemodels pages 12-14)
GRHL3 Grainyhead like transcription factor 3 608317 Cleft palate; downstream effector of IRF6; syndromic/non-syndromic palatal defects Periderm differentiation and epithelial barrier/fusion regulation Rare pathogenic variants; GWAS locus evidence for cleft palate Not listed in retrieved OpenTargets results (rahimov2024highincidenceand pages 1-4, alhazmi2024theapplicationof pages 1-3)
FOXE1 Forkhead box E1 602617 Associated with all major OFC types; non-syndromic CL/P susceptibility Craniofacial developmental transcription factor Susceptibility SNPs, including rs12347191 near FOXE1 Not listed in retrieved OpenTargets results (jaruga2022orofacialcleftand pages 5-6, im2025molecularregulationof pages 5-6, im2025molecularregulationof pages 6-8)
TGFB3 Transforming growth factor beta 3 190230 Cleft palate / CL/P susceptibility; smoking-interaction risk locus Key regulator of palatal shelf adhesion/fusion and MES breakdown Susceptibility variants/polymorphisms; gene-environment interaction variants Not listed in retrieved OpenTargets results (im2025molecularregulationof pages 6-8, im2025molecularregulationof pages 36-37, im2025molecularregulationof pages 15-16)
FGFR1 Fibroblast growth factor receptor 1 136350 CL/P susceptibility; craniofacial developmental anomalies FGF receptor mediating epithelial-mesenchymal signaling in palatogenesis Susceptibility variants; rare pathogenic variants in craniofacial syndromes Not listed in retrieved OpenTargets results (im2025molecularregulationof pages 5-6, im2025molecularregulationof pages 6-8, im2025molecularregulationof pages 9-12)
SUMO1 Small ubiquitin-like modifier 1 601912 Cleft lip/palate Post-translational modifier implicated in craniofacial development Rare pathogenic / copy-number-related evidence in curated datasets 0.42 (cleft lip/palate) (OpenTargets Search: cleft lip,cleft palate)

Table: This table summarizes high-priority genes implicated in cleft lip and/or palate, integrating curated disease-target associations with mechanistic and genetic evidence. It is useful for building a disease knowledge base entry and prioritizing genes for annotation, diagnostics, and pathway analysis.

Environmental Risk Factors

Multiple modifiable environmental risk factors have been identified. Maternal smoking is a significant risk factor with odds ratios ranging from 1.3–1.8 for unilateral CLP and up to 4.2 for bilateral cases when exceeding 25 cigarettes daily (viswapurna2024roleofepigenetics pages 3-4). Folate deficiency during the first trimester increases cleft lip risk 4.36-fold (viswapurna2024roleofepigenetics pages 3-4). Additional risk factors include maternal pre-pregnancy diabetes mellitus (OR 1.96), maternal obesity (OR 1.32 for grade II and extreme obesity), pre-pregnancy hypertension (OR 1.17), use of assisted reproductive technology (OR 1.40), maternal alcohol consumption, air pollutant exposure (PM2.5, PM10, ozone, carbon monoxide), teratogenic medications (corticosteroids, phenytoin), and TCDD/dioxin exposure (viswapurna2024roleofepigenetics pages 3-4, im2025molecularregulationof pages 46-47, iwaya2023micrornasandgene pages 10-12).

Protective Factors

Periconceptional folic acid supplementation (≥400 µg/day during the first four weeks of gestation) is the most well-established protective factor, supporting folate-dependent one-carbon metabolism, nucleotide synthesis, and methylation during neural crest and palatal development (viswapurna2024roleofepigenetics pages 3-4, im2025molecularregulationof pages 46-47, viswapurna2024roleofepigenetics pages 7-8).

Gene-Environment Interactions

Significant gene-environment interactions have been documented. Infants born to smoking mothers carrying the MSX1 susceptibility genotype have a 7.16-fold increased cleft risk (viswapurna2024roleofepigenetics pages 2-3). The RUNX2 genetic variant also increases cleft risk with maternal smoking exposure (viswapurna2024roleofepigenetics pages 3-4). Polymorphisms in TGF-α, TGFB3, and BMP4 interact with smoking to increase OFC risk (im2025molecularregulationof pages 36-37). MTHFR polymorphisms (C677T, 1298A>C) modify the impact of folate deficiency on cleft risk (viswapurna2024roleofepigenetics pages 3-4, alghonemy2025metaanalysisandsystematic pages 7-7).

The following table provides a detailed summary of environmental risk and protective factors:

Factor Category (Risk/Protective) Effect Size (OR if available) Mechanism Gene-Environment Interaction Source
Maternal smoking Risk OR 1.3-1.8 overall; up to OR 4.2 for bilateral cases with >25 cigarettes/day Nicotine-mediated vasoconstriction may impair uteroplacental blood flow and fetal oxygen delivery; smoke exposure is also linked to DNA methylation changes and oxidative-stress/cell-cycle dysregulation during craniofacial development Reported interactions with MSX1, RUNX2, TGFA, TGFB3, and BMP4 susceptibility variants (viswapurna2024roleofepigenetics pages 3-4, im2025molecularregulationof pages 36-37, viswapurna2024roleofepigenetics pages 2-3, iwaya2023micrornasandgene pages 10-12)
Folate deficiency / low periconceptional folate Risk OR 4.36 Reduced one-carbon metabolism and methyl-donor availability can impair neural crest/palatal development and alter DNA methylation during embryogenesis Strongly linked to MTHFR and other folate-pathway variants such as SHMT1 (viswapurna2024roleofepigenetics pages 3-4, im2025molecularregulationof pages 46-47, alghonemy2025metaanalysisandsystematic pages 7-7)
Maternal alcohol exposure Risk Not consistently quantified in retrieved evidence Alcohol can inhibit retinoic acid biosynthesis via acetaldehyde and disrupt craniofacial morphogenesis; first-trimester binge drinking is particularly implicated Gene-environment interaction frameworks reported; PDGFRA noted as protective in animal models against alcohol-related craniofacial defects (im2025molecularregulationof pages 46-47, cheng2023geneticinheritancemodels pages 14-15, iwaya2023micrornasandgene pages 10-12)
Maternal obesity (including grade II/extreme obesity) Risk OR 1.32 Likely contributes through metabolic/inflammatory dysregulation during early development No specific interaction quantified in retrieved evidence (viswapurna2024roleofepigenetics pages 3-4, cheng2023geneticinheritancemodels pages 14-15)
Pre-pregnancy diabetes mellitus Risk OR 1.96 Hyperglycemia and metabolic teratogenicity may perturb craniofacial development No specific interaction quantified in retrieved evidence (viswapurna2024roleofepigenetics pages 3-4)
Pre-pregnancy hypertension Risk OR 1.17 Vascular and placental dysfunction may adversely affect embryonic craniofacial development No specific interaction quantified in retrieved evidence (viswapurna2024roleofepigenetics pages 3-4)
Assisted reproductive technology Risk OR 1.40 Mechanism uncertain; may reflect parental/subfertility factors or early embryologic influences No specific interaction quantified in retrieved evidence (viswapurna2024roleofepigenetics pages 3-4)
TCDD / dioxins Risk Not quantified in retrieved evidence TCDD can inhibit palatal fusion and acts through epigenetic mechanisms including histone acetylation and microRNA dysregulation Interacts with genetically susceptible developmental pathways; exact human genotype modifier not specified in retrieved evidence (im2025molecularregulationof pages 46-47)
Retinoic acid excess / vitamin A toxicity Risk Not quantified in retrieved evidence Excess retinoids impair key signaling pathways during palatogenesis and are recognized teratogens; dysregulated RA signaling disrupts facial process fusion Alcohol-related RA deficiency and retinoid pathway susceptibility may modify risk (im2025molecularregulationof pages 46-47, viswapurna2024roleofepigenetics pages 2-3)
Air pollutants (PM2.5, PM10, ozone, carbon monoxide) Risk Not quantified in retrieved evidence Early gestational pollutant exposure may induce oxidative stress and developmental disruption No specific interaction quantified in retrieved evidence (viswapurna2024roleofepigenetics pages 3-4)
Maternal stress Risk Not quantified in retrieved evidence Psychophysiologic stress is associated with increased risk in observational studies; likely mediated through neuroendocrine and inflammatory pathways No specific interaction quantified in retrieved evidence (cheng2023geneticinheritancemodels pages 14-15, viswapurna2024roleofepigenetics pages 2-3)
Folic acid supplementation (>=400 µg/day during first 4 weeks/periconception) Protective Protective; inverse association reported Supports folate-dependent one-carbon metabolism, nucleotide synthesis, and methylation during neural crest/palatal development Particularly relevant in carriers of folate-pathway risk variants such as MTHFR (viswapurna2024roleofepigenetics pages 3-4, im2025molecularregulationof pages 46-47, viswapurna2024roleofepigenetics pages 7-8, alghonemy2025metaanalysisandsystematic pages 7-7)
MTHFR polymorphisms (e.g., C677T, 1298A>C) Genetic susceptibility / risk modifier Not uniform across studies Reduced folate utilization and lower SAM availability may lead to hypomethylation and increased susceptibility to clefting Modifies impact of folate deficiency and may alter response to folic acid supplementation (viswapurna2024roleofepigenetics pages 3-4, im2025molecularregulationof pages 46-47, alghonemy2025metaanalysisandsystematic pages 7-7)
MSX1 genotype with maternal smoking Gene-environment risk interaction 7.16-fold increased risk Smoking exposure plus cleft-susceptibility genotype likely amplifies developmental signaling disruption during lip/palate fusion MSX1 × smoking (viswapurna2024roleofepigenetics pages 2-3)
RUNX2 variant with maternal smoking Gene-environment risk interaction Increased risk reported; exact OR not provided in retrieved evidence Smoking appears to enhance the effect of craniofacial regulatory variation on cleft risk RUNX2 × smoking (viswapurna2024roleofepigenetics pages 3-4, viswapurna2024roleofepigenetics pages 2-3)
TGFA / TGFB3 / BMP4 polymorphisms with smoking Gene-environment risk interaction Increased risk reported; exact ORs not provided in retrieved evidence Tobacco exposure may interact with growth-factor signaling and methylation-sensitive pathways central to fusion and epithelial-mesenchymal signaling TGFA × smoking, TGFB3 × smoking, BMP4 × smoking (im2025molecularregulationof pages 36-37, viswapurna2024roleofepigenetics pages 2-3)

Table: This table summarizes major environmental and gene-environment contributors to cleft lip/palate risk, including effect sizes where available. It is useful for etiologic annotation, prevention planning, and linking modifiable exposures to molecular susceptibility pathways.

3. Phenotypes

Clinical Features

CL/P phenotypes are characterized by structural discontinuity in the lip and/or palate, resulting in impairment of multiple critical functions (jaruga2022orofacialcleftand pages 3-5). The most common presentation is unilateral cleft lip and palate (UCLP, 30–35%), followed by isolated CL or CP (20–25% each), with bilateral cleft lip and palate (BCLP) being least common (10%) (wongsirichat2022theprevalenceof pages 2-5). Unilateral clefts are twice as frequent on the left side (jaruga2022orofacialcleftand pages 3-5).

Feeding difficulties (HP:0011968): Cleft lip prevents proper nipple seal during breastfeeding, while cleft palate prevents negative pressure generation needed for milk intake and impairs tongue compression, leading to poor nutrition and inadequate weight gain (wongsirichat2022theprevalenceof pages 2-5, jaruga2022orofacialcleftand pages 3-5). Surgical palatal repair improved feeding in 79% of cases (wongsirichat2022theprevalenceof pages 5-6, wongsirichat2022theprevalenceof pages 2-5).

Speech and language impairment (HP:0000750): Patients manifest atypical consonant production, abnormal nasal resonance (hypernasality), and delayed language acquisition. Velopharyngeal insufficiency (VPI) requiring surgical intervention occurs in approximately 59% of bilateral cleft patients (wongsirichat2022theprevalenceof pages 5-6, hattori2023longtermtreatmentoutcome pages 1-2).

Hearing loss/otitis media (HP:0000365, HP:0000388): High rates of otitis media with effusion and hearing problems are documented in CL/P patients (NCT00829101 chunk 1).

Dental anomalies (HP:0000164): Dental development is delayed an average of 6–7 months compared to unaffected children. Complications include hypodontia, malocclusion, transverse maxillary arch collapse with crossbite, crowding, and incisor retroclination (wongsirichat2022theprevalenceof pages 5-6, jaruga2022orofacialcleftand pages 3-5).

Maxillary growth impairment (HP:0000347): Maxillary underdevelopment is a significant complication, with skeletal class III anteroposterior deficiency occurring in operated cleft patients (wongsirichat2022theprevalenceof pages 2-5). Orthognathic surgery was required in 60.7% of BCLP patients with midface retrusion (hattori2023longtermtreatmentoutcome pages 1-2).

Quality of Life Impact: CL/P causes major morbidity throughout life as a result of problems with facial appearance, feeding, speaking, obstructive apnea, hearing, and social adjustment, requiring complex multidisciplinary care at considerable cost to healthcare systems worldwide (wongsirichat2022theprevalenceof pages 1-2).

Suggested HPO Terms

  • HP:0000175 (Cleft palate)
  • HP:0000204 (Cleft upper lip)
  • HP:0000202 (Cleft lip and palate)
  • HP:0011968 (Feeding difficulties)
  • HP:0000750 (Delayed speech and language development)
  • HP:0000164 (Abnormality of the dentition)
  • HP:0000347 (Micrognathia/maxillary hypoplasia)
  • HP:0000365 (Hearing impairment)
  • HP:0000388 (Otitis media)

4. Genetic/Molecular Information

Causal Genes and Pathogenic Variants

For syndromic forms, IRF6 (OMIM 607199) heterozygous pathogenic mutations cause Van der Woude syndrome (autosomal dominant); CDH1 heterozygous mutations cause blepharocheilodontic syndrome; TP63 mutations are associated with ectrodactyly-ectodermal dysplasia-cleft syndrome, Hay-Wells syndrome, and Rapp-Hodgkin syndrome (cheng2023geneticinheritancemodels pages 2-5, cheng2023geneticinheritancemodels pages 5-6). A regulatory variant (rs570516915) disrupting an IRF6 transcription factor binding site in an enhancer was identified as strongly associated with CP in the Finnish population (rahimov2024highincidenceand pages 1-4).

For nonsyndromic forms, pathogenic variants in CTNND1, PLEKHA5, and ESRP2 influence epithelial Cadherin-p120-Catenin complex expression (cheng2023geneticinheritancemodels pages 5-6, im2025molecularregulationof pages 15-16). Whole-genome sequencing in 130 African case-parent trios identified high-confidence protein-altering de novo mutations in ACTL6A, ARHGAP10, MINK1, TMEM5, TTN, DHRS3, DLX6, EPHB2, SHH, and TP63, among others (alhazmi2024theapplicationof pages 1-3).

GWAS Loci

Major GWAS-identified susceptibility regions include 1p36, 2p21, 3p11.1, 8q21.3, 8q24, 13q31.1, and 15q22 (cheng2023geneticinheritancemodels pages 5-6). Key SNPs include rs8001641, rs58593329, rs7650466, rs2235371, rs4791774, rs6072081, and rs76479869 in TP63 (jaruga2022orofacialcleftand pages 5-6, cheng2023geneticinheritancemodels pages 2-5, cheng2023geneticinheritancemodels pages 5-6). Fifteen GWAS loci for cleft palate specifically include candidate genes GRHL3, IRF6, CTNNA2, PTCH1, YAP1, PAX9, and others (rahimov2024highincidenceand pages 1-4).

Epigenetic Information

DNA methylation alterations are involved in CL/P etiology. Hypomethylated genes include MYC, FAT1, WHSC1, VAX1, NTN1, BICC1, and MTHFR, while hypermethylated genes include IRF6, TBX1, CRISPLD2, WNT3A, GLI2, SOX2, and PITX2 (viswapurna2024roleofepigenetics pages 4-5). MicroRNAs serve as critical epigenetic regulators: miR-21, miR-181a, miR-452, miR-133b, miR-374a-5p, miR-497-5p, miR-27b, and miR-205 regulate genes involved in cell proliferation, apoptosis, and EMT during palatal development (im2025molecularregulationof pages 23-24, iwaya2023micrornasandgene pages 4-6, im2025molecularregulationof pages 24-26). The mir-17-92 cluster is functionally associated with mammalian CL/P and regulates TGF-β signaling (im2025molecularregulationof pages 24-26). Histone modifications including H3K4 methylation and H4R3me2a (via PRMT1), and regulation by HDAC3 and HDAC4, contribute to palatogenesis (im2025molecularregulationof pages 23-24).

5. Environmental Information

Environmental teratogens are detailed in Section 2 above. Key lifestyle factors include maternal cigarette smoking (vasoconstriction, DNA methylation changes, oxidative stress) (im2025molecularregulationof pages 36-37), alcohol consumption (inhibition of retinoic acid biosynthesis via acetaldehyde) (im2025molecularregulationof pages 46-47), and inadequate dietary folate intake. Occupational and ambient environmental exposures include air pollutants (PM2.5, PM10, ozone, CO) during early gestation and TCDD/dioxin exposure through histone acetylation and microRNA dysregulation mechanisms (viswapurna2024roleofepigenetics pages 3-4, im2025molecularregulationof pages 46-47).

6. Mechanism / Pathophysiology

Molecular Pathways

Palatogenesis is regulated by a complex network of signaling pathways including TGF-β, BMP, SHH, WNT, and FGF, which control palatal shelf outgrowth, elevation, adhesion, and fusion (won2023generegulatorynetworks pages 1-2, im2025molecularregulationof pages 12-13, won2023generegulatorynetworks pages 5-7). These pathways operate through reciprocal epithelial-mesenchymal interactions along the anterior-posterior axis (won2023generegulatorynetworks pages 4-5).

Pathway Name Key Components/Genes Role in Palatogenesis Consequence of Disruption Associated Mouse Models
TGF-β TGFB3, TGFBR2, SMAD2, TAK1, p38 MAPK, CTNNB1-linked regulation of TGF-β3 Essential for palatal shelf adhesion and fusion; promotes midline epithelial seam (MES) breakdown, periderm desquamation, and epithelial remodeling during fusion; also modulates epithelial-mesenchymal interactions and influences Shh signaling via lipid metabolism (im2025molecularregulationof pages 12-13, im2025molecularregulationof pages 15-16, won2023generegulatorynetworks pages 13-14, im2025molecularregulationof pages 16-18) Failure of palatal fusion, persistent MES, delayed/abnormal periderm removal, cleft palate (im2025molecularregulationof pages 15-16, im2025molecularregulationof pages 16-18) Tgfbr2 conditional inactivation in cranial neural crest causes cleft palate and calvarial defects (won2023generegulatorynetworks pages 13-14)
BMP BMP2, BMP4, BMPR1A, NOGGIN, p-SMAD1/5/8, PAX9-BMP4 network Regulates palatal mesenchymal proliferation, differentiation, apoptosis, and anterior-posterior patterning; interacts with Shh to stimulate mesenchymal proliferation; crucial in cranial neural crest-derived mesenchyme (im2025molecularregulationof pages 12-13, won2023generegulatorynetworks pages 5-7, won2023generegulatorynetworks pages 13-14) Dysregulated BMP signaling causes cleft palate/cleft lip, impaired palatal growth, abnormal patterning; BMP antagonism (Noggin) leads to retarded growth and cleft palate (im2025molecularregulationof pages 12-13, won2023generegulatorynetworks pages 5-7) Mesenchymal/neural crest Bmpr1a loss causes severe craniofacial defects; Msx1-null cleft palate can be linked to altered BMP/Shh network activity (im2025molecularregulationof pages 12-13, won2023generegulatorynetworks pages 13-14)
SHH (Sonic Hedgehog) SHH, SMO, primary cilia, FOXF1/2, FGF10, BMP2, PTCH Drives palatal shelf outgrowth through reciprocal epithelial-mesenchymal signaling; maintains proliferation of palatal epithelial and mesenchymal cells; participates in regional patterning and works in feedback with FGF and BMP pathways (won2023generegulatorynetworks pages 1-2, won2023generegulatorynetworks pages 5-7, won2023generegulatorynetworks pages 13-14, im2025molecularregulationof pages 9-12, won2023generegulatorynetworks pages 4-5) Reduced cell proliferation, defective palatal outgrowth, impaired shelf development, cleft palate (won2023generegulatorynetworks pages 13-14, im2025molecularregulationof pages 9-12, won2023generegulatorynetworks pages 4-5) Epithelial Shh inactivation impairs palatal cell proliferation; mesodermal Smo inactivation disrupts outgrowth (im2025molecularregulationof pages 9-12, won2023generegulatorynetworks pages 4-5)
WNT Canonical WNT/β-catenin (CTNNB1), PAX9, OSR2, WNT5A, SFRP2 Regulates proliferation, migration, differentiation, mediolateral/anterior-posterior patterning, and secondary palate development; also regulates TGFB3 expression and integrates with BMP/FGF/SHH signaling (im2025molecularregulationof pages 12-13, im2025molecularregulationof pages 15-16, won2023generegulatorynetworks pages 5-7, won2023generegulatorynetworks pages 13-14) Disrupted WNT signaling contributes to cleft pathogenesis through abnormal proliferation/patterning; persistent canonical WNT can induce ectopic mesenchymal condensation, soft palate agenesis, and impaired palatal osteogenesis (im2025molecularregulationof pages 12-13, won2023generegulatorynetworks pages 13-14) Osr2-cre; Ctnnb1 constitutive activation model shows abnormal mesenchymal condensation, impaired osteogenesis, and soft palate defects; Osr2−/−; Pax9−/− embryos exhibit cleft palate (won2023generegulatorynetworks pages 4-5)
FGF FGF10, FGFR2b, FGF7, FGF18, JAG2/NOTCH, FOXF1/2 Controls epithelial-mesenchymal crosstalk, palatal epithelial differentiation, shelf outgrowth, and proliferation; FGF10-FGFR2b maintains epithelial Shh and coordinates with Jag2-Notch signaling; FGF7 can suppress Shh (im2025molecularregulationof pages 15-16, won2023generegulatorynetworks pages 5-7, won2023generegulatorynetworks pages 13-14, won2023generegulatorynetworks pages 8-10, im2025molecularregulationof pages 9-12, won2023generegulatorynetworks pages 4-5) Cleft palate due to impaired shelf outgrowth, defective epithelial differentiation/adhesion, and disrupted epithelial-mesenchymal signaling (im2025molecularregulationof pages 15-16, won2023generegulatorynetworks pages 8-10, im2025molecularregulationof pages 9-12) Fgf10−/− mice develop cleft palate with impaired palatal shelf outgrowth; Fgf10/Fgfr2b disruption causes cleft palate through disturbed epithelial-mesenchymal interactions (won2023generegulatorynetworks pages 4-5, won2023generegulatorynetworks pages 13-14)

Table: This table summarizes the core developmental signaling pathways implicated in palatogenesis and cleft lip/palate pathogenesis, linking pathway-level functions to disruption phenotypes and representative mouse models. It is useful for connecting mechanistic biology with disease annotations and experimental systems.

Cellular Processes

The causal chain from initial trigger to clinical manifestation involves: (1) Cranial neural crest cell (NCC) specification, migration, and colonization of the facial primordia (upstream); (2) Palatal shelf outgrowth from maxillary prominences regulated by SHH-FGF feedback loops and BMP signaling (intermediate); (3) Palatal shelf elevation above the tongue; (4) Shelf contact, epithelial adhesion, midline epithelial seam (MES) formation, and periderm removal; and (5) MES dissolution through apoptosis and epithelial-mesenchymal transition (EMT), achieving mesenchymal continuity (downstream) (im2025molecularregulationof pages 15-16, won2023generegulatorynetworks pages 8-10, im2025molecularregulationof pages 16-18).

Key cell types involved include cranial neural crest-derived mesenchyme (CL:0000008, neural crest cell), palatal epithelium, periderm cells, and medial edge epithelium (MEE). Periderm cells express CEACAM1 and undergo desquamation regulated by Snai1/Snai2-mediated E-cadherin downregulation and TGF-β3 signaling, which is essential for palatal fusion (im2025molecularregulationof pages 16-18).

GO Terms for Biological Processes

  • GO:0060021 (palate development)
  • GO:0060022 (hard palate development)
  • GO:0060023 (soft palate development)
  • GO:0001843 (neural tube closure)
  • GO:0001838 (neural crest cell migration)
  • GO:0001837 (epithelial to mesenchymal transition)
  • GO:0006915 (apoptotic process)
  • GO:0042476 (odontogenesis)

7. Anatomical Structures Affected

Organ and Tissue Level

  • Primary structures: Upper lip (UBERON:0001833), primary palate (UBERON:0005620), secondary palate (hard palate UBERON:0003216, soft palate UBERON:0001785), alveolar ridge (UBERON:0004535)
  • Secondary involvement: Nasal cavity (communication due to oronasal fistula), middle ear (otitis media), dentition, maxilla (UBERON:0002397)
  • Body systems: Craniofacial (UBERON:0007811), digestive (feeding impairment), respiratory (obstructive apnea), auditory

Cell Types

  • Cranial neural crest cells (CL:0000008)
  • Palatal mesenchymal cells
  • Oral epithelial cells (CL:0002251)
  • Periderm cells
  • Osteoblasts (CL:0000062)

Lateralization

Unilateral clefts are approximately twice as common as bilateral clefts, with left-sided clefts being more frequent than right-sided (jaruga2022orofacialcleftand pages 3-5).

8. Temporal Development

Onset

CL/P is congenital, with the developmental defect occurring during weeks 4–12 of embryogenesis. Upper lip fusion occurs during weeks 4–8, while secondary palate fusion occurs during weeks 6–12. The condition is detectable prenatally via ultrasound.

Progression

CL/P itself is a static structural malformation present at birth, but its consequences are lifelong and progressive in terms of functional impact on feeding (neonatal), speech (childhood), dental development (childhood–adolescence), and maxillofacial growth (adolescence–adulthood) (wongsirichat2022theprevalenceof pages 5-6, hattori2023longtermtreatmentoutcome pages 1-2, wongsirichat2022theprevalenceof pages 1-2). Cleft patients show lower weight and smaller size compared to non-cleft children, with maxillary underdevelopment peaking in adulthood (wongsirichat2022theprevalenceof pages 2-5).

Critical Periods

  • Weeks 4–8 gestation: lip/primary palate fusion (critical window for CL)
  • Weeks 6–12 gestation: secondary palate fusion (critical window for CP)
  • First trimester: maximum sensitivity to environmental teratogens (viswapurna2024roleofepigenetics pages 3-4, iwaya2023micrornasandgene pages 10-12)

9. Inheritance and Population

Epidemiology

In 2021, there were approximately 4,124,007 prevalent cases of orofacial clefts globally, with an age-standardized prevalence rate of 53.4 per 100,000 population (wang2025globalregionaland pages 1-2, ma2025burdenoforofacial pages 1-2). The global incidence is approximately 1 in 700 live births (ma2025burdenoforofacial pages 1-2). From 1990–2021, prevalence decreased 40.38%, mortality decreased 86.08%, and DALYs decreased 68.33% (ma2025burdenoforofacial pages 1-2). Over 80% of the burden is borne by low- and middle-income countries (ma2025burdenoforofacial pages 1-2, ma2025burdenoforofacial pages 7-9).

The total prevalence per 10,000 births from 2016–2021 in the United States was 4.88, with 5.96 for males and 3.75 for females (viswapurna2024roleofepigenetics pages 3-4). International surveillance data report a CLP prevalence of 6.4 per 10,000 births (goldrick2023amultiprogramanalysis pages 8-10).

Inheritance Pattern

NSCLP follows multifactorial/polygenic inheritance with both genetic and environmental contributions (cheng2023geneticinheritancemodels pages 2-5, im2025molecularregulationof pages 5-6). Syndromic forms follow Mendelian patterns (autosomal dominant for Van der Woude syndrome/IRF6, etc.) (cheng2023geneticinheritancemodels pages 2-5).

Population Demographics

Males have a higher prevalence of CL/P than females (male:female ratio approximately 1.6:1), while isolated CP shows more equal sex distribution (wang2025globalregionaland pages 1-2, wang2023globalregionaland pages 1-2, jaruga2022orofacialcleftand pages 3-5). Ethnic variation is notable: American Indians show the highest rate (3.6 per 1,000), followed by Asians and Whites, with African Americans having the lowest incidence (~0.5 per 1,000) (im2025molecularregulationof pages 5-6, jaruga2022orofacialcleftand pages 3-5). Geographically, CL/P occurs more frequently in China, Japan, and Latin America but is less common in Israel, South Africa, and Southern Europe (jaruga2022orofacialcleftand pages 3-5). In 2021, South Asia, North Africa/Middle East, and Central Asia had the highest prevalence rates (wang2025globalregionaland pages 1-2, ma2025burdenoforofacial pages 1-2).

10. Diagnostics

Clinical Diagnosis

CL/P is primarily diagnosed by physical examination at birth. Prenatal detection via ultrasound is possible, particularly for cleft lip; cleft palate alone is more difficult to detect prenatally. AI-based prenatal ultrasound systems utilizing deep learning (e.g., YOLOv5) have achieved AUC of 0.971 for standard coronal nasal-lip sections in single-center studies (wongsirichat2022theprevalenceof pages 5-6).

Genetic Testing

Given the complex genetic architecture, genetic testing approaches include: - Chromosomal microarray (CMA): For detecting copy number variants and regions of homozygosity - Gene panels: Targeting known CL/P genes (IRF6, MSX1, CDH1, TP63, ARHGAP29, CTNND1, etc.) - Whole exome/genome sequencing (WES/WGS): For identifying rare de novo and inherited variants, particularly useful in unexplained syndromic presentations - Karyotyping: For ruling out chromosomal abnormalities in syndromic cases

Differential Diagnosis

  • Isolated CL vs. CLP vs. CP
  • Nonsyndromic vs. syndromic forms (>400 syndromes including Van der Woude, Pierre Robin, DiGeorge/22q11.2 deletion, Treacher Collins, EEC syndrome)
  • Submucosal cleft palate (may be clinically occult)

Screening

Prenatal ultrasound (routine second-trimester anatomy scan), newborn physical examination. Cascade genetic testing is recommended for families with affected members.

11. Outcome/Prognosis

Survival and Mortality

Global mortality from orofacial clefts was 1,719 deaths in 2021, with 408,775 DALYs (ma2025burdenoforofacial pages 1-2). Mortality has declined 86.08% from 1990–2021 globally (ma2025burdenoforofacial pages 1-2). Isolated CLP cases have the highest survival rate at 97.7%, while cases associated with genetic/chromosomal syndromes have significantly worse survival at 40.9% (goldrick2023amultiprogramanalysis pages 8-10). Long-term outcomes include increased mortality compared with unaffected siblings (wongsirichat2022theprevalenceof pages 1-2).

Morbidity

The age-standardized DALY rate was 5.8 per 100,000 in 2021, with burden strongly correlating with socioeconomic development (wang2025globalregionaland pages 1-2, ma2025burdenoforofacial pages 7-9). Morbidity is lifelong, encompassing feeding difficulties, speech impairment, hearing loss, dental anomalies, psychological/social impacts, and maxillofacial growth disturbances (wongsirichat2022theprevalenceof pages 1-2).

Treatment Burden

Patients with complete BCLP require an average of 5.9 surgical operations to complete treatment (hattori2023longtermtreatmentoutcome pages 1-2). Revisional lip/nose surgery was performed in 73% of patients, with VPI surgery in 59% and orthognathic surgery in 60.7% (hattori2023longtermtreatmentoutcome pages 1-2, hattori2023longtermtreatmentoutcome pages 5-6).

12. Treatment

Surgical Interventions (MAXO:0000004, Surgical procedure)

Treatment follows a staged, multidisciplinary protocol: - Presurgical nasoalveolar molding (NAM): Performed in early infancy to approximate cleft segments - Lip adhesion: ~3 months of age (in selected cases) - Primary cheiloplasty (lip repair): ~3–8 months (MAXO:0000004) - Palatoplasty (palate repair): ~12–18 months, typically two-flap technique (NCT00829101 chunk 1, hattori2023longtermtreatmentoutcome pages 1-2, hattori2023longtermtreatmentoutcome pages 5-6) - VPI surgery: As needed (pharyngeal flap or sphincter pharyngoplasty) - Alveolar bone grafting: ~9–10 years of age - Orthodontic treatment: Throughout childhood and adolescence - Orthognathic surgery: At skeletal maturity (~18 years), applied in 60.7% of BCLP patients with midface retrusion; 97.3% underwent two-jaw surgery (hattori2023longtermtreatmentoutcome pages 1-2) - Revisional rhinoplasty/lip surgery: After skeletal maturity for esthetic enhancement (hattori2023longtermtreatmentoutcome pages 5-6)

Supportive and Rehabilitative Care

  • Speech therapy (MAXO:0000930): Essential for managing VPI and articulation disorders
  • Audiology management: Monitoring for otitis media and hearing loss
  • Psychological support (MAXO:0000016): Addressing social adjustment and self-esteem
  • Nutritional support: Specialized feeding techniques and devices in infancy

Experimental Treatments

Active clinical trials include: - BIOCLEFT (NCT06408337): Phase I-IIa evaluating safety and efficacy of a tissue-engineered product for cleft palate treatment - AI applications (NCT04342234, NCT06970158): Neural network-based morphological assessment and clinical decision support - Analgesic innovations (NCT04928352, NCT04771156): Nebulized bupivacaine and ketorolac for post-palatoplasty pain management

13. Prevention

Primary Prevention

  • Folic acid supplementation: Periconceptional supplementation (≥400 µg/day) is the most established primary prevention strategy (viswapurna2024roleofepigenetics pages 3-4, im2025molecularregulationof pages 46-47, viswapurna2024roleofepigenetics pages 7-8)
  • Smoking cessation: Given the significant dose-dependent risk (OR up to 4.2 for heavy smoking) (viswapurna2024roleofepigenetics pages 3-4)
  • Maternal health optimization: Managing pre-pregnancy diabetes, hypertension, and obesity (viswapurna2024roleofepigenetics pages 3-4)
  • Avoidance of teratogens: Including excess alcohol, retinoids, and certain medications during first trimester

Secondary Prevention

  • Prenatal ultrasound screening: Routine second-trimester anatomy scan for early detection
  • Genetic counseling (MAXO:0000079): Risk assessment for families with history of CL/P, particularly given 4–10% recurrence risk (im2025molecularregulationof pages 5-6)
  • Preimplantation genetic diagnosis: Available for known monogenic syndromic forms

Tertiary Prevention

  • Multidisciplinary team care: Preventing complications through coordinated surgical, orthodontic, speech, audiology, and psychological management from birth through adulthood (hattori2023longtermtreatmentoutcome pages 1-2, wongsirichat2022theprevalenceof pages 1-2)

14. Other Species / Natural Disease

Orofacial clefts occur naturally in multiple species, most notably in dogs (particularly brachycephalic breeds including Bulldogs, Boxers, and Labrador Retrievers), cats, cattle, sheep, and horses. The condition is documented in OMIA (Online Mendelian Inheritance in Animals).

Comparative Biology

The developmental mechanisms underlying palatal fusion are highly conserved across vertebrates. Key signaling pathways (SHH, BMP, FGF, TGF-β, WNT) controlling palatogenesis are conserved from zebrafish to humans, enabling cross-species study of cleft mechanisms (alhazmi2024theapplicationof pages 1-3, jaruga2022orofacialcleftand pages 13-15).

15. Model Organisms

Mouse Models (Mus musculus; NCBI Taxon: 10090)

The mouse is the preeminent animal model for studying CL/P, with 395 genes identified in mice and 131 in humans related to cleft palate as of 2021 (iwaya2023micrornasandgene pages 6-8). A total of 365 mouse strains exhibit complete cleft of the secondary palate (CPO), 44 strains show CLP, 14 display anterior cleft palate, 16 present posterior/soft palate cleft, and 37 have submucous cleft palate (iwaya2023micrornasandgene pages 6-8). Key knockout models include: - Fgf10−/−: Cleft palate with impaired palatal shelf outgrowth (won2023generegulatorynetworks pages 4-5) - Msx1-null: Cleft palate, rescued by Dlx5 modulation of Shh signaling (won2023generegulatorynetworks pages 13-14) - Tgfbr2 conditional inactivation in cranial neural crest: Cleft palate and calvarial defects (won2023generegulatorynetworks pages 13-14) - Osr2−/−; Pax9−/−: Cleft palate (won2023generegulatorynetworks pages 4-5) - Foxf1/Foxf2 ablation in neural crest: Defective palatal outgrowth (won2023generegulatorynetworks pages 4-5) - DicerF/F;Wnt1-Cre: Severe craniofacial deformities including cleft palate (iwaya2023micrornasandgene pages 2-4) - Bmpr1a conditional loss in neural crest: Severe craniofacial defects (im2025molecularregulationof pages 12-13)

Zebrafish Models (Danio rerio; NCBI Taxon: 7955)

Zebrafish have emerged as a powerful complementary model. The zebrafish ethmoid plate serves as the functional equivalent of the mammalian palate. Genetic control of palatal development is conserved across vertebrates, enabling study of human cleft genes (alhazmi2024theapplicationof pages 1-3, jaruga2022orofacialcleftand pages 13-15). IRF6-deficient zebrafish demonstrate a cleft phenotype, with downstream genes GRHL3, KLF17, and ESRP1/2 also critical (alhazmi2024theapplicationof pages 1-3). Advantages include transparent embryos, rapid external development, and amenability to CRISPR/Cas9 editing (alhazmi2024theapplicationof pages 1-3, jaruga2022orofacialcleftand pages 13-15).

Xenopus Models (NCBI Taxon: 8364)

Xenopus has emerged as a powerful model for investigating craniofacial morphogenesis, owing to external fertilization, large experimentally accessible embryos, and evolutionarily conserved developmental pathways. These allow direct in vivo visualization and manipulation of cranial neural crest cell behaviors at single-cell resolution (jaruga2022orofacialcleftand pages 13-15).

Model Limitations

Mouse palate development occurs in utero, limiting real-time observation (jaruga2022orofacialcleftand pages 13-15). Zebrafish, while genetically manipulable, have anatomical differences from mammalian palates (alhazmi2024theapplicationof pages 1-3). No single model fully recapitulates all aspects of human CL/P, necessitating multi-model approaches (jaruga2022orofacialcleftand pages 13-15).

Summary

Cleft lip and/or palate is a complex congenital malformation with global prevalence of approximately 1 in 700 births, imposing substantial morbidity particularly in low- and middle-income countries. The condition arises from disrupted palatogenesis involving multiple conserved signaling pathways (TGF-β, BMP, SHH, WNT, FGF) and is influenced by both genetic susceptibility (IRF6, MSX1, BMP4, TP63, ARHGAP29, and many others) and environmental factors (maternal smoking, folate deficiency, diabetes). Treatment requires lifelong, staged, multidisciplinary management including multiple surgical procedures, orthodontic care, speech therapy, and psychological support. Primary prevention through periconceptional folic acid supplementation and maternal health optimization represents the most actionable public health intervention. Advances in genomics, AI-assisted diagnostics, and tissue engineering (BIOCLEFT trial) represent promising frontiers in CL/P research and care.

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