Orofaciodigital Syndrome

Mendelian MONDO:0015375 Pathograph 9 Show in embeddings browser Ciliopathy

Orofaciodigital syndrome (OFDS; oral-facial-digital syndrome) is the umbrella entry for a clinically and genetically heterogeneous group of ciliopathies defined by the co-occurrence of malformations of the oral cavity (accessory frenula, lobulated or bifid tongue, tongue hamartomas/nodules, cleft palate, dental anomalies), the face (hypertelorism, median cleft or pseudocleft of the upper lip, hypoplastic alae nasi, micrognathia) and the digits (pre-, post- and mesoaxial polydactyly, syndactyly, brachydactyly, clinodactyly), with variable additional involvement of the brain, kidneys, retina and skeleton that distinguishes the numbered subtypes from one another. The archetypal and by far the most frequent form is OFD type I, an X-linked dominant, male-lethal disorder caused by heterozygous OFD1 variants; almost all other subtypes are autosomal recessive, with OFD VIII and OFD 21 X-linked recessive. Nearly every causal gene encodes a centriolar, basal-body, transition-zone or CPLANE/intraflagellar transport protein, so the shared mechanism is failure of primary-cilium assembly or ciliary compartmentalization, which deranges cilium-dependent Hedgehog signal transduction and thereby the patterning of the cranial neural crest derivatives and the autopod. Two of the most recently delineated subtypes (OFD 19, SCNM1; OFD 21, ZRSR2) instead disrupt the minor (U12) spliceosome and reach the same ciliary endpoint indirectly, by depleting transcripts of ciliary genes. Because the shared mechanism is elaborated in the ciliopathy_dysfunction module and the digit bundle in limb_digit_patterning_serial_homology, this entry declares conformance to both rather than re-deriving them, and cross-references the existing per-subtype entries Orofaciodigital_Syndrome_Type_I and Orofaciodigital_Syndrome_17 rather than duplicating their detail.

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Classifications

Harrison's Part

Mechanistic Nosology

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Mappings

MONDO

MONDO:0015375 orofaciodigital syndrome

Primary MONDO identifier for the orofaciodigital syndrome group; carries the OMIM phenotypic series OMIMPS:311200 and Orphanet:140997 cross-references.

MONDO:1040039 OFD1-related ciliopathy Not Yet Curated

Gene-based MONDO node spanning the OFD1 allelic series (OFD type I, Joubert syndrome 10, primary ciliary dyskinesia, retinitis pigmentosa 23). It is a per-locus concept that cuts across this clinical grouping rather than nesting inside it, so the relation is recorded as a related match.

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Inheritance

Autosomal Recessive HP:0000007

The majority of orofaciodigital subtypes are inherited as autosomal recessive traits, with biallelic variants in a ciliary, centriolar or minor-spliceosome gene; many reported families are consanguineous.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:27141300 SUPPORT Other

"With the exception of OFD types I and VIII, which are X-linked, the majority of OFDS is transmitted as an autosomal recessive syndrome."

States directly that most orofaciodigital subtypes are autosomal recessive. Evidence source is OTHER because this is a narrative review.

X-linked Dominant (male-lethal) HP:0001423

OFD type I is transmitted as an X-linked dominant trait with lethality in hemizygous males, so affected individuals are predominantly female; most cases are sporadic.

X-linked dominant inheritance

Show evidence (2 references)

PMID:27141300 SUPPORT Other

"It is transmitted as an X-linked dominant condition with male lethality, which usually occurs during the first and second trimester of pregnancy"

Specifies the X-linked dominant, male-lethal mode of inheritance of OFD type I and the gestational timing of male lethality. Evidence source is OTHER because this is a narrative review.

PMID:20301367 SUPPORT Human Clinical

"Oral-facial-digital syndrome type I (OFD1) is usually male lethal during gestation and predominantly affects females."

Independent confirmation of male lethality and the female predominance it produces in OFD type I.

X-linked Recessive HP:0001419

A minority of subtypes are X-linked recessive and affect males: OFD VIII (Edwards syndrome, molecularly undefined) and OFD 21 (ZRSR2), in which affected males were hemizygous for a last-exon frameshift variant.

X-linked recessive inheritance

Show evidence (1 reference)

PMID:38158857 SUPPORT Human Clinical

"7 affected males from 5 unrelated families were hemizygous for the ZRSR2 variant"

Documents hemizygous affected males, the X-linked recessive pattern recorded for OFD 21.

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Subtypes

Orofaciodigital syndrome type I (Papillon-Leage-Psaume syndrome) MONDO:0010702

OFD1 hgnc:2567

X-linked dominant, male-lethal form caused by heterozygous OFD1 variants; the most frequent subtype. Oral, facial and digital malformations with polycystic kidney disease, corpus callosum agenesis and intracerebral cysts. Curated in full in Orofaciodigital_Syndrome_Type_I. Listed here on clinical and OMIM-phenotypic-series grounds despite not being a MONDO descendant of the grouping term (see notes).

Show evidence (1 reference)

PMID:11179005 SUPPORT Human Clinical

"we analyzed several transcripts mapping to the region and found mutations in OFD1"

Original identification of OFD1 as the gene mutated in orofaciodigital syndrome type I, which is the gene assignment recorded for this subtype.

Orofaciodigital syndrome type II (Mohr syndrome) MONDO:0009642

INTS13 hgnc:20174

Autosomal recessive form with lobulated tongue, midline cleft lip, broad nasal tip, conductive hearing loss and polysyndactyly, classically including reduplicated hallux. Long molecularly undefined; biallelic INTS13 variants were reported in two families with variable OFD type 2.

Show evidence (1 reference)

PMID:36229431 SUPPORT Human Clinical

"Through homozygosity mapping and exome sequencing of two families with variable OFD type 2, we identified distinct germline variants in INTS13"

Supplies the gene assignment for OFD type II, which MONDO does not record. The authors' own qualifier "variable OFD type 2" is retained rather than strengthened.

Orofaciodigital syndrome type III (Sugarman syndrome) MONDO:0009793

TMEM231 hgnc:37234

Autosomal recessive form distinguished by metronome-like ocular motor apraxia in addition to lingual hamartomas and postaxial polydactyly, with cerebellar vermis hypoplasia and Dandy-Walker malformation; TMEM231 variants have been reported in affected sibs.

Show evidence (1 reference)

PMID:28289185 SUPPORT Human Clinical

"related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231 and WDPCP) to OFDS"

Places TMEM231 within the OFDS gene set. Classified PARTIAL because it supports gene-group membership rather than the specific type III assignment, which rests on the Franco and Thauvin-Robinet review classification.

Orofaciodigital syndrome type IV (Mohr-Majewski / Baraitser-Burn syndrome) MONDO:0009794

TCTN3 hgnc:24519

Severe autosomal recessive form combining the orofaciodigital triad with tibial dysplasia (the discriminating feature), short ribs, cystic kidneys and brain anomalies; caused by biallelic TCTN3 variants and overlapping phenotypically with Meckel syndrome.

Show evidence (1 reference)

PMID:22883145 SUPPORT Human Clinical

"we identified truncating TCTN3 mutations as the cause of an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain anomalies (OFD IV, Mohr-Majewski syndrome)"

Establishes both the gene assignment and the discriminating tibial and skeletal features of OFD type IV.

Orofaciodigital syndrome type V (Thurston syndrome) MONDO:0008267

DDX59 hgnc:25360

Autosomal recessive form reported predominantly in families of Indian origin, characterized by median cleft lip with postaxial polydactyly and relatively little visceral involvement; biallelic DDX59 variants were identified in two consanguineous multiplex families.

Show evidence (1 reference)

PMID:23972372 SUPPORT Human Clinical

"Exome sequencing revealed a different homozygous variant in DDX59 in each of the two families"

Records the DDX59 gene assignment for this subtype in two multiplex consanguineous families affected by OFD.

Orofaciodigital syndrome type VI (Varadi-Papp syndrome) MONDO:0010176

CPLANE1 hgnc:25801 TMEM216 hgnc:25018

Autosomal recessive form defined by the molar tooth sign plus tongue hamartoma/additional frenula, mesoaxial polydactyly and/or hypothalamic hamartoma; a Joubert-syndrome-related disorder. CPLANE1 (C5orf42) is the major gene, with TMEM216, TMEM107 and OFD1 also reported.

Show evidence (2 references)

PMID:24178751 SUPPORT Human Clinical

"Oral-facial-digital syndrome type VI (OFD VI) is a recessive ciliopathy defined by two diagnostic criteria: molar tooth sign (MTS) and one or more of the following: (1) tongue hamartoma (s) and/or additional frenula and/or upper lip notch; (2) mesoaxial polydactyly of one or more hands or feet;..."

Gives the operational diagnostic criteria that separate OFD VI from the other subtypes and from pure Joubert syndrome.

PMID:24178751 SUPPORT Human Clinical

"We identified a total of 14 novel mutations in the C5orf42 gene in 9/11 families with positive OFD VI diagnostic criteria"

Supports CPLANE1 (C5orf42) as the major gene for OFD VI.

Orofaciodigital syndrome type VII (Whelan syndrome) MONDO:0012049

Rare form reported with the orofaciodigital triad accompanied by facial asymmetry and hydronephrosis. Molecularly undefined; enumerated here for completeness of the numbered series, not curated in depth.

Orofaciodigital syndrome type VIII (Edwards syndrome) MONDO:0010336

X-linked recessive form affecting males, with the orofaciodigital triad, duplicated hallux and radial/tibial defects. Molecularly undefined; enumerated here for completeness of the numbered series, not curated in depth.

Orofaciodigital syndrome type IX (Gurrieri syndrome) MONDO:0009795

TBC1D32 hgnc:21485 SCLT1 hgnc:26406

Autosomal recessive form distinguished by retinal colobomata in addition to the typical orofaciodigital findings; TBC1D32 and SCLT1 variants have been reported in severe cases.

Show evidence (1 reference)

PMID:27141300 SUPPORT Other

"OFD type IX is characterized by retinal colobomata in addition to the typical oro-facio-digital findings. It is inherited as an autosomal recessive trait."

Records the discriminating retinal feature and inheritance mode of OFD type IX. Evidence source is OTHER because this is a narrative review.

Orofaciodigital syndrome type X (Figuera syndrome) MONDO:0008137

Rare form reported with the orofaciodigital triad and radial defects with fibular aplasia. Molecularly undefined; enumerated here for completeness of the numbered series, not curated in depth.

Orofaciodigital syndrome type XI (Gabrielli syndrome) MONDO:0013035

Rare form reported with the orofaciodigital triad and vertebral and dental anomalies. Molecularly undefined; enumerated here for completeness of the numbered series, not curated in depth.

Orofaciodigital syndrome type XII (Moran-Barroso syndrome) MONDO:0015421

Rare form reported with the orofaciodigital triad, cardiac defect and cerebral malformation. Molecularly undefined; enumerated here for completeness of the numbered series, not curated in depth.

Orofaciodigital syndrome type XIV MONDO:0014413

C2CD3 hgnc:24564

Autosomal recessive form distinguished from the other subtypes by severe microcephaly and cerebral malformation including the molar tooth sign; caused by biallelic variants in C2CD3, a positive regulator of centriole elongation that is antagonized by OFD1.

Show evidence (1 reference)

PMID:24997988 SUPPORT Human Clinical

"Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene."

Establishes both the gene assignment and the microcephaly and cerebral malformation features that delineate this subtype.

Orofaciodigital syndrome type XV MONDO:0014932

KIAA0753 hgnc:29110

Autosomal recessive form caused by biallelic KIAA0753 variants; KIAA0753 acts with FOPNL and OFD1 in the centriole-elongation module and its allelic spectrum also includes Joubert syndrome and short-rib skeletal dysplasia.

Show evidence (1 reference)

PMID:29138412 SUPPORT Human Clinical

"Mutations in the KIAA0753 gene have recently been associated with Joubert syndrome (JBTS) and orofaciodigital (OFD) syndrome."

Confirms the KIAA0753-OFD association and the allelic overlap with Joubert syndrome recorded in this subtype description.

Orofaciodigital syndrome type XVI MONDO:0033045

TMEM107 hgnc:28128

Autosomal recessive form caused by biallelic TMEM107 variants; features include postaxial polydactyly of the hands and mesoaxial polydactyly of the feet, cerebellar vermis hypoplasia with molar tooth sign, retinopathy and developmental delay, and tibial dysplasia has been reported.

Show evidence (1 reference)

PMID:35361766 SUPPORT Human Clinical

"The clinical features of OFD syndrome type XVI mainly include postaxial polydactyly of the hands and feet, vermis hypoplasia, MTS, retinopathy, apnea/hyperpnea, and developmental delay"

Supplies the clinical delineation of OFD type XVI recorded in this subtype description.

Orofaciodigital syndrome type XVII MONDO:0033375

INTU hgnc:29239

Autosomal recessive form caused by biallelic INTU variants, a subunit of the CPLANE module required for IFT-A assembly. Curated in full in Orofaciodigital_Syndrome_17.

Show evidence (1 reference)

PMID:28289185 SUPPORT Human Clinical

"We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57)"

Identifies INTU among the OFD-causing ciliary genes, the assignment recorded for this subtype.

Orofaciodigital syndrome type XVIII MONDO:0054770

IFT57 hgnc:17367

Autosomal recessive form caused by biallelic variants in IFT57, a core component of the IFT-B intraflagellar transport complex.

Show evidence (1 reference)

PMID:28289185 SUPPORT Human Clinical

"We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57)"

Identifies IFT57 among the OFD-causing ciliary genes, the assignment recorded for this subtype.

Orofaciodigital syndrome type XIX MONDO:0859310

SCNM1 hgnc:23136

Autosomal recessive form caused by biallelic loss-of-function variants in SCNM1, a component of the minor (U12) spliceosome. Patient cells show defective minor-intron processing, reduced expression of ciliary and basal body genes, and abnormally elongated cilia.

Show evidence (1 reference)

PMID:36084634 SUPPORT Human Clinical

"We describe individuals with OFD from three unrelated families having bi-allelic loss-of-function variants in SCNM1 as the cause of their condition."

Establishes the SCNM1 gene assignment and biallelic loss-of-function mechanism for this subtype.

Orofaciodigital syndrome type XX MONDO:0958230

RAB34 hgnc:16519

Autosomal recessive form caused by biallelic missense variants clustered near the RAB34 C-terminus, accompanied by cardiac, cerebral, skeletal and anorectal defects. RAB34 acts selectively in the intracellular ciliogenesis pathway.

Show evidence (1 reference)

PMID:37384395 SUPPORT Human Clinical

"We identified by exome sequencing bi-allelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families."

Establishes the RAB34 gene assignment for this most recently delineated autosomal recessive subtype.

Orofaciodigital syndrome type XXI MONDO:0975827

ZRSR2 hgnc:23019

X-linked recessive form caused by ZRSR2 variants affecting the last exon, presenting with brain anomalies ranging from alobar holoprosencephaly to pituitary anomalies. ZRSR2 encodes a minor-spliceosome splicing factor; patient cells show minor-intron retention and elongated primary cilia.

Show evidence (1 reference)

PMID:38158857 SUPPORT Human Clinical

"We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families."

Establishes the ZRSR2-associated subtype and its distinguishing brain phenotype.

Discussions and Knowledge Gaps

Should the orofaciodigital syndromes be modeled as this Disease entry with has_subtypes, or as a Grouping over the already-standalone member entries?

OPEN QUESTION OPEN ofds_disease_versus_grouping

The case for a Grouping is real and should not be lost. Two members are already independent Disease entries with their own pathographs (Orofaciodigital_Syndrome_Type_I, Orofaciodigital_Syndrome_17) and a third OFD-spectrum disorder is curated under a non-OFD name (Heart_Defect_Tongue_Hamartoma_Polysyndactyly_Syndrome, WDPCP); the project convention is that a grouping sits over already-distinct entries. The subtypes are heterogeneous in inheritance (X-linked dominant male-lethal, X-linked recessive, autosomal recessive) and in ciliary subcompartment, and Bruel et al. state that the wide heterogeneity makes the initial classification obsolete, proposing a clinical classification restricted to three well-delineated subtypes with genotype-based classification for the rest, which is closer to a curated union with membership criteria than to a single blended graph. The case for the present Disease modeling is that the entry also has to carry a shared mechanism (ciliary Hedgehog derangement) that all members instantiate, that seventeen of the twenty numbered types have no standalone entry to group over, and that the MONDO term itself is a disease node with a curated pathophysiology to attach to. This entry takes the Disease form (the priority dashboard's CURATE_ROOT_WITH_SUBTYPES recommendation) and records the counter-argument here rather than deciding silently. If the per-subtype entry count grows, converting to a Grouping with NECESSARY criteria over an oral/facial arm, a digital arm and the ciliopathy_dysfunction basal-body/transition-zone node would be the natural migration.

Show evidence (1 reference)

PMID:28289185 SUPPORT Human Clinical

"A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype."

The nosological proposal that motivates the Grouping alternative recorded in this discussion.

MONDO:0015375 does not have MONDO:0010702 (orofaciodigital syndrome I) among its descendants, so the eponymous and commonest subtype falls outside the MONDO grouping term for its own disease family. Should this be raised upstream?

CURATION TODO OPEN ofds_mondo_excludes_type_i

Verified with OAK against the local MONDO build on 2026-08-19: MONDO:0015375 has nineteen is_a descendants (types II, III, IV, V, 6, VII, VIII, IX, X, XI, 12, 14, XV, 16, 17, 18, 19, 20, 21) and OFD I is not among them; OFD I's asserted parents are MONDO:0002254 syndromic disease, MONDO:0100500 Mendelian neurodevelopmental disorder and MONDO:1040039 OFD1-related ciliopathy. Three of MONDO:0015375's own annotations contradict the omission: its MeSH-derived definition names Type I explicitly, its OMIM cross-reference is the phenotypic series OMIMPS:311200 anchored on OFD I, and its Orphanet cross-reference (Orphanet:140997) is the OFD group record that includes OFD I. This entry therefore lists OFD I as a subtype on clinical and phenotypic-series grounds. The remaining action is to report the missing is_a edge to MONDO; it has not been filed from this session.

Consequence for tooling: any process that builds an OFDS member list from the MONDO descendant closure will silently omit the commonest type. Related, but a separate observation: OFD XIII (Degner syndrome) has no MONDO term at all.

How does minor (U12-type) spliceosome dysfunction produce a specifically orofaciodigital phenotype rather than a generic multisystem disorder, and is ciliary transcript depletion the whole explanation?

KNOWLEDGE GAP OPEN ofds_minor_spliceosome_route

Attached to

pathophysiology#Minor Spliceosome Dysfunction and Ciliary Transcript Depletion

Two subtypes (OFD 19, SCNM1; OFD 21, ZRSR2) are caused by loss of minor spliceosome components rather than of ciliary proteins, and both show minor-intron retention, depletion of ciliary transcripts including TMEM107, and abnormally elongated primary cilia. What is not established is whether ciliary transcript depletion is sufficient to account for the phenotype, or whether non-ciliary U12-dependent targets contribute; the SCNM1 study lists DERL2, ZC3H8 and C17orf75 among the severely reduced transcripts alongside the ciliary ones, and the ZRSR2 phenotype includes holoprosencephaly and pituitary anomaly, which are not typical of the ciliary subtypes. Note also that both reports describe cilia that are abnormally elongated, whereas several ciliary OFD genes give absent or short cilia, so the cellular phenotype is not simply a phenocopy. dismech separately curates minor-spliceosome disorders (RNU12-related_Minor_Spliceopathy, Roifman-syndrome) with no link to the ciliopathy tree; a shared minor-spliceosome module would be the structural place to resolve this.

Proposed experiments

Rescue of the ciliary phenotype by restoring individual U12-dependent ciliary transcripts

ofds_u12_ciliary_transcript_rescue

In SCNM1- or ZRSR2-deficient patient fibroblasts, re-express the depleted ciliary and basal-body transcripts (TMEM107, FAM92A) individually and in combination, and measure cilium length and Hedgehog reporter output. Full rescue would establish ciliary transcript depletion as sufficient; partial rescue would implicate non-ciliary U12 targets.

Show evidence (1 reference)

PMID:36084634 SUPPORT In Vitro

"Conversely, cilia length and expression of SCNM1-regulated genes were restored in SCNM1-deficient fibroblasts following reintroduction of SCNM1 via retroviral delivery."

Establishes the feasibility precedent for the proposed design: rescue by re-expression in the same patient-fibroblast system, read out as cilium length, has already been performed for SCNM1 itself. Evidence source is IN_VITRO because the rescue was done in cultured fibroblasts.

Show evidence (1 reference)

PMID:36084634 SUPPORT In Vitro

"Notably, expression of TMEM107 and FAM92A encoding primary cilia and basal body proteins, respectively, and that of DERL2, ZC3H8, and C17orf75, were severely reduced in SCNM1-deficient cells."

Shows that the depleted transcript set is not confined to ciliary genes, which is the open question this discussion records. Evidence source is IN_VITRO because the transcriptome comparison used patient fibroblasts and engineered cell lines.

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Pathophysiology

Ciliary and Centriolar Gene Defect

The initiating lesion in most orofaciodigital subtypes is a germline variant in a gene encoding a centriolar, basal-body, transition-zone or CPLANE/intraflagellar transport protein. Functional dissection of the OFDS gene set resolves it into three ciliary protein modules: the KIAA0753-FOPNL-OFD1 complex regulating centriole elongation, the Meckel-Gruber transition-zone module (TMEM107, TMEM216, TMEM231, TCTN3), and the CPLANE complex required for IFT-A assembly (INTU, CPLANE1, WDPCP, FUZ). Different subtypes enter the shared downstream cascade through different modules, which is one source of their phenotypic divergence.

centriole elongation GO:0061511 ⚠ ABNORMAL

ciliary basal body GO:0036064 ciliary transition zone GO:0035869

Downstream

Impaired Ciliogenesis and Ciliary Compartment Function Loss of the centriolar, transition-zone or CPLANE protein prevents assembly of a structurally and functionally competent primary cilium.

Show evidence (2 references)

PMID:28289185 SUPPORT Human Clinical

"Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major..."

Directly supports the three-module decomposition of the OFDS gene set that this node records.

PMID:24997988 SUPPORT In Vitro

"whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3 results in short centrioles without subdistal and distal appendages"

Shows that two OFD genes act antagonistically on centriole length, the molecular-scale defect captured by this node. Evidence source is IN_VITRO because the centriole measurements were made in cultured cells.

Minor Spliceosome Dysfunction and Ciliary Transcript Depletion

A second, mechanistically distinct entry route operates in the two most recently delineated subtypes. SCNM1 (OFD 19) and ZRSR2 (OFD 21) encode components of the minor (U12-type) spliceosome. Loss of function causes retention or mis-splicing of the small set of U12-type introns, which are enriched in ciliary and basal-body genes, so ciliary transcripts such as TMEM107 are depleted without any primary defect in a ciliary protein itself. The convergence onto the ciliary phenotype is therefore indirect but experimentally demonstrated.

fibroblast CL:0000057

minor (U12-type) pre-mRNA splicing GO:0000398 ⚠ ABNORMAL

Downstream

Impaired Ciliogenesis and Ciliary Compartment Function Depletion of correctly spliced ciliary transcripts produces a structurally abnormal primary cilium, observed as abnormal cilium elongation in patient and knockout cells.

Show evidence (2 references)

PMID:36084634 SUPPORT In Vitro

"Notably, expression of TMEM107 and FAM92A encoding primary cilia and basal body proteins, respectively, and that of DERL2, ZC3H8, and C17orf75, were severely reduced in SCNM1-deficient cells."

Demonstrates depletion of ciliary and basal-body transcripts as the direct consequence of minor-spliceosome loss. Evidence source is IN_VITRO because the measurements were made in patient fibroblasts and engineered cell lines.

PMID:38158857 SUPPORT In Vitro

"Patient samples showed significant enrichment of minor intron retention. Among differentially spliced targets are ciliopathy-related genes, such as TMEM107 and CIBAR1."

Independent confirmation in a second minor-spliceosome gene that the mis-spliced targets are ciliopathy genes. Evidence source is IN_VITRO because the analysis used patient lymphoblastoid and fibroblast lines.

Impaired Ciliogenesis and Ciliary Compartment Function

Both entry routes converge on failure to build, or to correctly compartmentalize, the primary cilium: cilia may be absent, short, abnormally elongated, or structurally present but unable to gate signaling machinery at the transition zone. This is the shared cellular lesion of the orofaciodigital syndromes and the node at which they conform to the ciliopathy module. The specific module affected biases which downstream tissue is worst hit.

ciliated cell CL:0000064

cilium assembly GO:0060271 ↓ DECREASED protein localization to cilium GO:0061512 ⚠ ABNORMAL intraciliary transport GO:0042073 ⚠ ABNORMAL

primary cilium GO:0005929

Downstream

Dysregulated Hedgehog Signal Transduction and GLI Processing Because the primary cilium is the obligate compartment for vertebrate Hedgehog signal transduction, a defective cilium or transition zone deranges GLI processing and the balance of GLI activator and repressor.

Multisystem Ciliopathy Involvement The same ciliary lesion acts in renal tubular epithelium, retina and developing CNS, producing the cystic kidney disease, retinal degeneration and cerebellar/CNS malformation that distinguish the subtypes.

Show evidence (2 references)

PMID:27141300 SUPPORT Other

"A number of genes have already found to be mutated in OFDS and most of the encoded proteins are predicted or proven to be involved in primary cilia/basal body function."

Supports treating primary cilium and basal body function as the shared cellular lesion across the OFDS gene set. Evidence source is OTHER because this is a narrative review.

PMID:37384395 SUPPORT Human Clinical

"Pathogenic variants in over 20 genes encoding ciliary proteins have been found to cause OFDS through deleterious structural or functional impacts on primary cilia."

States that the OFDS gene set acts through structural or functional damage to primary cilia, which is what this node asserts.

Dysregulated Hedgehog Signal Transduction and GLI Processing

Hedgehog pathway components traffic through the ciliary compartment, where full-length GLI2 and GLI3 are proteolytically processed into repressor forms. A defective cilium perturbs this processing and shifts the activator to repressor ratio, so Hedgehog output is not simply reduced but deranged, and can be excessive in tissues such as the facial mesenchyme. Because Hedgehog patterns both the cranial neural crest derivatives and the limb bud, this single signaling lesion generates the oral-facial and the digital arms of the phenotype together.

Hedgehog (smoothened) signaling pathway GO:0007224 ↕ DYSREGULATED

Downstream

Cranial Neural Crest and Facial Midline Patterning Failure Deranged Hedgehog activity in cranial neural crest cells and the facial prominences alters midline patterning, producing hypertelorism and frontonasal dysplasia rather than the hypotelorism of Hedgehog loss.

Disrupted Autopod Digit Number and Identity Specification The same cilium-dependent Hedgehog derangement acts in the limb bud, where it alters the posterior patterning programme that specifies digit number and identity.

Show evidence (2 references)

PMID:27802276 SUPPORT Model Organism

"Our findings suggest that ciliopathic facial phenotypes are generated via loss of both GLI3R and GLI2R and that this pathology occurs via a de-repression mechanism."

Identifies loss of GLI repressor forms, that is de-repression rather than simple pathway loss, as the mechanism of the ciliopathic facial phenotype. Evidence source is MODEL_ORGANISM because the conclusion rests on mouse conditional knockouts.

PMID:36084634 SUPPORT In Vitro

"functional analysis in SCNM1-retrotransduced fibroblasts showed that SCNM1 is a positive mediator of Hedgehog (Hh) signaling"

Shows that the minor-spliceosome entry route also converges on Hedgehog signaling, supporting this node as the shared effector for both routes. Evidence source is IN_VITRO because the assay used patient-derived fibroblasts.

Cranial Neural Crest and Facial Midline Patterning Failure

The facial skeleton and the oral soft tissues derive from cranial neural crest cells populating the frontonasal and pharyngeal-arch prominences. Ciliary Hedgehog derangement in these cells broadens the domains of Hedgehog target gene expression and alters neural crest proliferation in the facial prominences, so the midline is patterned incorrectly. This is the tissue-level step that generates the oral and facial arms of the orofaciodigital triad.

embryonic cranial skeleton morphogenesis GO:0048701 ⚠ ABNORMAL roof of mouth development GO:0060021 ⚠ ABNORMAL

Downstream

Oral and Facial Malformation Mis-patterning of the facial prominences and their neural crest populations yields the clinically observed facial and oral malformations.

Show evidence (1 reference)

PMID:20106874 SUPPORT Model Organism

"Elimination of the intraflagellar transport protein Kif3a leads to excessive Hedgehog responsiveness in facial mesenchyme, which is accompanied by broader expression domains of Gli1, Ptc and Shh, and reduced expression domains of Gli3."

Documents the molecular signature of ciliary Hedgehog derangement within the facial mesenchyme that this tissue-level node describes. Evidence source is MODEL_ORGANISM because the analysis is in conditional-knockout mouse embryos.

Disrupted Autopod Digit Number and Identity Specification

Ciliary Hedgehog derangement in the limb bud perturbs the anteroposterior patterning gradient that specifies how many digits form and what identity each takes. In the orofaciodigital syndromes this typically adds digits, giving preaxial, postaxial or mesoaxial polydactyly, and also disturbs phalangeal segmentation, giving brachydactyly, syndactyly and clinodactyly. Because the autopod patterning programme is serially reused in fore- and hindlimb, the lesion is expressed in hands and feet alike.

chondrocyte CL:0000138

limb morphogenesis GO:0035108 ⚠ ABNORMAL

Downstream

Serially Homologous Autopod Malformation The mis-specified autopod programme is expressed in both fore- and hindlimb, so a single patterning lesion produces a digit-anomaly bundle across hands and feet rather than an isolated defect.

Show evidence (1 reference)

PMID:16311594 SUPPORT Model Organism

"we found impaired patterning of the neural tube and altered expression of the 5' Hoxa and Hoxd genes in the limb buds of mice lacking Ofd1"

Documents altered posterior HOX expression in the limb bud on loss of an OFD gene, the patterning derangement this node records. Evidence source is MODEL_ORGANISM because the limb buds are from Ofd1 knockout mice.

Oral and Facial Malformation

The oral and facial arms of the defining triad: accessory or hyperplastic frenula, lobulated or bifid tongue, tongue nodules and hamartomas, cleft of the hard or soft palate, median cleft or pseudocleft of the upper lip, hypodontia and other dental anomalies, hypertelorism or telecanthus, hypoplastic alae nasi and micrognathia. The precise combination varies by subtype and is part of what separates them clinically.

roof of mouth development GO:0060021 ⚠ ABNORMAL

Show evidence (2 references)

PMID:20301367 SUPPORT Human Clinical

"oral features (lobulated tongue, tongue nodules, cleft of the hard or soft palate, accessory gingival frenulae, hypodontia, and other dental abnormalities)"

Enumerates the oral malformations that constitute this node, in the best-characterized subtype.

PMID:20301367 SUPPORT Human Clinical

"facial features (widely spaced eyes, telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft of the upper lip, micrognathia)"

Enumerates the facial malformations that constitute this node, in the best-characterized subtype.

Serially Homologous Autopod Malformation

The digital arm of the defining triad, expressed across serially homologous elements: polydactyly (preaxial, postaxial or the mesoaxial form characteristic of OFD VI), syndactyly, brachydactyly, clinodactyly of the fifth finger and duplicated hallux, characteristically affecting hands and feet together.

chondrocyte CL:0000138

Show evidence (2 references)

PMID:20301367 SUPPORT Human Clinical

"digital features (brachydactyly, syndactyly, clinodactyly of the fifth finger, duplicated great toe)"

Enumerates the hand and foot anomalies of this node in the best-characterized subtype, including the hallux duplication that shows hindlimb involvement.

PMID:35361766 SUPPORT Human Clinical

"bilateral postaxial polydactyly of the hands, bilateral mesoaxial polydactyly of the feet"

A second subtype showing the same hands-and-feet bundle, supporting the serial-homology framing rather than a subtype-specific coincidence.

Multisystem Ciliopathy Involvement

Beyond the defining triad, the shared ciliary lesion produces organ involvement that varies by subtype and supplies most of the discriminating features: polycystic kidney disease (OFD I), intracerebral cysts, agenesis of the corpus callosum and cerebellar vermis hypoplasia with the molar tooth sign (OFD III, 6, 14, 16, 17), retinal colobomata (OFD IX) and retinopathy (OFD 16), tibial dysplasia and short ribs (OFD IV), hypothalamic hamartoma (OFD 6), and holoprosencephaly or pituitary anomaly (OFD 21). Intellectual disability is present in roughly half of individuals with OFD type I.

neural retina development GO:0003407 ⚠ ABNORMAL

Show evidence (2 references)

PMID:20301367 SUPPORT Human Clinical

"polycystic kidney disease; brain MRI findings (intracerebral cysts, agenesis of the corpus callosum, cerebellar agenesis with or without Dandy-Walker malformation); and intellectual disability (in approximately 50% of affected individuals)"

Records the renal, CNS and cognitive involvement that this node describes for OFD type I, including the quantified frequency of intellectual disability.

PMID:27141300 SUPPORT Other

"Additional signs may involve brain, kidneys and other organs thus better defining the different clinical subtypes."

Supports the framing that the extra-triad organ involvement is what discriminates the numbered subtypes. Evidence source is OTHER because this is a narrative review.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Ear 1

Hearing impairment HP:0000365

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"hearing aids and community hearing services as needed"

The management recommendation implies hearing impairment is an expected manifestation. Classified PARTIAL because the source states the intervention rather than reporting a frequency or severity of hearing loss.

Eye 1

Hypertelorism HP:0000316

Show evidence (1 reference)

PMID:35361766 SUPPORT Human Clinical

"He had a broad forehead, hypertelorism, short nose, anteverted nares, broad nasal bridge, broad nasal tip, thin upper lip"

Documents hypertelorism in an individual with a molecularly confirmed orofaciodigital subtype.

Head and Neck 3

Lobulated tongue HP:0000180

Show evidence (1 reference)

PMID:35361766 SUPPORT Human Clinical

"hyperplastic oral frenula, high-arched palate, lobulated tongue, oral lingual nodules, tongue hamartomas"

Documents a lobulated tongue in an individual with a molecularly confirmed orofaciodigital subtype.

Cleft palate HP:0000175

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"oral features (lobulated tongue, tongue nodules, cleft of the hard or soft palate, accessory gingival frenulae, hypodontia, and other dental abnormalities)"

Lists cleft of the hard or soft palate among the defining oral features.

Median cleft upper lip HP:0000161

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"facial features (widely spaced eyes, telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft of the upper lip, micrognathia)"

Lists median cleft or pseudocleft of the upper lip as a defining facial feature.

Limbs 5

Polydactyly HP:0010442

Show evidence (1 reference)

PMID:24178751 SUPPORT Human Clinical

"mesoaxial polydactyly of one or more hands or feet"

Records mesoaxial polydactyly as a formal diagnostic criterion of an orofaciodigital subtype.

Postaxial polydactyly HP:0100259

Show evidence (1 reference)

PMID:35361766 SUPPORT Human Clinical

"The clinical features of OFD syndrome type XVI mainly include postaxial polydactyly of the hands and feet"

Records postaxial polydactyly as a core feature of OFD type XVI.

Syndactyly HP:0001159

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"digital features (brachydactyly, syndactyly, clinodactyly of the fifth finger, duplicated great toe)"

Lists syndactyly among the defining digital features.

Brachydactyly HP:0001156

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"digital features (brachydactyly, syndactyly, clinodactyly of the fifth finger, duplicated great toe)"

Lists brachydactyly among the defining digital features.

Clinodactyly HP:0030084

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"digital features (brachydactyly, syndactyly, clinodactyly of the fifth finger, duplicated great toe)"

Lists clinodactyly of the fifth finger among the defining digital features.

Musculoskeletal 1

Short ribs HP:0000773

Show evidence (1 reference)

PMID:38702430 SUPPORT Human Clinical

"Herein, we describe two Indian patients carrying biallelic variants in FUZ with digital anomalies, orofacial cleft, short ribs and cardiac defects resembling orofaciodigital syndrome."

Documents short ribs alongside the orofaciodigital triad in CPLANE-module disease.

Nervous System 4

Agenesis of corpus callosum HP:0001274

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"brain MRI findings (intracerebral cysts, agenesis of the corpus callosum, cerebellar agenesis with or without Dandy-Walker malformation)"

Records agenesis of the corpus callosum among the characteristic brain findings.

Molar tooth sign on MRI HP:0002419

Show evidence (1 reference)

PMID:24178751 SUPPORT Human Clinical

"Because of the MTS, OFD VI belongs to the "Joubert syndrome related disorders"."

Establishes the molar tooth sign as the feature that places OFD VI among the Joubert-syndrome-related disorders.

Cerebellar vermis hypoplasia HP:0001320

Show evidence (1 reference)

PMID:35361766 SUPPORT Human Clinical

"MRI showed cerebellar vermis hypoplasia and a molar tooth sign"

Documents cerebellar vermis hypoplasia on brain MRI in a molecularly confirmed orofaciodigital subtype.

Intellectual disability FREQUENT HP:0001249

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"intellectual disability (in approximately 50% of affected individuals)"

Gives the quantitative estimate of approximately 50% that justifies the FREQUENT band, which spans 30-79%. The figure is specific to OFD type I.

Other 4

Abnormal oral frenulum morphology HP:0000190

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"oral features (lobulated tongue, tongue nodules, cleft of the hard or soft palate, accessory gingival frenulae, hypodontia, and other dental abnormalities)"

Lists accessory gingival frenulae among the defining oral features.

Tongue nodules HP:0000199

Show evidence (1 reference)

PMID:35361766 SUPPORT Human Clinical

"hyperplastic oral frenula, high-arched palate, lobulated tongue, oral lingual nodules, tongue hamartomas"

Documents lingual nodules and tongue hamartomas in a molecularly confirmed orofaciodigital subtype.

Polycystic kidney dysplasia OCCASIONAL HP:0000113

Show evidence (1 reference)

PMID:16311594 SUPPORT Human Clinical

"affected individuals have craniofacial and digital abnormalities and, in 15% of cases, polycystic kidney"

Gives the quantitative estimate of 15% of cases that justifies the OCCASIONAL frequency band, which spans 5-29%. The figure describes human OFD type I patients, so the evidence source is HUMAN_CLINICAL even though the paper's own experiments are in mice.

Retinal coloboma HP:0000480

Show evidence (1 reference)

PMID:27141300 SUPPORT Other

"OFD type IX is characterized by retinal colobomata in addition to the typical oro-facio-digital findings."

Records retinal colobomata as the discriminating ophthalmological feature of OFD type IX. Evidence source is OTHER because this is a narrative review.

🧬

Genetic Associations

OFD1

Gene: OFD1 hgnc:2567 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:11179005 SUPPORT Human Clinical

"Analysis of the familial cases revealed a missense mutation, a 19-bp deletion, and a single base-pair deletion leading to a frameshift."

Documents the variant spectrum found in OFD1 in familial OFD type I cases.

PMID:28289185 SUPPORT Human Clinical

"The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein."

Confirms the heterozygous OFD1 mechanism and the centrosomal identity of the protein.

C2CD3

Gene: C2CD3 hgnc:24564 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:24997988 SUPPORT In Vitro

"we propose that C2CD3 directly promotes centriole elongation and that OFD1 acts as a negative regulator of C2CD3"

Establishes the antagonistic relationship between two OFD gene products at the centriole. Evidence source is IN_VITRO because the localization and length experiments were done in cultured cells.

TCTN3

Gene: TCTN3 hgnc:24519 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:22883145 SUPPORT Human Clinical

"Overall, our data show the involvement of the transition zone protein TCTN3 in the regulation of the key SHH signaling pathway and that its disruption causes a severe form of ciliopathy, combining features of Meckel and OFD IV syndromes."

Establishes TCTN3 as a transition-zone gene whose disruption causes OFD IV through Hedgehog dysregulation.

CPLANE1

Gene: CPLANE1 hgnc:25801 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:24178751 SUPPORT Human Clinical

"C5orf42 mutations have already been reported in Joubert syndrome confirming that OFD VI and JBS are allelic disorders"

Documents both the causal role in OFD VI and the allelism with Joubert syndrome that this entry records.

INTU

Gene: INTU hgnc:29239 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:28289185 SUPPORT Human Clinical

"We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57)"

Identifies INTU as one of the OFD causal genes recorded in this entry.

SCNM1

Gene: SCNM1 hgnc:23136 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:36084634 SUPPORT Human Clinical

"Our findings demonstrate that defective U12 intron splicing can lead to a typical ciliopathy such as OFD and reveal that primary cilia length and Hh signaling are regulated by the minor spliceosome through SCNM1 activity."

Establishes the indirect, minor-spliceosome route to the ciliary phenotype recorded for this gene.

ZRSR2

Gene: ZRSR2 hgnc:23019 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:38158857 SUPPORT Human Clinical

"ZRSR2, located on chromosome Xp22.2, encodes a splicing factor of the minor spliceosome complex, which recognizes minor introns, representing 0.35% of human introns."

Records the gene's location and minor-spliceosome function, the basis of the mechanism assigned to OFD 21.

RAB34

Gene: RAB34 hgnc:16519 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:37384395 SUPPORT In Vitro

"We find that the protein products of these pathogenic variants, which are clustered near the RAB34 C-terminus, exhibit a strong loss of function."

Establishes the loss-of-function mechanism of the OFD 20 variants. Evidence source is IN_VITRO because the functional characterization was in cultured cells.

INTS13

Gene: INTS13 hgnc:20174 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:36229431 SUPPORT In Vitro

"Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes."

Establishes the ciliary consequence of INTS13 loss. Evidence source is IN_VITRO because the ciliogenesis assays were performed in cultured human cells.

FUZ

Gene: FUZ hgnc:26219 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:38702430 SUPPORT Human Clinical

"Our findings underscore the association between biallelic loss of function variants in FUZ and skeletal ciliopathy akin to orofaciodigital syndrome."

Supports a FUZ-OFD spectrum association. Classified PARTIAL because the authors describe the phenotype as akin to orofaciodigital syndrome rather than assigning a numbered OFD type.

💊

Medical Actions

Surgical correction of oral, facial and digital malformations

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Management is symptomatic. Surgery addresses cleft lip and palate, tongue nodules and hamartomas, accessory frenula, syndactyly and polydactyly; timing and staging follow standard craniofacial and hand-surgery practice.

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"Surgery for cleft lip/palate, tongue nodules, accessory frenulae, syndactyly, and polydactyly"

States the surgical management of the malformation triad recommended for OFD type I.

Speech therapy and management of otitis media

Action: speech and language therapy Ontology label: Speech Language Therapy NCIT:C159273

Speech and language therapy is required because of the combined palatal, lingual and hearing involvement; recurrent otitis media is treated aggressively to protect hearing and speech development.

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"speech therapy and aggressive treatment of otitis media as needed"

States the speech-therapy and otitis-media management recommended for OFD type I.

Renal and blood-pressure surveillance with standard treatment of kidney disease

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Because polycystic kidney disease in OFD type I is generally adult-onset and progressive, annual blood pressure, serum creatinine and abdominal ultrasound from age ten allow kidney disease to be treated by standard nephrological management before it presents late.

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"Annual blood pressure; serum creatinine; and kidney, liver, pancreas, and ovarian ultrasound for cystic disease beginning at age ten years."

States the renal surveillance programme underpinning this management recommendation.

Genetic counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counseling must be subtype-specific: OFD type I carries X-linked dominant, male-lethal recurrence risks with most cases sporadic, whereas the autosomal recessive subtypes carry a 25% sibling recurrence risk, and OFD VIII and OFD 21 are X-linked recessive. Evaluating apparently asymptomatic female relatives in OFD type I families is recommended because they may still be at risk of kidney disease.

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"It is appropriate to evaluate the genetic status of apparently asymptomatic female relatives (even in the absence of oral, facial, and digital anomalies) to determine if they are at risk for kidney disease."

States the family-evaluation recommendation that this counseling intervention implements.

🔬

Diagnosis

Clinical recognition of the oral-facial-digital triad

Diagnosis begins with recognition of the characteristic combination of oral (frenula, lobulated tongue, tongue nodules, clefting), facial (hypertelorism, median upper-lip cleft or pseudocleft, hypoplastic alae nasi) and digital (polydactyly, syndactyly, brachydactyly, clinodactyly) anomalies. The additional organ findings then direct subtype assignment.

clinical evaluation NCIT:C124351

Show evidence (1 reference)

PMID:37384395 SUPPORT Human Clinical

"Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogeneous disorders characterized by defects in the development of the face and oral cavity along with digit anomalies."

Defines the clinical triad on which the initial diagnostic recognition rests.

Brain MRI for cerebral and cerebellar malformation

Brain MRI identifies the molar tooth sign and cerebellar vermis hypoplasia that assign a case to the Joubert-overlapping subtypes (notably OFD VI), and detects the intracerebral cysts, corpus callosum agenesis and Dandy-Walker malformation seen in OFD type I.

magnetic resonance imaging NCIT:C16809

Show evidence (2 references)

PMID:24178751 SUPPORT Human Clinical

"Oral-facial-digital syndrome type VI (OFD VI) is a recessive ciliopathy defined by two diagnostic criteria: molar tooth sign (MTS) and one or more of the following"

Establishes the molar tooth sign, an MRI finding, as a formal diagnostic criterion for a subtype.

PMID:35361766 SUPPORT Human Clinical

"MRI showed cerebellar vermis hypoplasia and a molar tooth sign"

Worked example of brain MRI making the subtype-defining CNS findings in an orofaciodigital case.

Skeletal radiography of hands, feet and thorax

Radiographs delineate the digital anomalies (extra rays, phalangeal number and shape, metacarpal form) and detect the tibial dysplasia and short ribs that identify the severe skeletal subtypes OFD IV and OFD XV.

radiography NCIT:C38101

Show evidence (1 reference)

PMID:35361766 SUPPORT Human Clinical

"Radiographic imaging at 48 days showed the 6th finger, including two proximal phalanxes and one distal phalanx"

Worked example of radiography resolving the digital anatomy in an orofaciodigital case.

Molecular genetic testing

Diagnosis is confirmed by identifying the causal variant. For OFD type I this is a heterozygous OFD1 variant in a female or a hemizygous variant in a male; for the other subtypes a multigene ciliopathy panel or exome sequencing is required.

molecular genetic testing NCIT:C19770

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"The diagnosis of OFD1 is established in a female proband with suggestive findings and a heterozygous OFD1 pathogenic variant identified by molecular genetic testing."

States the molecular diagnostic criterion for the commonest subtype.

Exome sequencing for the molecularly undefined subtypes

Because several of the classically described subtypes still lack a molecular definition, exome or genome sequencing is the appropriate test when a case does not fit a gene-defined type; this is how C2CD3, TMEM107, INTU, KIAA0753, IFT57, SCNM1, RAB34 and ZRSR2 were each identified.

genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:27141300 SUPPORT Other

"To date, seven of the described OFDS still await a molecular definition and two unclassified forms need further clinical and molecular validation."

Establishes the residual diagnostic gap that motivates untargeted sequencing in this group. Evidence source is OTHER because this is a narrative review.

Renal ultrasound surveillance

Because polycystic kidney disease in OFD type I is typically adult-onset, imaging surveillance rather than one-off testing is required; kidney, liver, pancreas and ovarian ultrasound is recommended annually from age ten.

renal ultrasound NCIT:C159885

Show evidence (1 reference)

PMID:20301367 SUPPORT Human Clinical

"Annual blood pressure; serum creatinine; and kidney, liver, pancreas, and ovarian ultrasound for cystic disease beginning at age ten years."

States the imaging surveillance schedule for cystic organ disease in OFD type I.

📊

Prevalence

Worldwide (OFD type I only)

Birth Prevalence 2.0 per 100,000 1–9 per 100,000

Estimate is specific to OFD type I, the most frequent subtype; no group-level incidence figure covering all orofaciodigital subtypes has been published, and the remaining subtypes are individually much rarer, several being single-family reports.

Show evidence (1 reference)

PMID:27141300 SUPPORT Other

"It has an estimated incidence of 1:50,000 live births"

Provides the published incidence estimate for OFD type I, normalized here to 2 per 100,000. Evidence source is OTHER because this is a narrative review.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Orofaciodigital Syndrome:

Joubert syndrome MONDO:0018772

Overlapping Features The closest differential. OFD VI is formally a Joubert-syndrome-related disorder and shares the molar tooth sign and several genes (CPLANE1, TMEM216, TMEM107, OFD1), so the two are allelic rather than merely similar.

Distinguishing Features

OFD VI requires oral-facial-digital findings (tongue hamartoma, additional frenula, mesoaxial polydactyly or hypothalamic hamartoma) in addition to the molar tooth sign; pure Joubert syndrome lacks them.
Joubert syndrome presents with hypotonia, ataxia, oculomotor apraxia and episodic hyperpnea as the leading features rather than a malformation triad.

Show evidence (1 reference)

PMID:24178751 SUPPORT Human Clinical

"C5orf42 mutations have already been reported in Joubert syndrome confirming that OFD VI and JBS are allelic disorders, thus enhancing our knowledge of the complex, highly heterogeneous nature of ciliopathies."

Establishes the allelic relationship that makes Joubert syndrome the primary differential for the molar-tooth-sign subtypes.

Meckel syndrome MONDO:0018921

Overlapping Features A lethal transition-zone ciliopathy sharing genes with the severe OFD subtypes; TCTN3 truncating variants were found in fetal cases with overlapping Meckel and OFD IV phenotypes.

Distinguishing Features

Meckel syndrome is defined by the triad of occipital encephalocele, cystic renal dysplasia and hepatic ductal plate malformation, and is perinatally lethal.
The oral findings characteristic of OFDS (accessory frenula, lobulated tongue, tongue hamartoma) are not part of the Meckel definition.

Show evidence (1 reference)

PMID:22883145 SUPPORT Human Clinical

"led us to identify four additional truncating TCTN3 mutations in unrelated fetal cases with overlapping Meckel and OFD IV syndromes"

Documents the phenotypic overlap that makes Meckel syndrome a differential for the severe OFD subtypes.

Bardet-Biedl syndrome MONDO:0015229

Overlapping Features A pleiotropic ciliopathy that also features polydactyly, and shares the ciliary mechanism, but with a quite different clinical centre of gravity.

Distinguishing Features

Bardet-Biedl syndrome is defined by rod-cone dystrophy, obesity, hypogonadism and renal dysfunction; postaxial polydactyly is its only overlap with the orofaciodigital triad.
The oral and facial midline malformations of OFDS are not features of Bardet-Biedl syndrome.

Show evidence (1 reference)

PMID:35361766 SUPPORT Human Clinical

"OFD syndromes are classified under ciliopathies, which also include Joubert syndrome (JBS), Meckel–Gruber syndrome (MKS), Bardet–Biedl syndrome, nephronophthisis (NPHP), and several chondrodysplasias"

Places Bardet-Biedl syndrome alongside OFDS within the ciliopathies, which is why it is carried as a differential.

📊

Related Datasets

INTS13 Mutations Causing a Developmental Ciliopathy Disrupt Integrator Complex Assembly geo:GSE154197

RNA-seq of human cells depleted of INTS13, generated in the study that identified biallelic INTS13 variants in two families with variable orofaciodigital syndrome type 2 and showed that INTS13 depletion disrupts ciliogenesis and dysregulates a broad collection of ciliary genes.

human BULK RNA SEQ n=9

PMID:36229431

Accession, title, organism and sample count verified against the NCBI GEO E-utilities record on 2026-08-19. Relevance is DIRECT rather than gene-only: the linked publication reports the affected families as having orofaciodigital syndrome type 2, not merely a ciliary gene of interest.

Show evidence (1 reference)

PMID:36229431 SUPPORT In Vitro

"Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes."

States the transcriptional result this dataset reports. Evidence source is IN_VITRO because the profiling was performed in cultured human cells.

{ }

Source YAML

click to show

name: Orofaciodigital Syndrome
creation_date: "2026-08-19T10:00:00Z"
category: Mendelian
description: >-
  Orofaciodigital syndrome (OFDS; oral-facial-digital syndrome) is the umbrella
  entry for a clinically and genetically heterogeneous group of ciliopathies
  defined by the co-occurrence of malformations of the oral cavity (accessory
  frenula, lobulated or bifid tongue, tongue hamartomas/nodules, cleft palate,
  dental anomalies), the face (hypertelorism, median cleft or pseudocleft of the
  upper lip, hypoplastic alae nasi, micrognathia) and the digits (pre-, post- and
  mesoaxial polydactyly, syndactyly, brachydactyly, clinodactyly), with variable
  additional involvement of the brain, kidneys, retina and skeleton that
  distinguishes the numbered subtypes from one another. The archetypal and by far
  the most frequent form is OFD type I, an X-linked dominant, male-lethal disorder
  caused by heterozygous OFD1 variants; almost all other subtypes are autosomal
  recessive, with OFD VIII and OFD 21 X-linked recessive. Nearly every causal gene
  encodes a centriolar, basal-body, transition-zone or CPLANE/intraflagellar
  transport protein, so the shared mechanism is failure of primary-cilium assembly
  or ciliary compartmentalization, which deranges cilium-dependent Hedgehog signal
  transduction and thereby the patterning of the cranial neural crest derivatives
  and the autopod. Two of the most recently delineated subtypes (OFD 19, SCNM1;
  OFD 21, ZRSR2) instead disrupt the minor (U12) spliceosome and reach the same
  ciliary endpoint indirectly, by depleting transcripts of ciliary genes. Because
  the shared mechanism is elaborated in the ciliopathy_dysfunction module and the
  digit bundle in limb_digit_patterning_serial_homology, this entry declares
  conformance to both rather than re-deriving them, and cross-references the
  existing per-subtype entries Orofaciodigital_Syndrome_Type_I and
  Orofaciodigital_Syndrome_17 rather than duplicating their detail.
disease_term:
  preferred_term: orofaciodigital syndrome
  term:
    id: MONDO:0015375
    label: orofaciodigital syndrome
parents:
- Ciliopathy
synonyms:
- OFDS
- OFD
- oral-facial-digital syndrome
- oral-facial-digital syndromes
- orofaciodigital syndromes
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A group of Mendelian malformation syndromes whose members are defined by
      germline variants in ciliary, centriolar and minor-spliceosome genes.
    evidence:
    - reference: PMID:27141300
      reference_title: Update on oral-facial-digital syndromes (OFDS).
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        With the exception of OFD types I and VIII, which are X-linked, the
        majority of OFDS is transmitted as an autosomal recessive syndrome.
      explanation: >-
        Establishes OFDS as a set of Mendelian disorders with defined modes of
        inheritance, which is why the entry is assigned to the genetics chapter.
        Evidence source is OTHER because this is a narrative review.
  mechanistic_category:
  - classification_value: ciliopathy
    notes: >-
      Assigned on the basis of the ciliary/centriolar identity of the OFDS gene
      set rather than on any single subtype.
    evidence:
    - reference: PMID:28289185
      reference_title: "Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        OFDS now appear to be a distinct subgroup of ciliopathies with wide
        heterogeneity
      explanation: >-
        States explicitly that the orofaciodigital syndromes form a subgroup of
        the ciliopathies, which is the mechanistic category assigned here.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0015375
      label: orofaciodigital syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO identifier for the orofaciodigital syndrome group; carries the
      OMIM phenotypic series OMIMPS:311200 and Orphanet:140997 cross-references.
  - term:
      id: MONDO:1040039
      label: OFD1-related ciliopathy
    mapping_predicate: skos:relatedMatch
    mapping_source: MONDO
    mapping_justification: >-
      Gene-based MONDO node spanning the OFD1 allelic series (OFD type I, Joubert
      syndrome 10, primary ciliary dyskinesia, retinitis pigmentosa 23). It is a
      per-locus concept that cuts across this clinical grouping rather than
      nesting inside it, so the relation is recorded as a related match.
notes: >-
  Scope and subtype-list provenance. The has_subtypes list below enumerates all
  twenty numbered orofaciodigital types that carry a MONDO identifier, each bound
  to a CURIE and canonical label verified with OAK against the local MONDO build
  on 2026-08-19. Depth of curation is deliberately uneven and should not be read
  as a completeness claim: the well-delineated types (I, II, III, IV, V, 6, IX,
  14, XV, 16, 17, 18, 19, 20, 21) carry a gene assignment and, where a quotable
  primary source exists, subtype-level evidence, whereas types VII, VIII, X, XI
  and 12 are enumerated with their MONDO binding and a one-line clinical
  descriptor only, because they remain molecularly undefined. OFD XIII (Degner
  syndrome) is named in the classical series but has no MONDO term and is
  therefore absent from the list entirely.

  Inclusion of OFD type I. OFD type I (MONDO:0010702) is listed here as a subtype
  even though MONDO does not place it under MONDO:0015375: its asserted is_a
  parents are syndromic disease, Mendelian neurodevelopmental disorder and
  OFD1-related ciliopathy, so it is not among the nineteen descendants of the
  grouping term. Building the list from the MONDO descendant closure alone would
  silently omit the eponymous and commonest type. Three independent authorities
  place it inside the group: MONDO:0015375 itself carries the cross-reference
  OMIMPS:311200, an OMIM phenotypic series anchored on OFD type I (OMIM:311200);
  MONDO's own definition text for the grouping names Type I (Papillon-Leage and
  Psaume syndrome, Gorlin-Psaume syndrome) as one of its two members; and
  Orphanet:140997, the other cross-reference, is likewise the OFD group record.
  The omission is judged to be an artifact of MONDO's classification of OFD I
  under the gene-based OFD1-related ciliopathy node, and is worth reporting
  upstream rather than reproducing here. See the ofds_mondo_excludes_type_i
  discussion.

  Relationship to existing entries. Two members are already curated as standalone
  Disease entries (Orofaciodigital_Syndrome_Type_I, Orofaciodigital_Syndrome_17)
  and a third OFD-spectrum disorder is curated under a non-OFD name
  (Heart_Defect_Tongue_Hamartoma_Polysyndactyly_Syndrome, WDPCP, related to OFDS
  by PMID:28289185). This entry is the group-level view and deliberately does not
  restate their pathographs. Whether the group is better modeled as a Grouping
  over those entries is recorded as an open discussion below rather than being
  decided silently.
references:
- reference: PMID:20301367
  title: Oral-Facial-Digital Syndrome Type I.
  tags:
  - GeneReviews
has_subtypes:
- name: OFD I
  display_name: Orofaciodigital syndrome type I (Papillon-Leage-Psaume syndrome)
  description: >-
    X-linked dominant, male-lethal form caused by heterozygous OFD1 variants; the
    most frequent subtype. Oral, facial and digital malformations with polycystic
    kidney disease, corpus callosum agenesis and intracerebral cysts. Curated in
    full in Orofaciodigital_Syndrome_Type_I. Listed here on clinical and
    OMIM-phenotypic-series grounds despite not being a MONDO descendant of the
    grouping term (see notes).
  subtype_term:
    preferred_term: orofaciodigital syndrome I
    term:
      id: MONDO:0010702
      label: orofaciodigital syndrome I
  genes:
  - preferred_term: OFD1
    term:
      id: hgnc:2567
      label: OFD1
  evidence:
  - reference: PMID:11179005
    reference_title: Identification of the gene for oral-facial-digital type I syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we analyzed several transcripts mapping to the region and found mutations in
      OFD1
    explanation: >-
      Original identification of OFD1 as the gene mutated in orofaciodigital
      syndrome type I, which is the gene assignment recorded for this subtype.
- name: OFD II
  display_name: Orofaciodigital syndrome type II (Mohr syndrome)
  description: >-
    Autosomal recessive form with lobulated tongue, midline cleft lip, broad nasal
    tip, conductive hearing loss and polysyndactyly, classically including
    reduplicated hallux. Long molecularly undefined; biallelic INTS13 variants
    were reported in two families with variable OFD type 2.
  subtype_term:
    preferred_term: orofaciodigital syndrome type II
    term:
      id: MONDO:0009642
      label: orofaciodigital syndrome type II
  genes:
  - preferred_term: INTS13
    term:
      id: hgnc:20174
      label: INTS13
  evidence:
  - reference: PMID:36229431
    reference_title: INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through homozygosity mapping and exome sequencing of two families with
      variable OFD type 2, we identified distinct germline variants in INTS13
    explanation: >-
      Supplies the gene assignment for OFD type II, which MONDO does not record.
      The authors' own qualifier "variable OFD type 2" is retained rather than
      strengthened.
- name: OFD III
  display_name: Orofaciodigital syndrome type III (Sugarman syndrome)
  description: >-
    Autosomal recessive form distinguished by metronome-like ocular motor apraxia
    in addition to lingual hamartomas and postaxial polydactyly, with cerebellar
    vermis hypoplasia and Dandy-Walker malformation; TMEM231 variants have been
    reported in affected sibs.
  subtype_term:
    preferred_term: orofaciodigital syndrome III
    term:
      id: MONDO:0009793
      label: orofaciodigital syndrome III
  genes:
  - preferred_term: TMEM231
    term:
      id: hgnc:37234
      label: TMEM231
  evidence:
  - reference: PMID:28289185
    reference_title: "Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      related the clinical spectrum of four genes in other ciliopathies (C5orf42,
      TMEM138, TMEM231 and WDPCP) to OFDS
    explanation: >-
      Places TMEM231 within the OFDS gene set. Classified PARTIAL because it
      supports gene-group membership rather than the specific type III
      assignment, which rests on the Franco and Thauvin-Robinet review
      classification.
- name: OFD IV
  display_name: Orofaciodigital syndrome type IV (Mohr-Majewski / Baraitser-Burn syndrome)
  description: >-
    Severe autosomal recessive form combining the orofaciodigital triad with
    tibial dysplasia (the discriminating feature), short ribs, cystic kidneys and
    brain anomalies; caused by biallelic TCTN3 variants and overlapping
    phenotypically with Meckel syndrome.
  subtype_term:
    preferred_term: orofaciodigital syndrome IV
    term:
      id: MONDO:0009794
      label: orofaciodigital syndrome IV
  genes:
  - preferred_term: TCTN3
    term:
      id: hgnc:24519
      label: TCTN3
  evidence:
  - reference: PMID:22883145
    reference_title: TCTN3 mutations cause Mohr-Majewski syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified truncating TCTN3 mutations as the cause of an extreme form of
      OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain
      anomalies (OFD IV, Mohr-Majewski syndrome)
    explanation: >-
      Establishes both the gene assignment and the discriminating tibial and
      skeletal features of OFD type IV.
- name: OFD V
  display_name: Orofaciodigital syndrome type V (Thurston syndrome)
  description: >-
    Autosomal recessive form reported predominantly in families of Indian origin,
    characterized by median cleft lip with postaxial polydactyly and relatively
    little visceral involvement; biallelic DDX59 variants were identified in two
    consanguineous multiplex families.
  subtype_term:
    preferred_term: orofaciodigital syndrome V
    term:
      id: MONDO:0008267
      label: orofaciodigital syndrome V
  genes:
  - preferred_term: DDX59
    term:
      id: hgnc:25360
      label: DDX59
  evidence:
  - reference: PMID:23972372
    reference_title: Mutations in DDX59 implicate RNA helicase in the pathogenesis of orofaciodigital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing revealed a different homozygous variant in DDX59 in each of
      the two families
    explanation: >-
      Records the DDX59 gene assignment for this subtype in two multiplex
      consanguineous families affected by OFD.
- name: OFD 6
  display_name: Orofaciodigital syndrome type VI (Varadi-Papp syndrome)
  description: >-
    Autosomal recessive form defined by the molar tooth sign plus tongue
    hamartoma/additional frenula, mesoaxial polydactyly and/or hypothalamic
    hamartoma; a Joubert-syndrome-related disorder. CPLANE1 (C5orf42) is the major
    gene, with TMEM216, TMEM107 and OFD1 also reported.
  subtype_term:
    preferred_term: orofaciodigital syndrome type 6
    term:
      id: MONDO:0010176
      label: orofaciodigital syndrome type 6
  genes:
  - preferred_term: CPLANE1
    term:
      id: hgnc:25801
      label: CPLANE1
  - preferred_term: TMEM216
    term:
      id: hgnc:25018
      label: TMEM216
  evidence:
  - reference: PMID:24178751
    reference_title: C5orf42 is the major gene responsible for OFD syndrome type VI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Oral-facial-digital syndrome type VI (OFD VI) is a recessive ciliopathy
      defined by two diagnostic criteria: molar tooth sign (MTS) and one or more
      of the following: (1) tongue hamartoma (s) and/or additional frenula and/or
      upper lip notch; (2) mesoaxial polydactyly of one or more hands or feet; (3)
      hypothalamic hamartoma.
    explanation: >-
      Gives the operational diagnostic criteria that separate OFD VI from the
      other subtypes and from pure Joubert syndrome.
  - reference: PMID:24178751
    reference_title: C5orf42 is the major gene responsible for OFD syndrome type VI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a total of 14 novel mutations in the C5orf42 gene in 9/11
      families with positive OFD VI diagnostic criteria
    explanation: >-
      Supports CPLANE1 (C5orf42) as the major gene for OFD VI.
- name: OFD VII
  display_name: Orofaciodigital syndrome type VII (Whelan syndrome)
  description: >-
    Rare form reported with the orofaciodigital triad accompanied by facial
    asymmetry and hydronephrosis. Molecularly undefined; enumerated here for
    completeness of the numbered series, not curated in depth.
  subtype_term:
    preferred_term: orofaciodigital syndrome VII
    term:
      id: MONDO:0012049
      label: orofaciodigital syndrome VII
- name: OFD VIII
  display_name: Orofaciodigital syndrome type VIII (Edwards syndrome)
  description: >-
    X-linked recessive form affecting males, with the orofaciodigital triad,
    duplicated hallux and radial/tibial defects. Molecularly undefined; enumerated
    here for completeness of the numbered series, not curated in depth.
  subtype_term:
    preferred_term: orofaciodigital syndrome VIII
    term:
      id: MONDO:0010336
      label: orofaciodigital syndrome VIII
- name: OFD IX
  display_name: Orofaciodigital syndrome type IX (Gurrieri syndrome)
  description: >-
    Autosomal recessive form distinguished by retinal colobomata in addition to
    the typical orofaciodigital findings; TBC1D32 and SCLT1 variants have been
    reported in severe cases.
  subtype_term:
    preferred_term: orofaciodigital syndrome IX
    term:
      id: MONDO:0009795
      label: orofaciodigital syndrome IX
  genes:
  - preferred_term: TBC1D32
    term:
      id: hgnc:21485
      label: TBC1D32
  - preferred_term: SCLT1
    term:
      id: hgnc:26406
      label: SCLT1
  evidence:
  - reference: PMID:27141300
    reference_title: Update on oral-facial-digital syndromes (OFDS).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      OFD type IX is characterized by retinal colobomata in addition to the
      typical oro-facio-digital findings. It is inherited as an autosomal
      recessive trait.
    explanation: >-
      Records the discriminating retinal feature and inheritance mode of OFD type
      IX. Evidence source is OTHER because this is a narrative review.
- name: OFD X
  display_name: Orofaciodigital syndrome type X (Figuera syndrome)
  description: >-
    Rare form reported with the orofaciodigital triad and radial defects with
    fibular aplasia. Molecularly undefined; enumerated here for completeness of
    the numbered series, not curated in depth.
  subtype_term:
    preferred_term: orofaciodigital syndrome X
    term:
      id: MONDO:0008137
      label: orofaciodigital syndrome X
- name: OFD XI
  display_name: Orofaciodigital syndrome type XI (Gabrielli syndrome)
  description: >-
    Rare form reported with the orofaciodigital triad and vertebral and dental
    anomalies. Molecularly undefined; enumerated here for completeness of the
    numbered series, not curated in depth.
  subtype_term:
    preferred_term: orofaciodigital syndrome XI
    term:
      id: MONDO:0013035
      label: orofaciodigital syndrome XI
- name: OFD 12
  display_name: Orofaciodigital syndrome type XII (Moran-Barroso syndrome)
  description: >-
    Rare form reported with the orofaciodigital triad, cardiac defect and cerebral
    malformation. Molecularly undefined; enumerated here for completeness of the
    numbered series, not curated in depth.
  subtype_term:
    preferred_term: orofaciodigital syndrome type 12
    term:
      id: MONDO:0015421
      label: orofaciodigital syndrome type 12
- name: OFD 14
  display_name: Orofaciodigital syndrome type XIV
  description: >-
    Autosomal recessive form distinguished from the other subtypes by severe
    microcephaly and cerebral malformation including the molar tooth sign; caused
    by biallelic variants in C2CD3, a positive regulator of centriole elongation
    that is antagonized by OFD1.
  subtype_term:
    preferred_term: orofaciodigital syndrome type 14
    term:
      id: MONDO:0014413
      label: orofaciodigital syndrome type 14
  genes:
  - preferred_term: C2CD3
    term:
      id: hgnc:24564
      label: C2CD3
  evidence:
  - reference: PMID:24997988
    reference_title: The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we uncover a new subtype of OFD with severe microcephaly and cerebral
      malformations and identify distinct mutations in two affected families in
      the evolutionarily conserved C2CD3 gene.
    explanation: >-
      Establishes both the gene assignment and the microcephaly and cerebral
      malformation features that delineate this subtype.
- name: OFD XV
  display_name: Orofaciodigital syndrome type XV
  description: >-
    Autosomal recessive form caused by biallelic KIAA0753 variants; KIAA0753 acts
    with FOPNL and OFD1 in the centriole-elongation module and its allelic
    spectrum also includes Joubert syndrome and short-rib skeletal dysplasia.
  subtype_term:
    preferred_term: orofaciodigital syndrome XV
    term:
      id: MONDO:0014932
      label: orofaciodigital syndrome XV
  genes:
  - preferred_term: KIAA0753
    term:
      id: hgnc:29110
      label: KIAA0753
  evidence:
  - reference: PMID:29138412
    reference_title: Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the KIAA0753 gene have recently been associated with Joubert
      syndrome (JBTS) and orofaciodigital (OFD) syndrome.
    explanation: >-
      Confirms the KIAA0753-OFD association and the allelic overlap with Joubert
      syndrome recorded in this subtype description.
- name: OFD 16
  display_name: Orofaciodigital syndrome type XVI
  description: >-
    Autosomal recessive form caused by biallelic TMEM107 variants; features
    include postaxial polydactyly of the hands and mesoaxial polydactyly of the
    feet, cerebellar vermis hypoplasia with molar tooth sign, retinopathy and
    developmental delay, and tibial dysplasia has been reported.
  subtype_term:
    preferred_term: orofaciodigital syndrome 16
    term:
      id: MONDO:0033045
      label: orofaciodigital syndrome 16
  genes:
  - preferred_term: TMEM107
    term:
      id: hgnc:28128
      label: TMEM107
  evidence:
  - reference: PMID:35361766
    reference_title: Additional findings of tibial dysplasia in a male with orofaciodigital syndrome type XVI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical features of OFD syndrome type XVI mainly include postaxial
      polydactyly of the hands and feet, vermis hypoplasia, MTS, retinopathy,
      apnea/hyperpnea, and developmental delay
    explanation: >-
      Supplies the clinical delineation of OFD type XVI recorded in this subtype
      description.
- name: OFD 17
  display_name: Orofaciodigital syndrome type XVII
  description: >-
    Autosomal recessive form caused by biallelic INTU variants, a subunit of the
    CPLANE module required for IFT-A assembly. Curated in full in
    Orofaciodigital_Syndrome_17.
  subtype_term:
    preferred_term: orofaciodigital syndrome 17
    term:
      id: MONDO:0033375
      label: orofaciodigital syndrome 17
  genes:
  - preferred_term: INTU
    term:
      id: hgnc:29239
      label: INTU
  evidence:
  - reference: PMID:28289185
    reference_title: "Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified causal variants in five new genes (C2CD3, TMEM107, INTU,
      KIAA0753 and IFT57)
    explanation: >-
      Identifies INTU among the OFD-causing ciliary genes, the assignment recorded
      for this subtype.
- name: OFD 18
  display_name: Orofaciodigital syndrome type XVIII
  description: >-
    Autosomal recessive form caused by biallelic variants in IFT57, a core
    component of the IFT-B intraflagellar transport complex.
  subtype_term:
    preferred_term: orofaciodigital syndrome 18
    term:
      id: MONDO:0054770
      label: orofaciodigital syndrome 18
  genes:
  - preferred_term: IFT57
    term:
      id: hgnc:17367
      label: IFT57
  evidence:
  - reference: PMID:28289185
    reference_title: "Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified causal variants in five new genes (C2CD3, TMEM107, INTU,
      KIAA0753 and IFT57)
    explanation: >-
      Identifies IFT57 among the OFD-causing ciliary genes, the assignment
      recorded for this subtype.
- name: OFD 19
  display_name: Orofaciodigital syndrome type XIX
  description: >-
    Autosomal recessive form caused by biallelic loss-of-function variants in
    SCNM1, a component of the minor (U12) spliceosome. Patient cells show
    defective minor-intron processing, reduced expression of ciliary and basal
    body genes, and abnormally elongated cilia.
  subtype_term:
    preferred_term: orofaciodigital syndrome 19
    term:
      id: MONDO:0859310
      label: orofaciodigital syndrome 19
  genes:
  - preferred_term: SCNM1
    term:
      id: hgnc:23136
      label: SCNM1
  evidence:
  - reference: PMID:36084634
    reference_title: Mutations in SCNM1 cause orofaciodigital syndrome due to minor intron splicing defects affecting primary cilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe individuals with OFD from three unrelated families having
      bi-allelic loss-of-function variants in SCNM1 as the cause of their
      condition.
    explanation: >-
      Establishes the SCNM1 gene assignment and biallelic loss-of-function
      mechanism for this subtype.
- name: OFD 20
  display_name: Orofaciodigital syndrome type XX
  description: >-
    Autosomal recessive form caused by biallelic missense variants clustered near
    the RAB34 C-terminus, accompanied by cardiac, cerebral, skeletal and anorectal
    defects. RAB34 acts selectively in the intracellular ciliogenesis pathway.
  subtype_term:
    preferred_term: orofaciodigital syndrome 20
    term:
      id: MONDO:0958230
      label: orofaciodigital syndrome 20
  genes:
  - preferred_term: RAB34
    term:
      id: hgnc:16519
      label: RAB34
  evidence:
  - reference: PMID:37384395
    reference_title: Pathogenic RAB34 variants impair primary cilium assembly and cause a novel oral-facial-digital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified by exome sequencing bi-allelic missense variants in a novel
      disease-causing ciliary gene RAB34 in four individuals from three unrelated
      families.
    explanation: >-
      Establishes the RAB34 gene assignment for this most recently delineated
      autosomal recessive subtype.
- name: OFD 21
  display_name: Orofaciodigital syndrome type XXI
  description: >-
    X-linked recessive form caused by ZRSR2 variants affecting the last exon,
    presenting with brain anomalies ranging from alobar holoprosencephaly to
    pituitary anomalies. ZRSR2 encodes a minor-spliceosome splicing factor;
    patient cells show minor-intron retention and elongated primary cilia.
  subtype_term:
    preferred_term: orofaciodigital syndrome 21
    term:
      id: MONDO:0975827
      label: orofaciodigital syndrome 21
  genes:
  - preferred_term: ZRSR2
    term:
      id: hgnc:23019
      label: ZRSR2
  evidence:
  - reference: PMID:38158857
    reference_title: Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a previously undescribed type of OFD with brain anomalies,
      ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated
      families.
    explanation: >-
      Establishes the ZRSR2-associated subtype and its distinguishing brain
      phenotype.
inheritance:
- name: Autosomal Recessive
  description: >-
    The majority of orofaciodigital subtypes are inherited as autosomal recessive
    traits, with biallelic variants in a ciliary, centriolar or minor-spliceosome
    gene; many reported families are consanguineous.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:27141300
    reference_title: Update on oral-facial-digital syndromes (OFDS).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      With the exception of OFD types I and VIII, which are X-linked, the majority
      of OFDS is transmitted as an autosomal recessive syndrome.
    explanation: >-
      States directly that most orofaciodigital subtypes are autosomal recessive.
      Evidence source is OTHER because this is a narrative review.
- name: X-linked Dominant (male-lethal)
  description: >-
    OFD type I is transmitted as an X-linked dominant trait with lethality in
    hemizygous males, so affected individuals are predominantly female; most cases
    are sporadic.
  inheritance_term:
    preferred_term: X-linked dominant inheritance
    term:
      id: HP:0001423
      label: X-linked dominant inheritance
  evidence:
  - reference: PMID:27141300
    reference_title: Update on oral-facial-digital syndromes (OFDS).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is transmitted as an X-linked dominant condition with male lethality,
      which usually occurs during the first and second trimester of pregnancy
    explanation: >-
      Specifies the X-linked dominant, male-lethal mode of inheritance of OFD type
      I and the gestational timing of male lethality. Evidence source is OTHER
      because this is a narrative review.
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Oral-facial-digital syndrome type I (OFD1) is usually male lethal during
      gestation and predominantly affects females.
    explanation: >-
      Independent confirmation of male lethality and the female predominance it
      produces in OFD type I.
- name: X-linked Recessive
  description: >-
    A minority of subtypes are X-linked recessive and affect males: OFD VIII
    (Edwards syndrome, molecularly undefined) and OFD 21 (ZRSR2), in which
    affected males were hemizygous for a last-exon frameshift variant.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:38158857
    reference_title: Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      7 affected males from 5 unrelated families were hemizygous for the ZRSR2
      variant
    explanation: >-
      Documents hemizygous affected males, the X-linked recessive pattern recorded
      for OFD 21.
prevalence:
- population: Worldwide (OFD type I only)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.0
  notes: >-
    Estimate is specific to OFD type I, the most frequent subtype; no group-level
    incidence figure covering all orofaciodigital subtypes has been published, and
    the remaining subtypes are individually much rarer, several being
    single-family reports.
  evidence:
  - reference: PMID:27141300
    reference_title: Update on oral-facial-digital syndromes (OFDS).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: It has an estimated incidence of 1:50,000 live births
    explanation: >-
      Provides the published incidence estimate for OFD type I, normalized here to
      2 per 100,000. Evidence source is OTHER because this is a narrative review.
pathophysiology:
- name: Ciliary and Centriolar Gene Defect
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    The initiating lesion in most orofaciodigital subtypes is a germline variant
    in a gene encoding a centriolar, basal-body, transition-zone or
    CPLANE/intraflagellar transport protein. Functional dissection of the OFDS
    gene set resolves it into three ciliary protein modules: the
    KIAA0753-FOPNL-OFD1 complex regulating centriole elongation, the Meckel-Gruber
    transition-zone module (TMEM107, TMEM216, TMEM231, TCTN3), and the CPLANE
    complex required for IFT-A assembly (INTU, CPLANE1, WDPCP, FUZ). Different
    subtypes enter the shared downstream cascade through different modules, which
    is one source of their phenotypic divergence.
  biological_processes:
  - preferred_term: centriole elongation
    term:
      id: GO:0061511
      label: centriole elongation
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: ciliary basal body
    term:
      id: GO:0036064
      label: ciliary basal body
  - preferred_term: ciliary transition zone
    term:
      id: GO:0035869
      label: ciliary transition zone
  evidence:
  - reference: PMID:28289185
    reference_title: "Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Functional studies revealed the involvement of centriole elongation,
      transition zone and intraflagellar transport defects in OFDS, thus
      characterising three ciliary protein modules: the complex
      KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber
      syndrome module, a major component of the transition zone; and the CPLANE
      complex necessary for IFT-A assembly.
    explanation: >-
      Directly supports the three-module decomposition of the OFDS gene set that
      this node records.
  - reference: PMID:24997988
    reference_title: The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3
      results in short centrioles without subdistal and distal appendages
    explanation: >-
      Shows that two OFD genes act antagonistically on centriole length, the
      molecular-scale defect captured by this node. Evidence source is IN_VITRO
      because the centriole measurements were made in cultured cells.
  downstream:
  - target: Impaired Ciliogenesis and Ciliary Compartment Function
    description: >-
      Loss of the centriolar, transition-zone or CPLANE protein prevents assembly
      of a structurally and functionally competent primary cilium.
    evidence:
    - reference: PMID:37384395
      reference_title: Pathogenic RAB34 variants impair primary cilium assembly and cause a novel oral-facial-digital syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        cells expressing mutant RAB34 exhibit a significant defect in cilium
        assembly
      explanation: >-
        Demonstrates directly that an OFD-causing variant in a ciliary gene
        produces defective cilium assembly, which is the edge asserted here.
        Evidence source is IN_VITRO because the assays were in cultured cells.
    - reference: PMID:16311594
      reference_title: Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We found failure of left-right axis specification in mutant male embryos,
        and ultrastructural analysis showed a lack of cilia in the embryonic node.
      explanation: >-
        Shows loss of the OFD type I gene abolishes cilia in vivo. Evidence source
        is MODEL_ORGANISM because this is an Ofd1 knockout mouse.
- name: Minor Spliceosome Dysfunction and Ciliary Transcript Depletion
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    A second, mechanistically distinct entry route operates in the two most
    recently delineated subtypes. SCNM1 (OFD 19) and ZRSR2 (OFD 21) encode
    components of the minor (U12-type) spliceosome. Loss of function causes
    retention or mis-splicing of the small set of U12-type introns, which are
    enriched in ciliary and basal-body genes, so ciliary transcripts such as
    TMEM107 are depleted without any primary defect in a ciliary protein itself.
    The convergence onto the ciliary phenotype is therefore indirect but
    experimentally demonstrated.
  biological_processes:
  - preferred_term: minor (U12-type) pre-mRNA splicing
    term:
      id: GO:0000398
      label: "mRNA splicing, via spliceosome"
    modifier: ABNORMAL
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:36084634
    reference_title: Mutations in SCNM1 cause orofaciodigital syndrome due to minor intron splicing defects affecting primary cilia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Notably, expression of TMEM107 and FAM92A encoding primary cilia and basal
      body proteins, respectively, and that of DERL2, ZC3H8, and C17orf75, were
      severely reduced in SCNM1-deficient cells.
    explanation: >-
      Demonstrates depletion of ciliary and basal-body transcripts as the direct
      consequence of minor-spliceosome loss. Evidence source is IN_VITRO because
      the measurements were made in patient fibroblasts and engineered cell lines.
  - reference: PMID:38158857
    reference_title: Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient samples showed significant enrichment of minor intron retention.
      Among differentially spliced targets are ciliopathy-related genes, such as
      TMEM107 and CIBAR1.
    explanation: >-
      Independent confirmation in a second minor-spliceosome gene that the
      mis-spliced targets are ciliopathy genes. Evidence source is IN_VITRO
      because the analysis used patient lymphoblastoid and fibroblast lines.
  downstream:
  - target: Impaired Ciliogenesis and Ciliary Compartment Function
    description: >-
      Depletion of correctly spliced ciliary transcripts produces a structurally
      abnormal primary cilium, observed as abnormal cilium elongation in patient
      and knockout cells.
    evidence:
    - reference: PMID:36084634
      reference_title: Mutations in SCNM1 cause orofaciodigital syndrome due to minor intron splicing defects affecting primary cilia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout
        and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated
        cilia.
      explanation: >-
        Establishes the causal step from minor-spliceosome loss to an abnormal
        primary cilium. Evidence source is IN_VITRO because the cilia were
        measured in cultured patient and engineered cells.
    - reference: PMID:38158857
      reference_title: Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Primary fibroblasts containing the NM_005089.4:c.1207_1208del ZRSR2
        variant had abnormally elongated cilia, confirming an association between
        defective U12-type intron splicing, OFD and abnormal primary cilia
        formation.
      explanation: >-
        Replicates the same edge for the second minor-spliceosome subtype.
        Evidence source is IN_VITRO because the observation is in patient
        fibroblasts.
- name: Impaired Ciliogenesis and Ciliary Compartment Function
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    Both entry routes converge on failure to build, or to correctly
    compartmentalize, the primary cilium: cilia may be absent, short, abnormally
    elongated, or structurally present but unable to gate signaling machinery at
    the transition zone. This is the shared cellular lesion of the orofaciodigital
    syndromes and the node at which they conform to the ciliopathy module. The
    specific module affected biases which downstream tissue is worst hit.
  cell_types:
  - preferred_term: ciliated cell
    term:
      id: CL:0000064
      label: ciliated cell
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DECREASED
  - preferred_term: protein localization to cilium
    term:
      id: GO:0061512
      label: protein localization to cilium
    modifier: ABNORMAL
  - preferred_term: intraciliary transport
    term:
      id: GO:0042073
      label: intraciliary transport
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: primary cilium
    term:
      id: GO:0005929
      label: cilium
  evidence:
  - reference: PMID:27141300
    reference_title: Update on oral-facial-digital syndromes (OFDS).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A number of genes have already found to be mutated in OFDS and most of the
      encoded proteins are predicted or proven to be involved in primary
      cilia/basal body function.
    explanation: >-
      Supports treating primary cilium and basal body function as the shared
      cellular lesion across the OFDS gene set. Evidence source is OTHER because
      this is a narrative review.
  - reference: PMID:37384395
    reference_title: Pathogenic RAB34 variants impair primary cilium assembly and cause a novel oral-facial-digital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic variants in over 20 genes encoding ciliary proteins have been
      found to cause OFDS through deleterious structural or functional impacts on
      primary cilia.
    explanation: >-
      States that the OFDS gene set acts through structural or functional damage
      to primary cilia, which is what this node asserts.
  downstream:
  - target: Dysregulated Hedgehog Signal Transduction and GLI Processing
    description: >-
      Because the primary cilium is the obligate compartment for vertebrate
      Hedgehog signal transduction, a defective cilium or transition zone deranges
      GLI processing and the balance of GLI activator and repressor.
    evidence:
    - reference: PMID:22883145
      reference_title: TCTN3 mutations cause Mohr-Majewski syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we found that TCTN3 is necessary for transduction of the sonic hedgehog
        (SHH) signaling pathway, as revealed by abnormal processing of GLI3 in
        patient cells
      explanation: >-
        Demonstrates in cells from an OFD IV patient that loss of a transition
        zone protein produces abnormal GLI3 processing, which is precisely the
        edge asserted here. Evidence source is IN_VITRO because GLI3 processing
        was assayed in cultured patient cells.
    - reference: PMID:27802276
      reference_title: Craniofacial Ciliopathies Reveal Specific Requirements for GLI Proteins during Development of the Facial Midline.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We show that loss of intraflagellar transport proteins (KIF3a or IFT88)
        caused aberrant GLI processing such that the amount of GLI3FL and GLI2FL
        was increased, thus skewing the ratio of GLIFL to GLIR in favor of the FL
        isoform.
      explanation: >-
        Independent demonstration that loss of ciliary transport proteins skews
        GLI processing toward the full-length activator. Evidence source is
        MODEL_ORGANISM because the analysis was performed in conditional-knockout
        mice.
  - target: Multisystem Ciliopathy Involvement
    description: >-
      The same ciliary lesion acts in renal tubular epithelium, retina and
      developing CNS, producing the cystic kidney disease, retinal degeneration
      and cerebellar/CNS malformation that distinguish the subtypes.
    evidence:
    - reference: PMID:16311594
      reference_title: Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Formation of cilia was defective in cystic kidneys from heterozygous
        females, implicating ciliogenesis as a mechanism underlying cyst
        development.
      explanation: >-
        Directly implicates defective ciliogenesis in renal cyst formation, the
        organ arm of this edge. Evidence source is MODEL_ORGANISM because the
        kidneys examined were from Ofd1 heterozygous mice.
- name: Dysregulated Hedgehog Signal Transduction and GLI Processing
  conforms_to: "ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction"
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    Hedgehog pathway components traffic through the ciliary compartment, where
    full-length GLI2 and GLI3 are proteolytically processed into repressor forms.
    A defective cilium perturbs this processing and shifts the activator to
    repressor ratio, so Hedgehog output is not simply reduced but deranged, and
    can be excessive in tissues such as the facial mesenchyme. Because Hedgehog
    patterns both the cranial neural crest derivatives and the limb bud, this
    single signaling lesion generates the oral-facial and the digital arms of the
    phenotype together.
  biological_processes:
  - preferred_term: Hedgehog (smoothened) signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:27802276
    reference_title: Craniofacial Ciliopathies Reveal Specific Requirements for GLI Proteins during Development of the Facial Midline.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our findings suggest that ciliopathic facial phenotypes are generated via
      loss of both GLI3R and GLI2R and that this pathology occurs via a
      de-repression mechanism.
    explanation: >-
      Identifies loss of GLI repressor forms, that is de-repression rather than
      simple pathway loss, as the mechanism of the ciliopathic facial phenotype.
      Evidence source is MODEL_ORGANISM because the conclusion rests on mouse
      conditional knockouts.
  - reference: PMID:36084634
    reference_title: Mutations in SCNM1 cause orofaciodigital syndrome due to minor intron splicing defects affecting primary cilia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      functional analysis in SCNM1-retrotransduced fibroblasts showed that SCNM1
      is a positive mediator of Hedgehog (Hh) signaling
    explanation: >-
      Shows that the minor-spliceosome entry route also converges on Hedgehog
      signaling, supporting this node as the shared effector for both routes.
      Evidence source is IN_VITRO because the assay used patient-derived
      fibroblasts.
  downstream:
  - target: Cranial Neural Crest and Facial Midline Patterning Failure
    description: >-
      Deranged Hedgehog activity in cranial neural crest cells and the facial
      prominences alters midline patterning, producing hypertelorism and
      frontonasal dysplasia rather than the hypotelorism of Hedgehog loss.
    evidence:
    - reference: PMID:20106874
      reference_title: A primary cilia-dependent etiology for midline facial disorders.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we show that excessive Hedgehog activity, caused by truncating the
        primary cilia on cranial neural crest cells, causes hypertelorism and
        frontonasal dysplasia (FND).
      explanation: >-
        Directly asserts the causal step from cilium-dependent Hedgehog
        dysregulation in cranial neural crest to facial midline malformation.
        Evidence source is MODEL_ORGANISM because the demonstration is in mouse
        conditional knockouts and avian talpid embryos.
  - target: Disrupted Autopod Digit Number and Identity Specification
    description: >-
      The same cilium-dependent Hedgehog derangement acts in the limb bud, where
      it alters the posterior patterning programme that specifies digit number and
      identity.
    evidence:
    - reference: PMID:16311594
      reference_title: Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we found impaired patterning of the neural tube and altered expression of
        the 5' Hoxa and Hoxd genes in the limb buds of mice lacking Ofd1
      explanation: >-
        Shows that loss of the OFD type I gene alters the limb-bud patterning
        programme, the edge asserted here. Evidence source is MODEL_ORGANISM
        because the limb buds examined were from Ofd1 knockout mice.
- name: Cranial Neural Crest and Facial Midline Patterning Failure
  biological_scale: TISSUE
  role: intermediate
  description: >-
    The facial skeleton and the oral soft tissues derive from cranial neural crest
    cells populating the frontonasal and pharyngeal-arch prominences. Ciliary
    Hedgehog derangement in these cells broadens the domains of Hedgehog target
    gene expression and alters neural crest proliferation in the facial
    prominences, so the midline is patterned incorrectly. This is the tissue-level
    step that generates the oral and facial arms of the orofaciodigital triad.
  biological_processes:
  - preferred_term: embryonic cranial skeleton morphogenesis
    term:
      id: GO:0048701
      label: embryonic cranial skeleton morphogenesis
    modifier: ABNORMAL
  - preferred_term: roof of mouth development
    term:
      id: GO:0060021
      label: roof of mouth development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:20106874
    reference_title: A primary cilia-dependent etiology for midline facial disorders.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Elimination of the intraflagellar transport protein Kif3a leads to excessive
      Hedgehog responsiveness in facial mesenchyme, which is accompanied by broader
      expression domains of Gli1, Ptc and Shh, and reduced expression domains of
      Gli3.
    explanation: >-
      Documents the molecular signature of ciliary Hedgehog derangement within the
      facial mesenchyme that this tissue-level node describes. Evidence source is
      MODEL_ORGANISM because the analysis is in conditional-knockout mouse
      embryos.
  downstream:
  - target: Oral and Facial Malformation
    description: >-
      Mis-patterning of the facial prominences and their neural crest populations
      yields the clinically observed facial and oral malformations.
    evidence:
    - reference: PMID:20106874
      reference_title: A primary cilia-dependent etiology for midline facial disorders.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Furthermore, broader domains of Gli1 expression correspond to areas of
        enhanced neural crest cell proliferation in the facial prominences of
        Kif3a conditional knockouts. Avian Talpid embryos that lack primary cilia
        exhibit similar molecular changes and similar facial phenotypes.
      explanation: >-
        Links the neural crest patterning change to the resulting facial phenotype
        in two independent cilium-deficient model systems, which is the edge
        asserted here. Evidence source is MODEL_ORGANISM because the observations
        are in mouse and avian embryos.
- name: Disrupted Autopod Digit Number and Identity Specification
  conforms_to: "limb_digit_patterning_serial_homology#Disrupted Digit Number and Identity Specification"
  biological_scale: TISSUE
  role: intermediate
  description: >-
    Ciliary Hedgehog derangement in the limb bud perturbs the anteroposterior
    patterning gradient that specifies how many digits form and what identity each
    takes. In the orofaciodigital syndromes this typically adds digits, giving
    preaxial, postaxial or mesoaxial polydactyly, and also disturbs phalangeal
    segmentation, giving brachydactyly, syndactyly and clinodactyly. Because the
    autopod patterning programme is serially reused in fore- and hindlimb, the
    lesion is expressed in hands and feet alike.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: limb morphogenesis
    term:
      id: GO:0035108
      label: limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:16311594
    reference_title: Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we found impaired patterning of the neural tube and altered expression of
      the 5' Hoxa and Hoxd genes in the limb buds of mice lacking Ofd1
    explanation: >-
      Documents altered posterior HOX expression in the limb bud on loss of an OFD
      gene, the patterning derangement this node records. Evidence source is
      MODEL_ORGANISM because the limb buds are from Ofd1 knockout mice.
  downstream:
  - target: Serially Homologous Autopod Malformation
    description: >-
      The mis-specified autopod programme is expressed in both fore- and hindlimb,
      so a single patterning lesion produces a digit-anomaly bundle across hands
      and feet rather than an isolated defect.
    evidence:
    - reference: PMID:35361766
      reference_title: Additional findings of tibial dysplasia in a male with orofaciodigital syndrome type XVI.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        bilateral postaxial polydactyly of the hands, bilateral mesoaxial
        polydactyly of the feet
      explanation: >-
        A single OFD patient with polydactyly in both hands and both feet, which
        is the serially homologous bundle this edge asserts. Note the digit
        subtype differs between hand and foot in this patient, so the shared
        programme is not producing an identical malformation at each site.
- name: Oral and Facial Malformation
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The oral and facial arms of the defining triad: accessory or hyperplastic
    frenula, lobulated or bifid tongue, tongue nodules and hamartomas, cleft of
    the hard or soft palate, median cleft or pseudocleft of the upper lip,
    hypodontia and other dental anomalies, hypertelorism or telecanthus,
    hypoplastic alae nasi and micrognathia. The precise combination varies by
    subtype and is part of what separates them clinically.
  biological_processes:
  - preferred_term: roof of mouth development
    term:
      id: GO:0060021
      label: roof of mouth development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      oral features (lobulated tongue, tongue nodules, cleft of the hard or soft
      palate, accessory gingival frenulae, hypodontia, and other dental
      abnormalities)
    explanation: >-
      Enumerates the oral malformations that constitute this node, in the
      best-characterized subtype.
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      facial features (widely spaced eyes, telecanthus, hypoplasia of the alae
      nasi, median cleft or pseudocleft of the upper lip, micrognathia)
    explanation: >-
      Enumerates the facial malformations that constitute this node, in the
      best-characterized subtype.
- name: Serially Homologous Autopod Malformation
  conforms_to: "limb_digit_patterning_serial_homology#Serially Homologous Autopod Malformation"
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The digital arm of the defining triad, expressed across serially homologous
    elements: polydactyly (preaxial, postaxial or the mesoaxial form
    characteristic of OFD VI), syndactyly, brachydactyly, clinodactyly of the
    fifth finger and duplicated hallux, characteristically affecting hands and
    feet together.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      digital features (brachydactyly, syndactyly, clinodactyly of the fifth
      finger, duplicated great toe)
    explanation: >-
      Enumerates the hand and foot anomalies of this node in the
      best-characterized subtype, including the hallux duplication that shows
      hindlimb involvement.
  - reference: PMID:35361766
    reference_title: Additional findings of tibial dysplasia in a male with orofaciodigital syndrome type XVI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bilateral postaxial polydactyly of the hands, bilateral mesoaxial
      polydactyly of the feet
    explanation: >-
      A second subtype showing the same hands-and-feet bundle, supporting the
      serial-homology framing rather than a subtype-specific coincidence.
- name: Multisystem Ciliopathy Involvement
  conforms_to: "ciliopathy_dysfunction#Multisystem Pleiotropic Ciliopathy Phenotype"
  biological_scale: ORGANISM
  role: consequence
  description: >-
    Beyond the defining triad, the shared ciliary lesion produces organ
    involvement that varies by subtype and supplies most of the discriminating
    features: polycystic kidney disease (OFD I), intracerebral cysts, agenesis of
    the corpus callosum and cerebellar vermis hypoplasia with the molar tooth sign
    (OFD III, 6, 14, 16, 17), retinal colobomata (OFD IX) and retinopathy (OFD
    16), tibial dysplasia and short ribs (OFD IV), hypothalamic hamartoma (OFD 6),
    and holoprosencephaly or pituitary anomaly (OFD 21). Intellectual disability
    is present in roughly half of individuals with OFD type I.
  biological_processes:
  - preferred_term: neural retina development
    term:
      id: GO:0003407
      label: neural retina development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      polycystic kidney disease; brain MRI findings (intracerebral cysts, agenesis
      of the corpus callosum, cerebellar agenesis with or without Dandy-Walker
      malformation); and intellectual disability (in approximately 50% of affected
      individuals)
    explanation: >-
      Records the renal, CNS and cognitive involvement that this node describes
      for OFD type I, including the quantified frequency of intellectual
      disability.
  - reference: PMID:27141300
    reference_title: Update on oral-facial-digital syndromes (OFDS).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additional signs may involve brain, kidneys and other organs thus better
      defining the different clinical subtypes.
    explanation: >-
      Supports the framing that the extra-triad organ involvement is what
      discriminates the numbered subtypes. Evidence source is OTHER because this
      is a narrative review.
phenotypes:
- category: Oral
  name: Abnormal oral frenulum morphology
  description: >-
    Accessory, hyperplastic or aberrant gingival and labial frenula are among the
    most consistent oral findings and, with tongue anomalies, define the oral arm
    of the triad.
  phenotype_term:
    preferred_term: Accessory oral frenula
    term:
      id: HP:0000190
      label: Abnormal oral frenulum morphology
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      oral features (lobulated tongue, tongue nodules, cleft of the hard or soft
      palate, accessory gingival frenulae, hypodontia, and other dental
      abnormalities)
    explanation: Lists accessory gingival frenulae among the defining oral features.
- category: Oral
  name: Lobulated tongue
  description: >-
    A lobulated, cleft or bifid tongue is a hallmark oral finding across
    orofaciodigital subtypes.
  phenotype_term:
    preferred_term: Lobulated tongue
    term:
      id: HP:0000180
      label: Lobulated tongue
  evidence:
  - reference: PMID:35361766
    reference_title: Additional findings of tibial dysplasia in a male with orofaciodigital syndrome type XVI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hyperplastic oral frenula, high-arched palate, lobulated tongue, oral
      lingual nodules, tongue hamartomas
    explanation: >-
      Documents a lobulated tongue in an individual with a molecularly confirmed
      orofaciodigital subtype.
- category: Oral
  name: Tongue nodules
  description: >-
    Tongue nodules and lingual hamartomas are a distinguishing oral feature; in
    OFD VI a tongue hamartoma is one of the operational diagnostic criteria.
  phenotype_term:
    preferred_term: Tongue nodules and lingual hamartomas
    term:
      id: HP:0000199
      label: Tongue nodules
  evidence:
  - reference: PMID:35361766
    reference_title: Additional findings of tibial dysplasia in a male with orofaciodigital syndrome type XVI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hyperplastic oral frenula, high-arched palate, lobulated tongue, oral
      lingual nodules, tongue hamartomas
    explanation: >-
      Documents lingual nodules and tongue hamartomas in a molecularly confirmed
      orofaciodigital subtype.
- category: Oral
  name: Cleft palate
  description: >-
    Cleft of the hard or soft palate is a common oral malformation in the
    orofaciodigital syndromes.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      oral features (lobulated tongue, tongue nodules, cleft of the hard or soft
      palate, accessory gingival frenulae, hypodontia, and other dental
      abnormalities)
    explanation: Lists cleft of the hard or soft palate among the defining oral features.
- category: Facial
  name: Median cleft upper lip
  description: >-
    A median cleft or pseudocleft of the upper lip is a characteristic facial
    finding, particularly prominent in OFD types I and V.
  phenotype_term:
    preferred_term: Median cleft or pseudocleft of the upper lip
    term:
      id: HP:0000161
      label: Median cleft upper lip
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      facial features (widely spaced eyes, telecanthus, hypoplasia of the alae
      nasi, median cleft or pseudocleft of the upper lip, micrognathia)
    explanation: Lists median cleft or pseudocleft of the upper lip as a defining facial feature.
- category: Facial
  name: Hypertelorism
  description: >-
    Widely spaced eyes with telecanthus is the characteristic midfacial finding
    and, in cilium-deficient models, is the direct consequence of excessive
    Hedgehog activity in the facial mesenchyme.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:35361766
    reference_title: Additional findings of tibial dysplasia in a male with orofaciodigital syndrome type XVI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had a broad forehead, hypertelorism, short nose, anteverted nares, broad
      nasal bridge, broad nasal tip, thin upper lip
    explanation: >-
      Documents hypertelorism in an individual with a molecularly confirmed
      orofaciodigital subtype.
- category: Digital
  name: Polydactyly
  description: >-
    Extra digits are the commonest digital finding, occurring in preaxial,
    postaxial and mesoaxial forms; mesoaxial polydactyly is one of the operational
    diagnostic criteria for OFD VI.
  phenotype_term:
    preferred_term: Polydactyly
    term:
      id: HP:0010442
      label: Polydactyly
  evidence:
  - reference: PMID:24178751
    reference_title: C5orf42 is the major gene responsible for OFD syndrome type VI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mesoaxial polydactyly of one or more hands or feet
    explanation: >-
      Records mesoaxial polydactyly as a formal diagnostic criterion of an
      orofaciodigital subtype.
- category: Digital
  name: Postaxial polydactyly
  description: >-
    Extra digits on the ulnar or fibular side of the hand or foot, reported across
    several subtypes including OFD 16.
  phenotype_term:
    preferred_term: Postaxial polydactyly
    term:
      id: HP:0100259
      label: Postaxial polydactyly
  evidence:
  - reference: PMID:35361766
    reference_title: Additional findings of tibial dysplasia in a male with orofaciodigital syndrome type XVI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical features of OFD syndrome type XVI mainly include postaxial
      polydactyly of the hands and feet
    explanation: Records postaxial polydactyly as a core feature of OFD type XVI.
- category: Digital
  name: Syndactyly
  description: >-
    Cutaneous or bony fusion of digits, frequently coexisting with polydactyly as
    polysyndactyly.
  phenotype_term:
    preferred_term: Syndactyly
    term:
      id: HP:0001159
      label: Syndactyly
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      digital features (brachydactyly, syndactyly, clinodactyly of the fifth
      finger, duplicated great toe)
    explanation: Lists syndactyly among the defining digital features.
- category: Digital
  name: Brachydactyly
  description: >-
    Shortened digits, reflecting disturbed phalangeal segmentation rather than
    digit number.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      digital features (brachydactyly, syndactyly, clinodactyly of the fifth
      finger, duplicated great toe)
    explanation: Lists brachydactyly among the defining digital features.
- category: Digital
  name: Clinodactyly
  description: >-
    Curvature of the fifth finger in the plane of the palm, a recurrent digital
    finding.
  phenotype_term:
    preferred_term: Clinodactyly of the fifth finger
    term:
      id: HP:0030084
      label: Clinodactyly
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      digital features (brachydactyly, syndactyly, clinodactyly of the fifth
      finger, duplicated great toe)
    explanation: Lists clinodactyly of the fifth finger among the defining digital features.
- category: Renal
  name: Polycystic kidney dysplasia
  description: >-
    Polycystic kidney disease is the principal visceral manifestation of OFD type
    I, typically presenting in adulthood, and is the reason lifelong renal
    surveillance is recommended.
  phenotype_term:
    preferred_term: Polycystic kidney disease
    term:
      id: HP:0000113
      label: Polycystic kidney dysplasia
  subtype: OFD I
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:16311594
    reference_title: Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      affected individuals have craniofacial and digital abnormalities and, in 15%
      of cases, polycystic kidney
    explanation: >-
      Gives the quantitative estimate of 15% of cases that justifies the
      OCCASIONAL frequency band, which spans 5-29%. The figure describes human
      OFD type I patients, so the evidence source is HUMAN_CLINICAL even though
      the paper's own experiments are in mice.
- category: Neurological
  name: Agenesis of corpus callosum
  description: >-
    Agenesis of the corpus callosum, intracerebral cysts and cerebellar agenesis
    with or without Dandy-Walker malformation are the characteristic brain MRI
    findings of OFD type I.
  phenotype_term:
    preferred_term: Agenesis of the corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      brain MRI findings (intracerebral cysts, agenesis of the corpus callosum,
      cerebellar agenesis with or without Dandy-Walker malformation)
    explanation: Records agenesis of the corpus callosum among the characteristic brain findings.
- category: Neurological
  name: Molar tooth sign on MRI
  description: >-
    The molar tooth sign, produced by cerebellar vermis hypoplasia with thickened
    and horizontal superior cerebellar peduncles, is the defining brain finding of
    OFD VI and is also reported in OFD 14, 16 and 17, placing these subtypes
    within the Joubert-syndrome-related disorders.
  phenotype_term:
    preferred_term: Molar tooth sign
    term:
      id: HP:0002419
      label: Molar tooth sign on MRI
  evidence:
  - reference: PMID:24178751
    reference_title: C5orf42 is the major gene responsible for OFD syndrome type VI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because of the MTS, OFD VI belongs to the "Joubert syndrome related
      disorders".
    explanation: >-
      Establishes the molar tooth sign as the feature that places OFD VI among the
      Joubert-syndrome-related disorders.
- category: Neurological
  name: Cerebellar vermis hypoplasia
  description: >-
    Hypoplasia of the cerebellar vermis underlies the molar tooth sign and is
    reported in the Joubert-overlapping subtypes.
  phenotype_term:
    preferred_term: Cerebellar vermis hypoplasia
    term:
      id: HP:0001320
      label: Cerebellar vermis hypoplasia
  evidence:
  - reference: PMID:35361766
    reference_title: Additional findings of tibial dysplasia in a male with orofaciodigital syndrome type XVI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI showed cerebellar vermis hypoplasia and a molar tooth sign
    explanation: >-
      Documents cerebellar vermis hypoplasia on brain MRI in a molecularly
      confirmed orofaciodigital subtype.
- category: Neurological
  name: Intellectual disability
  description: >-
    Intellectual disability affects roughly half of individuals with OFD type I;
    severity varies and is worst in the subtypes with major cerebral malformation,
    notably OFD 14 with severe microcephaly.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  subtype: OFD I
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intellectual disability (in approximately 50% of affected individuals)
    explanation: >-
      Gives the quantitative estimate of approximately 50% that justifies the
      FREQUENT band, which spans 30-79%. The figure is specific to OFD type I.
- category: Ophthalmological
  name: Retinal coloboma
  description: >-
    Retinal colobomata are the discriminating feature of OFD type IX; retinopathy
    is separately reported in OFD 16.
  phenotype_term:
    preferred_term: Retinal colobomata
    term:
      id: HP:0000480
      label: Retinal coloboma
  subtype: OFD IX
  evidence:
  - reference: PMID:27141300
    reference_title: Update on oral-facial-digital syndromes (OFDS).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      OFD type IX is characterized by retinal colobomata in addition to the
      typical oro-facio-digital findings.
    explanation: >-
      Records retinal colobomata as the discriminating ophthalmological feature of
      OFD type IX. Evidence source is OTHER because this is a narrative review.
- category: Skeletal
  name: Short ribs
  description: >-
    Short ribs with a narrow thorax occur in the severe skeletal subtypes (OFD IV
    and KIAA0753-related OFD XV), overlapping the short-rib thoracic dysplasia
    spectrum.
  phenotype_term:
    preferred_term: Short ribs
    term:
      id: HP:0000773
      label: Short ribs
  evidence:
  - reference: PMID:38702430
    reference_title: Biallelic loss of function variants in FUZ result in an orofaciodigital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Herein, we describe two Indian patients carrying biallelic variants in FUZ
      with digital anomalies, orofacial cleft, short ribs and cardiac defects
      resembling orofaciodigital syndrome.
    explanation: >-
      Documents short ribs alongside the orofaciodigital triad in CPLANE-module
      disease.
- category: Auditory
  name: Hearing impairment
  description: >-
    Hearing loss, both conductive (associated with cleft palate and recurrent
    otitis media) and sensorineural, is common enough in OFD type I to warrant
    annual audiology surveillance.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hearing aids and community hearing services as needed
    explanation: >-
      The management recommendation implies hearing impairment is an expected
      manifestation. Classified PARTIAL because the source states the
      intervention rather than reporting a frequency or severity of hearing loss.
genetic:
- name: OFD1
  notes: >-
    OFD1 encodes a centrosomal and basal-body protein of the KIAA0753-FOPNL-OFD1
    centriole-elongation module. Heterozygous loss-of-function variants cause
    X-linked dominant, male-lethal OFD type I; frameshift variants predominate.
    The same gene has a broader allelic series in males (Joubert syndrome 10,
    primary ciliary dyskinesia, retinitis pigmentosa 23), captured by
    MONDO:1040039.
  gene_term:
    preferred_term: OFD1
    term:
      id: hgnc:2567
      label: OFD1
  relationship_type: CAUSATIVE
  subtype: OFD I
  evidence:
  - reference: PMID:11179005
    reference_title: Identification of the gene for oral-facial-digital type I syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of the familial cases revealed a missense mutation, a 19-bp
      deletion, and a single base-pair deletion leading to a frameshift.
    explanation: >-
      Documents the variant spectrum found in OFD1 in familial OFD type I cases.
  - reference: PMID:28289185
    reference_title: "Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequent, OFD type I, is caused by a heterozygous mutation in the
      OFD1 gene encoding a centrosomal protein.
    explanation: >-
      Confirms the heterozygous OFD1 mechanism and the centrosomal identity of the
      protein.
- name: C2CD3
  notes: >-
    C2CD3 localizes to the distal end of centrioles, physically associates with
    OFD1, and promotes centriole elongation, an activity OFD1 antagonizes.
    Biallelic variants cause autosomal recessive OFD 14, distinguished by severe
    microcephaly.
  gene_term:
    preferred_term: C2CD3
    term:
      id: hgnc:24564
      label: C2CD3
  relationship_type: CAUSATIVE
  subtype: OFD 14
  evidence:
  - reference: PMID:24997988
    reference_title: The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we propose that C2CD3 directly promotes centriole elongation and that OFD1
      acts as a negative regulator of C2CD3
    explanation: >-
      Establishes the antagonistic relationship between two OFD gene products at
      the centriole. Evidence source is IN_VITRO because the localization and
      length experiments were done in cultured cells.
- name: TCTN3
  notes: >-
    TCTN3 is a transition-zone protein that forms a complex with TCTN1 and TCTN2.
    Biallelic truncating variants cause the severe, autosomal recessive OFD type
    IV (Mohr-Majewski) phenotype and, in other families, overlapping Meckel and
    Joubert phenotypes.
  gene_term:
    preferred_term: TCTN3
    term:
      id: hgnc:24519
      label: TCTN3
  relationship_type: CAUSATIVE
  subtype: OFD IV
  evidence:
  - reference: PMID:22883145
    reference_title: TCTN3 mutations cause Mohr-Majewski syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, our data show the involvement of the transition zone protein TCTN3
      in the regulation of the key SHH signaling pathway and that its disruption
      causes a severe form of ciliopathy, combining features of Meckel and OFD IV
      syndromes.
    explanation: >-
      Establishes TCTN3 as a transition-zone gene whose disruption causes OFD IV
      through Hedgehog dysregulation.
- name: CPLANE1
  notes: >-
    CPLANE1 (formerly C5orf42) is a component of the CPLANE complex required for
    IFT-A assembly and is the major gene for autosomal recessive OFD VI. It is
    allelic with Joubert syndrome 17, and the comparison of CPLANE1-mutated with
    non-mutated OFD VI cases implicates it particularly in limb development.
  gene_term:
    preferred_term: CPLANE1
    term:
      id: hgnc:25801
      label: CPLANE1
  relationship_type: CAUSATIVE
  subtype: OFD 6
  evidence:
  - reference: PMID:24178751
    reference_title: C5orf42 is the major gene responsible for OFD syndrome type VI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      C5orf42 mutations have already been reported in Joubert syndrome confirming
      that OFD VI and JBS are allelic disorders
    explanation: >-
      Documents both the causal role in OFD VI and the allelism with Joubert
      syndrome that this entry records.
- name: INTU
  notes: >-
    INTU is a subunit of the CPLANE (ciliogenesis and planar cell polarity
    effector) module required for IFT-A assembly. Biallelic variants cause
    autosomal recessive OFD 17; the allelic spectrum also includes short-rib
    thoracic dysplasia 20 with polydactyly. Curated in detail in
    Orofaciodigital_Syndrome_17.
  gene_term:
    preferred_term: INTU
    term:
      id: hgnc:29239
      label: INTU
  relationship_type: CAUSATIVE
  subtype: OFD 17
  evidence:
  - reference: PMID:28289185
    reference_title: "Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified causal variants in five new genes (C2CD3, TMEM107, INTU,
      KIAA0753 and IFT57)
    explanation: >-
      Identifies INTU as one of the OFD causal genes recorded in this entry.
- name: SCNM1
  notes: >-
    SCNM1 encodes a component of the human minor (U12-type) spliceosome. Biallelic
    loss-of-function variants cause autosomal recessive OFD 19. This is a
    non-ciliary gene reaching the ciliary phenotype indirectly, through defective
    minor-intron processing of ciliary and basal-body transcripts.
  gene_term:
    preferred_term: SCNM1
    term:
      id: hgnc:23136
      label: SCNM1
  relationship_type: CAUSATIVE
  subtype: OFD 19
  evidence:
  - reference: PMID:36084634
    reference_title: Mutations in SCNM1 cause orofaciodigital syndrome due to minor intron splicing defects affecting primary cilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings demonstrate that defective U12 intron splicing can lead to a
      typical ciliopathy such as OFD and reveal that primary cilia length and Hh
      signaling are regulated by the minor spliceosome through SCNM1 activity.
    explanation: >-
      Establishes the indirect, minor-spliceosome route to the ciliary phenotype
      recorded for this gene.
- name: ZRSR2
  notes: >-
    ZRSR2, on Xp22.2, encodes a splicing factor of the minor spliceosome. Germline
    variants affecting the last exon cause X-linked recessive OFD 21 in hemizygous
    males, with brain anomalies ranging from alobar holoprosencephaly to pituitary
    anomalies.
  gene_term:
    preferred_term: ZRSR2
    term:
      id: hgnc:23019
      label: ZRSR2
  relationship_type: CAUSATIVE
  subtype: OFD 21
  evidence:
  - reference: PMID:38158857
    reference_title: Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ZRSR2, located on chromosome Xp22.2, encodes a splicing factor of the minor
      spliceosome complex, which recognizes minor introns, representing 0.35% of
      human introns.
    explanation: >-
      Records the gene's location and minor-spliceosome function, the basis of the
      mechanism assigned to OFD 21.
- name: RAB34
  notes: >-
    RAB34 is a Rab GTPase that mediates ciliary membrane formation specifically in
    cell types using the intracellular ciliogenesis pathway. Biallelic missense
    variants clustered near the C-terminus cause autosomal recessive OFD 20 and
    act through strong loss of function.
  gene_term:
    preferred_term: RAB34
    term:
      id: hgnc:16519
      label: RAB34
  relationship_type: CAUSATIVE
  subtype: OFD 20
  evidence:
  - reference: PMID:37384395
    reference_title: Pathogenic RAB34 variants impair primary cilium assembly and cause a novel oral-facial-digital syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We find that the protein products of these pathogenic variants, which are
      clustered near the RAB34 C-terminus, exhibit a strong loss of function.
    explanation: >-
      Establishes the loss-of-function mechanism of the OFD 20 variants. Evidence
      source is IN_VITRO because the functional characterization was in cultured
      cells.
- name: INTS13
  notes: >-
    INTS13 is a subunit of the Integrator complex, which associates with RNA
    polymerase II and cleaves nascent RNA. Biallelic germline variants disrupting
    binding to the Integrator cleavage module were reported in two families with
    variable OFD type 2; depletion disrupts ciliogenesis and dysregulates ciliary
    genes.
  gene_term:
    preferred_term: INTS13
    term:
      id: hgnc:20174
      label: INTS13
  relationship_type: CAUSATIVE
  subtype: OFD II
  evidence:
  - reference: PMID:36229431
    reference_title: INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes
      dysregulation of a broad collection of ciliary genes.
    explanation: >-
      Establishes the ciliary consequence of INTS13 loss. Evidence source is
      IN_VITRO because the ciliogenesis assays were performed in cultured human
      cells.
- name: FUZ
  notes: >-
    FUZ is a core CPLANE subunit involved in vesicular trafficking within primary
    cilia. Biallelic loss-of-function variants produce a skeletal ciliopathy with
    digital anomalies, orofacial cleft, short ribs and cardiac defects that the
    reporting authors describe as akin to orofaciodigital syndrome; no numbered
    OFD type has yet been assigned, so it is recorded here as a gene of the OFD
    spectrum rather than against a subtype.
  gene_term:
    preferred_term: FUZ
    term:
      id: hgnc:26219
      label: FUZ
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:38702430
    reference_title: Biallelic loss of function variants in FUZ result in an orofaciodigital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings underscore the association between biallelic loss of function
      variants in FUZ and skeletal ciliopathy akin to orofaciodigital syndrome.
    explanation: >-
      Supports a FUZ-OFD spectrum association. Classified PARTIAL because the
      authors describe the phenotype as akin to orofaciodigital syndrome rather
      than assigning a numbered OFD type.
diagnosis:
- name: Clinical recognition of the oral-facial-digital triad
  description: >-
    Diagnosis begins with recognition of the characteristic combination of oral
    (frenula, lobulated tongue, tongue nodules, clefting), facial (hypertelorism,
    median upper-lip cleft or pseudocleft, hypoplastic alae nasi) and digital
    (polydactyly, syndactyly, brachydactyly, clinodactyly) anomalies. The
    additional organ findings then direct subtype assignment.
  diagnosis_term:
    preferred_term: clinical evaluation
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:37384395
    reference_title: Pathogenic RAB34 variants impair primary cilium assembly and cause a novel oral-facial-digital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Oral-facial-digital syndromes (OFDS) are a group of clinically and
      genetically heterogeneous disorders characterized by defects in the
      development of the face and oral cavity along with digit anomalies.
    explanation: >-
      Defines the clinical triad on which the initial diagnostic recognition
      rests.
- name: Brain MRI for cerebral and cerebellar malformation
  description: >-
    Brain MRI identifies the molar tooth sign and cerebellar vermis hypoplasia
    that assign a case to the Joubert-overlapping subtypes (notably OFD VI), and
    detects the intracerebral cysts, corpus callosum agenesis and Dandy-Walker
    malformation seen in OFD type I.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:24178751
    reference_title: C5orf42 is the major gene responsible for OFD syndrome type VI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Oral-facial-digital syndrome type VI (OFD VI) is a recessive ciliopathy
      defined by two diagnostic criteria: molar tooth sign (MTS) and one or more
      of the following
    explanation: >-
      Establishes the molar tooth sign, an MRI finding, as a formal diagnostic
      criterion for a subtype.
  - reference: PMID:35361766
    reference_title: Additional findings of tibial dysplasia in a male with orofaciodigital syndrome type XVI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI showed cerebellar vermis hypoplasia and a molar tooth sign
    explanation: >-
      Worked example of brain MRI making the subtype-defining CNS findings in an
      orofaciodigital case.
- name: Skeletal radiography of hands, feet and thorax
  description: >-
    Radiographs delineate the digital anomalies (extra rays, phalangeal number and
    shape, metacarpal form) and detect the tibial dysplasia and short ribs that
    identify the severe skeletal subtypes OFD IV and OFD XV.
  diagnosis_term:
    preferred_term: radiography
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  evidence:
  - reference: PMID:35361766
    reference_title: Additional findings of tibial dysplasia in a male with orofaciodigital syndrome type XVI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographic imaging at 48 days showed the 6th finger, including two
      proximal phalanxes and one distal phalanx
    explanation: >-
      Worked example of radiography resolving the digital anatomy in an
      orofaciodigital case.
- name: Molecular genetic testing
  description: >-
    Diagnosis is confirmed by identifying the causal variant. For OFD type I this
    is a heterozygous OFD1 variant in a female or a hemizygous variant in a male;
    for the other subtypes a multigene ciliopathy panel or exome sequencing is
    required.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of OFD1 is established in a female proband with suggestive
      findings and a heterozygous OFD1 pathogenic variant identified by molecular
      genetic testing.
    explanation: >-
      States the molecular diagnostic criterion for the commonest subtype.
- name: Exome sequencing for the molecularly undefined subtypes
  description: >-
    Because several of the classically described subtypes still lack a molecular
    definition, exome or genome sequencing is the appropriate test when a case
    does not fit a gene-defined type; this is how C2CD3, TMEM107, INTU, KIAA0753,
    IFT57, SCNM1, RAB34 and ZRSR2 were each identified.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:27141300
    reference_title: Update on oral-facial-digital syndromes (OFDS).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      To date, seven of the described OFDS still await a molecular definition and
      two unclassified forms need further clinical and molecular validation.
    explanation: >-
      Establishes the residual diagnostic gap that motivates untargeted sequencing
      in this group. Evidence source is OTHER because this is a narrative review.
- name: Renal ultrasound surveillance
  description: >-
    Because polycystic kidney disease in OFD type I is typically adult-onset,
    imaging surveillance rather than one-off testing is required; kidney, liver,
    pancreas and ovarian ultrasound is recommended annually from age ten.
  diagnosis_term:
    preferred_term: renal ultrasound
    term:
      id: NCIT:C159885
      label: Renal Ultrasound
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Annual blood pressure; serum creatinine; and kidney, liver, pancreas, and
      ovarian ultrasound for cystic disease beginning at age ten years.
    explanation: >-
      States the imaging surveillance schedule for cystic organ disease in OFD
      type I.
differential_diagnoses:
- name: Joubert syndrome
  description: >-
    The closest differential. OFD VI is formally a Joubert-syndrome-related
    disorder and shares the molar tooth sign and several genes (CPLANE1, TMEM216,
    TMEM107, OFD1), so the two are allelic rather than merely similar.
  distinguishing_features:
  - >-
    OFD VI requires oral-facial-digital findings (tongue hamartoma, additional
    frenula, mesoaxial polydactyly or hypothalamic hamartoma) in addition to the
    molar tooth sign; pure Joubert syndrome lacks them.
  - >-
    Joubert syndrome presents with hypotonia, ataxia, oculomotor apraxia and
    episodic hyperpnea as the leading features rather than a malformation triad.
  disease_term:
    preferred_term: Joubert syndrome
    term:
      id: MONDO:0018772
      label: Joubert syndrome
  evidence:
  - reference: PMID:24178751
    reference_title: C5orf42 is the major gene responsible for OFD syndrome type VI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      C5orf42 mutations have already been reported in Joubert syndrome confirming
      that OFD VI and JBS are allelic disorders, thus enhancing our knowledge of
      the complex, highly heterogeneous nature of ciliopathies.
    explanation: >-
      Establishes the allelic relationship that makes Joubert syndrome the primary
      differential for the molar-tooth-sign subtypes.
- name: Meckel syndrome
  description: >-
    A lethal transition-zone ciliopathy sharing genes with the severe OFD
    subtypes; TCTN3 truncating variants were found in fetal cases with overlapping
    Meckel and OFD IV phenotypes.
  distinguishing_features:
  - >-
    Meckel syndrome is defined by the triad of occipital encephalocele, cystic
    renal dysplasia and hepatic ductal plate malformation, and is perinatally
    lethal.
  - >-
    The oral findings characteristic of OFDS (accessory frenula, lobulated tongue,
    tongue hamartoma) are not part of the Meckel definition.
  disease_term:
    preferred_term: Meckel syndrome
    term:
      id: MONDO:0018921
      label: Meckel syndrome
  evidence:
  - reference: PMID:22883145
    reference_title: TCTN3 mutations cause Mohr-Majewski syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      led us to identify four additional truncating TCTN3 mutations in unrelated
      fetal cases with overlapping Meckel and OFD IV syndromes
    explanation: >-
      Documents the phenotypic overlap that makes Meckel syndrome a differential
      for the severe OFD subtypes.
- name: Bardet-Biedl syndrome
  description: >-
    A pleiotropic ciliopathy that also features polydactyly, and shares the ciliary
    mechanism, but with a quite different clinical centre of gravity.
  distinguishing_features:
  - >-
    Bardet-Biedl syndrome is defined by rod-cone dystrophy, obesity, hypogonadism
    and renal dysfunction; postaxial polydactyly is its only overlap with the
    orofaciodigital triad.
  - >-
    The oral and facial midline malformations of OFDS are not features of
    Bardet-Biedl syndrome.
  disease_term:
    preferred_term: Bardet-Biedl syndrome
    term:
      id: MONDO:0015229
      label: Bardet-Biedl syndrome
  evidence:
  - reference: PMID:35361766
    reference_title: Additional findings of tibial dysplasia in a male with orofaciodigital syndrome type XVI.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      OFD syndromes are classified under ciliopathies, which also include Joubert
      syndrome (JBS), Meckel–Gruber syndrome (MKS), Bardet–Biedl syndrome,
      nephronophthisis (NPHP), and several chondrodysplasias
    explanation: >-
      Places Bardet-Biedl syndrome alongside OFDS within the ciliopathies, which
      is why it is carried as a differential.
treatments:
- name: Surgical correction of oral, facial and digital malformations
  description: >-
    Management is symptomatic. Surgery addresses cleft lip and palate, tongue
    nodules and hamartomas, accessory frenula, syndactyly and polydactyly; timing
    and staging follow standard craniofacial and hand-surgery practice.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgery for cleft lip/palate, tongue nodules, accessory frenulae,
      syndactyly, and polydactyly
    explanation: >-
      States the surgical management of the malformation triad recommended for OFD
      type I.
- name: Speech therapy and management of otitis media
  description: >-
    Speech and language therapy is required because of the combined palatal,
    lingual and hearing involvement; recurrent otitis media is treated
    aggressively to protect hearing and speech development.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      speech therapy and aggressive treatment of otitis media as needed
    explanation: >-
      States the speech-therapy and otitis-media management recommended for OFD
      type I.
- name: Renal and blood-pressure surveillance with standard treatment of kidney disease
  description: >-
    Because polycystic kidney disease in OFD type I is generally adult-onset and
    progressive, annual blood pressure, serum creatinine and abdominal ultrasound
    from age ten allow kidney disease to be treated by standard nephrological
    management before it presents late.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Annual blood pressure; serum creatinine; and kidney, liver, pancreas, and
      ovarian ultrasound for cystic disease beginning at age ten years.
    explanation: >-
      States the renal surveillance programme underpinning this management
      recommendation.
- name: Genetic counseling
  description: >-
    Counseling must be subtype-specific: OFD type I carries X-linked dominant,
    male-lethal recurrence risks with most cases sporadic, whereas the autosomal
    recessive subtypes carry a 25% sibling recurrence risk, and OFD VIII and OFD
    21 are X-linked recessive. Evaluating apparently asymptomatic female relatives
    in OFD type I families is recommended because they may still be at risk of
    kidney disease.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301367
    reference_title: Oral-Facial-Digital Syndrome Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is appropriate to evaluate the genetic status of apparently asymptomatic
      female relatives (even in the absence of oral, facial, and digital
      anomalies) to determine if they are at risk for kidney disease.
    explanation: >-
      States the family-evaluation recommendation that this counseling
      intervention implements.
datasets:
- accession: geo:GSE154197
  title: INTS13 Mutations Causing a Developmental Ciliopathy Disrupt Integrator Complex Assembly
  description: >-
    RNA-seq of human cells depleted of INTS13, generated in the study that
    identified biallelic INTS13 variants in two families with variable
    orofaciodigital syndrome type 2 and showed that INTS13 depletion disrupts
    ciliogenesis and dysregulates a broad collection of ciliary genes.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 9
  genes:
  - preferred_term: INTS13
    term:
      id: hgnc:20174
      label: INTS13
  publication: PMID:36229431
  evidence:
  - reference: PMID:36229431
    reference_title: INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes
      dysregulation of a broad collection of ciliary genes.
    explanation: >-
      States the transcriptional result this dataset reports. Evidence source is
      IN_VITRO because the profiling was performed in cultured human cells.
  notes: >-
    Accession, title, organism and sample count verified against the NCBI GEO
    E-utilities record on 2026-08-19. Relevance is DIRECT rather than gene-only:
    the linked publication reports the affected families as having orofaciodigital
    syndrome type 2, not merely a ciliary gene of interest.
discussions:
- discussion_id: ofds_disease_versus_grouping
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Should the orofaciodigital syndromes be modeled as this Disease entry with
    has_subtypes, or as a Grouping over the already-standalone member entries?
  rationale: >-
    The case for a Grouping is real and should not be lost. Two members are
    already independent Disease entries with their own pathographs
    (Orofaciodigital_Syndrome_Type_I, Orofaciodigital_Syndrome_17) and a third
    OFD-spectrum disorder is curated under a non-OFD name
    (Heart_Defect_Tongue_Hamartoma_Polysyndactyly_Syndrome, WDPCP); the project
    convention is that a grouping sits over already-distinct entries. The subtypes
    are heterogeneous in inheritance (X-linked dominant male-lethal, X-linked
    recessive, autosomal recessive) and in ciliary subcompartment, and Bruel et
    al. state that the wide heterogeneity makes the initial classification
    obsolete, proposing a clinical classification restricted to three
    well-delineated subtypes with genotype-based classification for the rest,
    which is closer to a curated union with membership criteria than to a single
    blended graph. The case for the present Disease modeling is that the entry
    also has to carry a shared mechanism (ciliary Hedgehog derangement) that all
    members instantiate, that seventeen of the twenty numbered types have no
    standalone entry to group over, and that the MONDO term itself is a disease
    node with a curated pathophysiology to attach to. This entry takes the Disease
    form (the priority dashboard's CURATE_ROOT_WITH_SUBTYPES recommendation) and
    records the counter-argument here rather than deciding silently. If the
    per-subtype entry count grows, converting to a Grouping with NECESSARY
    criteria over an oral/facial arm, a digital arm and the
    ciliopathy_dysfunction basal-body/transition-zone node would be the natural
    migration.
  evidence:
  - reference: PMID:28289185
    reference_title: "Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A clinical classification restricted to the three frequent/well-delineated
      subtypes could be proposed, and for patients who do not fit one of these
      three main subtypes, a further classification could be based on the
      genotype.
    explanation: >-
      The nosological proposal that motivates the Grouping alternative recorded in
      this discussion.
- discussion_id: ofds_mondo_excludes_type_i
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    MONDO:0015375 does not have MONDO:0010702 (orofaciodigital syndrome I) among
    its descendants, so the eponymous and commonest subtype falls outside the
    MONDO grouping term for its own disease family. Should this be raised
    upstream?
  rationale: >-
    Verified with OAK against the local MONDO build on 2026-08-19: MONDO:0015375
    has nineteen is_a descendants (types II, III, IV, V, 6, VII, VIII, IX, X, XI,
    12, 14, XV, 16, 17, 18, 19, 20, 21) and OFD I is not among them; OFD I's
    asserted parents are MONDO:0002254 syndromic disease, MONDO:0100500 Mendelian
    neurodevelopmental disorder and MONDO:1040039 OFD1-related ciliopathy. Three
    of MONDO:0015375's own annotations contradict the omission: its MeSH-derived
    definition names Type I explicitly, its OMIM cross-reference is the phenotypic
    series OMIMPS:311200 anchored on OFD I, and its Orphanet cross-reference
    (Orphanet:140997) is the OFD group record that includes OFD I. This entry
    therefore lists OFD I as a subtype on clinical and phenotypic-series grounds.
    The remaining action is to report the missing is_a edge to MONDO; it has not
    been filed from this session.
  notes: >-
    Consequence for tooling: any process that builds an OFDS member list from the
    MONDO descendant closure will silently omit the commonest type. Related, but a
    separate observation: OFD XIII (Degner syndrome) has no MONDO term at all.
- discussion_id: ofds_minor_spliceosome_route
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How does minor (U12-type) spliceosome dysfunction produce a specifically
    orofaciodigital phenotype rather than a generic multisystem disorder, and is
    ciliary transcript depletion the whole explanation?
  attaches_to:
  - pathophysiology#Minor Spliceosome Dysfunction and Ciliary Transcript Depletion
  rationale: >-
    Two subtypes (OFD 19, SCNM1; OFD 21, ZRSR2) are caused by loss of minor
    spliceosome components rather than of ciliary proteins, and both show
    minor-intron retention, depletion of ciliary transcripts including TMEM107,
    and abnormally elongated primary cilia. What is not established is whether
    ciliary transcript depletion is sufficient to account for the phenotype, or
    whether non-ciliary U12-dependent targets contribute; the SCNM1 study lists
    DERL2, ZC3H8 and C17orf75 among the severely reduced transcripts alongside the
    ciliary ones, and the ZRSR2 phenotype includes holoprosencephaly and pituitary
    anomaly, which are not typical of the ciliary subtypes. Note also that both
    reports describe cilia that are abnormally elongated, whereas several ciliary
    OFD genes give absent or short cilia, so the cellular phenotype is not simply
    a phenocopy. dismech separately curates minor-spliceosome disorders
    (RNU12-related_Minor_Spliceopathy, Roifman-syndrome) with no link to the
    ciliopathy tree; a shared minor-spliceosome module would be the structural
    place to resolve this.
  proposed_experiments:
  - experiment_id: ofds_u12_ciliary_transcript_rescue
    name: Rescue of the ciliary phenotype by restoring individual U12-dependent ciliary transcripts
    description: >-
      In SCNM1- or ZRSR2-deficient patient fibroblasts, re-express the depleted
      ciliary and basal-body transcripts (TMEM107, FAM92A) individually and in
      combination, and measure cilium length and Hedgehog reporter output. Full
      rescue would establish ciliary transcript depletion as sufficient; partial
      rescue would implicate non-ciliary U12 targets.
    evidence:
    - reference: PMID:36084634
      reference_title: Mutations in SCNM1 cause orofaciodigital syndrome due to minor intron splicing defects affecting primary cilia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Conversely, cilia length and expression of SCNM1-regulated genes were
        restored in SCNM1-deficient fibroblasts following reintroduction of SCNM1
        via retroviral delivery.
      explanation: >-
        Establishes the feasibility precedent for the proposed design: rescue by
        re-expression in the same patient-fibroblast system, read out as cilium
        length, has already been performed for SCNM1 itself. Evidence source is
        IN_VITRO because the rescue was done in cultured fibroblasts.
  evidence:
  - reference: PMID:36084634
    reference_title: Mutations in SCNM1 cause orofaciodigital syndrome due to minor intron splicing defects affecting primary cilia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Notably, expression of TMEM107 and FAM92A encoding primary cilia and basal
      body proteins, respectively, and that of DERL2, ZC3H8, and C17orf75, were
      severely reduced in SCNM1-deficient cells.
    explanation: >-
      Shows that the depleted transcript set is not confined to ciliary genes,
      which is the open question this discussion records. Evidence source is
      IN_VITRO because the transcriptome comparison used patient fibroblasts and
      engineered cell lines.

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PMID:20301367

Oral-Facial-Digital Syndrome Type I.

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