Meckel Syndrome

Genetic MONDO:0018921 Pathograph 20 Show in embeddings browser Ciliopathy

Meckel syndrome (Meckel-Gruber syndrome) is a rare, lethal ciliopathy with a classic triad of occipital encephalocele, cystic renal dysplasia, and postaxial polydactyly, often with multiorgan involvement.

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2
Inheritance
11
Pathophys.
5
Phenotypes
20
Pathograph
17
Genes
4
Medical Actions
14
Subtypes
5
Differentials
1
Trials
5
References
2
Deep Research
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Classifications

ISDS Skeletal Nosology
polydactyly syndactyly triphalangism
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Inheritance

2
Autosomal recessive
Meckel syndrome is inherited in an autosomal recessive pattern and sits on a ciliopathy spectrum with Joubert/related disorders, reflecting allelic series across shared ciliary genes.
Show evidence (2 references)
PMID:25182137 SUPPORT Human Clinical
"Meckel-Gruber Syndrome is a rare autosomal recessive lethal ciliopathy"
This statement supports autosomal recessive inheritance of MKS.
PMID:26729329 SUPPORT Human Clinical
"two clinically and genetically heterogeneous neurodevelopmental conditions that define a phenotypic spectrum, with MKS at the severe end."
This cohort study frames MKS and JBTS as a phenotypic spectrum, consistent with allelic series across ciliopathy genes.
Digenic inheritance HP:0010984
Beyond classic autosomal recessive transmission, Meckel syndrome can show digenic inheritance across the shared ciliopathy gene set, with pathogenic variants in two different ciliary genes (in trans) contributing to the phenotype.
Digenic inheritance
Show evidence (1 reference)
PMID:34821546 SUPPORT Human Clinical
"Multiexon deletion in TMEM67 and KIF14 present in trans was identified in the third case (Meckel syndrome), likely resulting in digenic inheritance."
This prenatal case series documents variants in two ciliary genes (TMEM67 and KIF14) in trans, consistent with digenic inheritance in Meckel syndrome.
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Subtypes

14
Meckel syndrome, type 1 MONDO:0009571
MKS1 hgnc:7121 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MKS1 (hgnc:7121). hgnc:7121 is a gene from the HUGO Gene Nomenclature Committee.
The founding Meckel locus. The MKS1 product localizes to the base of the cilium and is required for ciliogenesis.
Show evidence (2 references)
PMID:23349226 SUPPORT BACKGROUND Human Clinical
"Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
Maps each numbered MKS locus to its gene. Quoted from this paper's introduction, where it restates the established locus series rather than reporting the authors' own finding.
PMID:19776033 SUPPORT BACKGROUND Model Organism
"The gene mutated in type 1 MKS encodes a protein associated with the base of the cilium in vertebrates and nematodes."
Ties the type 1 locus to a ciliary base protein, which is the claim this row's description makes.
Meckel syndrome, type 2 MONDO:0011296
TMEM216 hgnc:25018 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TMEM216 (hgnc:25018). hgnc:25018 is a gene from the HUGO Gene Nomenclature Committee.
The MKS2 locus. TMEM216 encodes a tetraspan transmembrane protein, and the MKS2 and Joubert JBTS2 loci are allelic.
Show evidence (2 references)
PMID:23349226 SUPPORT BACKGROUND Human Clinical
"Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
Maps each numbered MKS locus to its gene. Quoted from this paper's introduction, where it restates the established locus series rather than reporting the authors' own finding.
PMID:20512146 SUPPORT Human Clinical
"We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein."
Assigns the MKS2 locus to TMEM216 explicitly, and records its allelism with the Joubert JBTS2 locus.
Meckel syndrome, type 3 MONDO:0011821
TMEM67 hgnc:28396 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TMEM67 (hgnc:28396). hgnc:28396 is a gene from the HUGO Gene Nomenclature Committee.
TMEM67 encodes meckelin, an integral protein of the renal epithelial cell and of the primary cilium membrane.
Show evidence (2 references)
PMID:23349226 SUPPORT BACKGROUND Human Clinical
"Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
Maps each numbered MKS locus to its gene. Quoted from this paper's introduction, where it restates the established locus series rather than reporting the authors' own finding.
PMID:19211713 SUPPORT BACKGROUND Human Clinical
"In humans, the underlying mutated gene, TMEM67, encodes transmembrane protein 67, also called meckelin (OMIM 609884), which is an integral protein of the renal epithelial cell and membrane of the primary cilium."
Names TMEM67/meckelin as the type 3 gene and gives the protein description used in this row.
Meckel syndrome, type 4 MONDO:0012626
CEP290 hgnc:29021 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CEP290 (hgnc:29021). hgnc:29021 is a gene from the HUGO Gene Nomenclature Committee.
CEP290 encodes a centrosomal protein; loss-of-function alleles give the lethal Meckel end of a wide CEP290 allelic spectrum.
Show evidence (2 references)
PMID:23349226 SUPPORT BACKGROUND Human Clinical
"Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
Maps each numbered MKS locus to its gene. Quoted from this paper's introduction, where it restates the established locus series rather than reporting the authors' own finding.
PMID:17705300 SUPPORT Human Clinical
"Sequencing of the CEP290 gene located in the minimal critical region showed a homozygous 1-bp deletion supposed to lead to loss of function of the encoded centrosomal protein CEP290/nephrocystin-6."
The positional-cloning result that mapped this Meckel locus to CEP290 and identified a loss-of-function allele in it.
Meckel syndrome, type 5 MONDO:0012695
RPGRIP1L hgnc:29168 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RPGRIP1L (hgnc:29168). hgnc:29168 is a gene from the HUGO Gene Nomenclature Committee.
RPGRIP1L is mutated in both cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome, the same gene spanning both severities.
Show evidence (2 references)
PMID:23349226 SUPPORT BACKGROUND Human Clinical
"Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
Maps each numbered MKS locus to its gene. Quoted from this paper's introduction, where it restates the established locus series rather than reporting the authors' own finding.
PMID:17558409 SUPPORT Human Clinical
"we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS"
Reports RPGRIP1L lesions in Meckel syndrome as well as in the milder cerebello-oculo-renal phenotype.
Meckel syndrome, type 6 MONDO:0012848
CC2D2A hgnc:29253 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CC2D2A (hgnc:29253). hgnc:29253 is a gene from the HUGO Gene Nomenclature Committee.
CC2D2A was the fifth Meckel gene identified and defines the sixth locus.
Show evidence (2 references)
PMID:23349226 SUPPORT BACKGROUND Human Clinical
"Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
Maps each numbered MKS locus to its gene. Quoted from this paper's introduction, where it restates the established locus series rather than reporting the authors' own finding.
PMID:18513680 SUPPORT Human Clinical
"we identified the sixth locus and the fifth gene, CC2D2A (MKS6), behind MKS."
Names CC2D2A as MKS6 explicitly, which is the claim this row makes.
Meckel syndrome, type 8 MONDO:0013482
TCTN2 hgnc:25774 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TCTN2 (hgnc:25774). hgnc:25774 is a gene from the HUGO Gene Nomenclature Committee.
The MKS8 locus, mapped to TCTN2 in a multiplex consanguineous family.
Show evidence (2 references)
PMID:23349226 SUPPORT BACKGROUND Human Clinical
"Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
Maps each numbered MKS locus to its gene. Quoted from this paper's introduction, where it restates the established locus series rather than reporting the authors' own finding.
PMID:21462283 SUPPORT Human Clinical
"In this article, we describe the identification of a novel MKS locus MKS8 that we map to TCTN2, in a multiplex consanguineous family."
Names MKS8 and maps it to TCTN2 explicitly, which is the claim this row makes.
Meckel syndrome, type 9 MONDO:0013630
B9D1 hgnc:24123 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in B9D1 (hgnc:24123). hgnc:24123 is a gene from the HUGO Gene Nomenclature Committee.
B9D1 is a component of the ciliary B9 protein complex whose disruption causes Meckel syndrome.
Show evidence (2 references)
PMID:23349226 SUPPORT BACKGROUND Human Clinical
"Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
Maps each numbered MKS locus to its gene. Quoted from this paper's introduction, where it restates the established locus series rather than reporting the authors' own finding.
PMID:40933483 SUPPORT Human Clinical
"Two compound heterozygous variants, c.341G>T (p.R114L) and c.405-308_405-304del, were identified in both probands, each inherited from one unaffected parent."
Human pedigree evidence for biallelic B9D1 variants in two fetuses with the Meckel phenotype.
Meckel syndrome, type 10 MONDO:0013609
B9D2 hgnc:28636 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in B9D2 (hgnc:28636). hgnc:28636 is a gene from the HUGO Gene Nomenclature Committee.
B9D2 is a further component of the same ciliary B9 protein complex, disrupted in Meckel syndrome alongside B9D1.
Show evidence (2 references)
PMID:23349226 SUPPORT BACKGROUND Human Clinical
"Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
Maps each numbered MKS locus to its gene. Quoted from this paper's introduction, where it restates the established locus series rather than reporting the authors' own finding.
PMID:21763481 SUPPORT Human Clinical
"We identified a homozygous c.301A>C (p.Ser101Arg) B9D2 mutation that segregates with MKS"
A pathogenic B9D2 variant segregating with Meckel syndrome.
Meckel syndrome, type 11 MONDO:0014164
TMEM231 hgnc:37234 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TMEM231 (hgnc:37234). hgnc:37234 is a gene from the HUGO Gene Nomenclature Committee.
TMEM231 was identified as a Meckel locus in two consanguineous families in which every previously known MKS gene had been excluded. It forms a transition-zone complex with the B9 proteins and CC2D2A, and the same gene also gives Joubert syndrome.
Show evidence (2 references)
PMID:23349226 SUPPORT Human Clinical
"TMEM231 represents a novel MKS locus."
The report that established TMEM231 as a Meckel locus, in two consanguineous families in which every previously known MKS gene had been excluded.
PMID:37736303 SUPPORT Human Clinical
"Two splice site variants of TMEM231 (NM_001077418.2, c.583-1G>C and c.583-2_588delinsTCCTCCC) were identified in the proband, and the two variants have not been previously reported."
Independent human pedigree confirming biallelic TMEM231 variants in Meckel syndrome.
Meckel syndrome 13 MONDO:0033044
TMEM107 hgnc:28128 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TMEM107 (hgnc:28128). hgnc:28128 is a gene from the HUGO Gene Nomenclature Committee.
TMEM107 defines MKS13, one of the loci found after the common Meckel genes were excluded.
Show evidence (1 reference)
PMID:26123494 SUPPORT Human Clinical
"This study shows that known MKS loci account for the overwhelming majority of MKS cases but additional loci exist including MKS13 caused by TMEM107 mutation."
Names MKS13 and its gene explicitly, which is the claim this row makes.
Meckel syndrome 14 MONDO:0030819
TXNDC15 hgnc:20652 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TXNDC15 (hgnc:20652). hgnc:20652 is a gene from the HUGO Gene Nomenclature Committee.
TXNDC15 defines MKS14. Biallelic variants have been reported in perinatally lethal Meckel phenotypes, and the same gene also appears in Joubert-range presentations.
Show evidence (3 references)
PMID:38156946 SUPPORT Human Clinical
"We report the case of a homozygous mutation in the TXNDC15 gene, causing MKS14 in the Chinese population."
Names MKS14 and its gene explicitly, which is the claim this row makes.
PMID:41518077 SUPPORT Model Organism
"Homozygous Txndc15mt/mt embryos displayed the complete MKS phenotype-fetal lethality, exencephaly, omphalocele, post-axial polydactyly, and polycystic kidneys-together with markedly reduced TXNDC15 protein in brain, liver, and kidney."
A mouse model reproducing the Meckel phenotype on TXNDC15 loss, supporting causation rather than association.
PMID:39304719 SUPPORT BACKGROUND Human Clinical
"Biallelic TXNDC15 variants have been reported in six individuals of Meckel syndrome (MKS) with perinatal lethal phenotypes"
Supports the perinatally lethal Meckel presentations recorded in this row's description, and the same report places TXNDC15 in the Joubert range too.
KIF14-related lethal fetal ciliopathy (OMIM MKS12) MONDO:0014552
KIF14 hgnc:19181 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KIF14 (hgnc:19181). hgnc:19181 is a gene from the HUGO Gene Nomenclature Committee.
The weakest row in this series, and deliberately labelled with MONDO's name rather than as "Meckel syndrome, type 12". OMIM numbers this entity MKS12 and MONDO classifies it under Meckel syndrome, but the report that defined it described an undescribed lethal fetal syndrome - intrauterine growth restriction, severe microcephaly, renal cystic dysplasia or agenesis, complex brain and genitourinary malformations - that was compatible with a ciliopathy but "not diagnostic of any known condition", and the classic occipital encephalocele plus postaxial polydactyly triad is not what it reports. A separate prenatal series does place KIF14 in a Meckel diagnosis, but in trans with a TMEM67 deletion and read by its authors as digenic.
Show evidence (3 references)
PMID:24128419 SUPPORT Human Clinical
"We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype."
Establishes biallelic KIF14 truncating variants as the cause of this entity.
PMID:24128419 SUPPORT Human Clinical
"The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition."
The authors' own statement that the phenotype is not that of a recognized condition, which is the basis for the nosological caveat in this row.
PMID:34821546 SUPPORT INDIRECT Human Clinical
"Multiexon deletion in TMEM67 and KIF14 present in trans was identified in the third case (Meckel syndrome), likely resulting in digenic inheritance."
The only cached report placing KIF14 in a case diagnosed as Meckel syndrome, and it is a digenic reading with a TMEM67 deletion, so it supports the link only indirectly.
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Pathophysiology

11
Primary cilium membrane protein dysfunction (TMEM67/meckelin)
Pathogenic variants in TMEM67 disrupt primary cilium membrane components.
TMEM67 hgnc:28396 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TMEM67 (hgnc:28396). hgnc:28396 is a gene from the HUGO Gene Nomenclature Committee.
primary cilium GO:0005929 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves primary cilium, annotated with cilium (GO:0005929). GO:0005929 is a cellular component from the Gene Ontology.
Show evidence (1 reference)
PMID:19211713 SUPPORT BACKGROUND Human Clinical
"In humans, the underlying mutated gene, TMEM67, encodes transmembrane protein 67, also called meckelin (OMIM 609884), which is an integral protein of the renal epithelial cell and membrane of the primary cilium."
TMEM67/meckelin is an integral primary cilium membrane protein implicated in MKS3. Regraded from MODEL_ORGANISM in the wiring-013 pass: the sentence states the human genetics, quoted from this mouse-model paper's background.
Ciliary base protein dysfunction (MKS1)
Loss of MKS1 perturbs proteins associated with the ciliary base/basal body.
MKS1 hgnc:7121 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MKS1 (hgnc:7121). hgnc:7121 is a gene from the HUGO Gene Nomenclature Committee.
ciliary basal body GO:0036064 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary basal body (GO:0036064). GO:0036064 is a cellular component from the Gene Ontology. ciliary base GO:0097546 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary base (GO:0097546). GO:0097546 is a cellular component from the Gene Ontology.
Show evidence (1 reference)
PMID:19776033 SUPPORT Model Organism
"The gene mutated in type 1 MKS encodes a protein associated with the base of the cilium in vertebrates and nematodes."
MKS1 encodes a protein associated with the ciliary base, supporting ciliary base dysfunction in MKS.
Basal body localization without proper ciliogenesis
Basal bodies localize apically, yet cilia fail to form in many tissues.
TMEM216 hgnc:25018 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TMEM216 (hgnc:25018). hgnc:25018 is a gene from the HUGO Gene Nomenclature Committee. TMEM231 hgnc:37234 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TMEM231 (hgnc:37234). hgnc:37234 is a gene from the HUGO Gene Nomenclature Committee. TCTN2 hgnc:25774 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TCTN2 (hgnc:25774). hgnc:25774 is a gene from the HUGO Gene Nomenclature Committee. TMEM237 hgnc:14432 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TMEM237 (hgnc:14432). hgnc:14432 is a gene from the HUGO Gene Nomenclature Committee. TMEM107 hgnc:28128 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TMEM107 (hgnc:28128). hgnc:28128 is a gene from the HUGO Gene Nomenclature Committee. TXNDC15 hgnc:20652 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TXNDC15 (hgnc:20652). hgnc:20652 is a gene from the HUGO Gene Nomenclature Committee. RPGRIP1L hgnc:29168 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPGRIP1L (hgnc:29168). hgnc:29168 is a gene from the HUGO Gene Nomenclature Committee. CEP290 hgnc:29021 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CEP290 (hgnc:29021). hgnc:29021 is a gene from the HUGO Gene Nomenclature Committee.
cilium assembly GO:0060271 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated cilium assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology. ↕ DYSREGULATED
primary cilium GO:0005929 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves primary cilium, annotated with cilium (GO:0005929). GO:0005929 is a cellular component from the Gene Ontology. ciliary basal body GO:0036064 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary basal body (GO:0036064). GO:0036064 is a cellular component from the Gene Ontology. ciliary base GO:0097546 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary base (GO:0097546). GO:0097546 is a cellular component from the Gene Ontology.
Show evidence (1 reference)
PMID:19776033 SUPPORT Model Organism
"loss of Mks1 in vivo does not interfere with apical localization of epithelial basal bodies but rather leads to defective cilia formation in most, but not all, tissues."
Basal body localization is preserved while ciliogenesis fails in Mks1-deficient tissues.
Defective cilia formation across multiple tissues
Primary cilia fail to form in many tissues in vivo.
cilium assembly GO:0060271 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated cilium assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology. ↕ DYSREGULATED
primary cilium GO:0005929 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves primary cilium, annotated with cilium (GO:0005929). GO:0005929 is a cellular component from the Gene Ontology. ciliary basal body GO:0036064 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary basal body (GO:0036064). GO:0036064 is a cellular component from the Gene Ontology. ciliary base GO:0097546 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary base (GO:0097546). GO:0097546 is a cellular component from the Gene Ontology.
Show evidence (1 reference)
PMID:19776033 SUPPORT Model Organism
"loss of Mks1 in vivo does not interfere with apical localization of epithelial basal bodies but rather leads to defective cilia formation in most, but not all, tissues."
Mks1 loss leads to defective cilia formation across tissues in vivo.
Loss of primary cilia (failed ciliogenesis)
Primary cilia are absent, reflecting failed ciliogenesis.
CC2D2A hgnc:29253 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CC2D2A (hgnc:29253). hgnc:29253 is a gene from the HUGO Gene Nomenclature Committee.
cilium assembly GO:0060271 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated cilium assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology. ↕ DYSREGULATED
primary cilium GO:0005929 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves primary cilium, annotated with cilium (GO:0005929). GO:0005929 is a cellular component from the Gene Ontology. ciliary basal body GO:0036064 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary basal body (GO:0036064). GO:0036064 is a cellular component from the Gene Ontology. ciliary base GO:0097546 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary base (GO:0097546). GO:0097546 is a cellular component from the Gene Ontology.
Show evidence (1 reference)
PMID:18513680 SUPPORT In Vitro
"Immunofluorescence staining of patient's fibroblast cells demonstrates that the cells lack cilia, providing evidence for the critical role of CC2D2A in cilia formation."
Patient fibroblasts lacking cilia link CC2D2A to cilia formation.
Reduced axonemal microtubule posttranslational modifications
Disruption of the B9-TMEM67 complex at the transition zone reduces axonemal microtubule modifications.
B9D1 hgnc:24123 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves B9D1 (hgnc:24123). hgnc:24123 is a gene from the HUGO Gene Nomenclature Committee. B9D2 hgnc:28636 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves B9D2 (hgnc:28636). hgnc:28636 is a gene from the HUGO Gene Nomenclature Committee.
primary cilium GO:0005929 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves primary cilium, annotated with cilium (GO:0005929). GO:0005929 is a cellular component from the Gene Ontology. axoneme GO:0005930 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves axoneme (GO:0005930). GO:0005930 is a cellular component from the Gene Ontology. ciliary basal body GO:0036064 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary basal body (GO:0036064). GO:0036064 is a cellular component from the Gene Ontology. ciliary base GO:0097546 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves ciliary base (GO:0097546). GO:0097546 is a cellular component from the Gene Ontology.
Show evidence (2 references)
PMID:41165761 SUPPORT In Vitro
"the B9 complex interacted with and anchored TMEM67 to the TZ membrane."
Disruption of the B9-TMEM67 transition zone interaction underlies downstream axonemal defects.
PMID:41165761 SUPPORT In Vitro
"Disruption of the B9-TMEM67 complex reduced posttranslational modifications of axonemal microtubules due to deregulation of tubulin-modifying enzymes within cilia."
B9 complex disruption impairs axonemal microtubule posttranslational modifications.
Impaired initiation of ciliogenesis
B9 proteins facilitate early ciliogenesis; disruption impairs initiation.
cilium assembly GO:0060271 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated cilium assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Show evidence (1 reference)
PMID:41165761 SUPPORT In Vitro
"B9 proteins localized to centrioles prior to ciliogenesis, where they facilitated the initiation of ciliogenesis."
B9 proteins are required for initiating ciliogenesis.
TMEM67 cleavage uncouples ciliogenesis and Wnt signaling
Proteolytic cleavage of TMEM67 separates ciliary assembly from Wnt pathway activity.
cilium assembly GO:0060271 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated cilium assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology. ↕ DYSREGULATED Wnt signaling pathway GO:0016055 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated Wnt signaling pathway (GO:0016055). GO:0016055 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Show evidence (1 reference)
PMID:40436881 SUPPORT In Vitro
"Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis."
TMEM67 cleavage separates Wnt signaling from ciliogenesis in MKS.
TMEM17 loss disrupts Sonic Hedgehog signaling
TMEM17 dysfunction at the ciliary transition zone abrogates Sonic Hedgehog signaling.
TMEM17 hgnc:26623 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TMEM17 (hgnc:26623). hgnc:26623 is a gene from the HUGO Gene Nomenclature Committee.
hedgehog signaling pathway GO:0007224 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated hedgehog signaling pathway, annotated with smoothened signaling pathway (GO:0007224). GO:0007224 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Show evidence (1 reference)
PMID:40841990 SUPPORT In Vitro
"Our study reveals severe functional consequences, including TMEM17 destabilization and mislocalization, anomalies in cilium composition and function, and abrogation of Sonic Hedgehog signaling."
TMEM17 variants disrupt ciliary function and abrogate SHH signaling.
Altered Hedgehog signaling in neural tube patterning
Hedgehog signaling is altered during neural tube development.
hedgehog signaling pathway GO:0007224 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated hedgehog signaling pathway, annotated with smoothened signaling pathway (GO:0007224). GO:0007224 is a biological process from the Gene Ontology. ↕ DYSREGULATED
primary cilium GO:0005929 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves primary cilium, annotated with cilium (GO:0005929). GO:0005929 is a cellular component from the Gene Ontology.
neural tube UBERON:0001049 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in neural tube (UBERON:0001049). UBERON:0001049 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:19776033 SUPPORT Model Organism
"Analysis of patterning in the neural tube and the limb demonstrates altered Hedgehog (Hh) pathway signaling underlies some MKS defects"
Neural tube patterning defects in Mks1 mutants reflect altered Hedgehog signaling.
PMID:34981460 SUPPORT In Vitro
"HEK293T transfected with over-expression wildtype/mutated ZNF77 plasmid showed that SHH was increased in wildtype ZNF77 cells, while SHH and CC2D2A were increased in mutated ZNF77 cells."
In vitro experiments from MKS cases link SHH signaling changes to MKS-associated genetic findings.
Altered Hedgehog signaling in limb patterning
Hedgehog signaling is altered during limb development.
hedgehog signaling pathway GO:0007224 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated hedgehog signaling pathway, annotated with smoothened signaling pathway (GO:0007224). GO:0007224 is a biological process from the Gene Ontology. ↕ DYSREGULATED
primary cilium GO:0005929 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves primary cilium, annotated with cilium (GO:0005929). GO:0005929 is a cellular component from the Gene Ontology.
Show evidence (2 references)
PMID:19776033 SUPPORT Model Organism
"Analysis of patterning in the neural tube and the limb demonstrates altered Hedgehog (Hh) pathway signaling underlies some MKS defects"
Limb patterning defects in Mks1 mutants reflect altered Hedgehog signaling.
PMID:34981460 SUPPORT In Vitro
"HEK293T transfected with over-expression wildtype/mutated ZNF77 plasmid showed that SHH was increased in wildtype ZNF77 cells, while SHH and CC2D2A were increased in mutated ZNF77 cells."
In vitro experiments from MKS cases link SHH signaling changes to MKS-associated genetic findings.
⬡

Pathograph

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

Phenotypes

5
Digestive 1
Hepatic fibrosis FREQUENT HP:0001395 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic fibrosis (HP:0001395). HP:0001395 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25182137 SUPPORT Human Clinical
"frequent features include other central nervous system anomalies (51.4%), fibrotic/cystic changes of the liver (65.5% of cases with"
This population-based study reports frequent hepatic fibrotic/cystic changes.
Genitourinary 1
Cystic renal dysplasia VERY_FREQUENT HP:0000800 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cystic renal dysplasia (HP:0000800). HP:0000800 is a phenotype from the Human Phenotype Ontology.
Show evidence (6 references)
PMID:24082939 SUPPORT Human Clinical
"Meckel-Gruber syndrome is a rare autosomal recessive lethal malformation characterized by typical manifestations of occipital encephalocele, bilateral polycystic kidneys and post axial polydactyly."
This review lists bilateral polycystic kidneys in the classic triad.
PMID:8725749 SUPPORT Human Clinical
"Both babies showed the classical triad of this conditions: occipital encephalocele, cystic kidneys, and postaxial polydactyly of all four limbs."
A case report of two siblings documents cystic kidneys in MKS.
PMID:28374938 SUPPORT Human Clinical
"Here, we document a boy with occipital encephalocele, post-axial polydactyly, and multicystic renal disease."
A case report documents multicystic renal disease in MKS.
+ 3 more references
Head and Neck 1
Occipital encephalocele VERY_FREQUENT HP:0002085 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Occipital encephalocele (HP:0002085). HP:0002085 is a phenotype from the Human Phenotype Ontology.
Show evidence (6 references)
PMID:24082939 SUPPORT Human Clinical
"Meckel-Gruber syndrome is a rare autosomal recessive lethal malformation characterized by typical manifestations of occipital encephalocele, bilateral polycystic kidneys and post axial polydactyly."
This review lists occipital encephalocele in the classic triad.
PMID:8725749 SUPPORT Human Clinical
"Both babies showed the classical triad of this conditions: occipital encephalocele, cystic kidneys, and postaxial polydactyly of all four limbs."
A case report of two siblings documents occipital encephalocele in MKS.
PMID:28374938 SUPPORT Human Clinical
"Here, we document a boy with occipital encephalocele, post-axial polydactyly, and multicystic renal disease."
A case report documents occipital encephalocele in MKS.
+ 3 more references
Limbs 1
Postaxial polydactyly VERY_FREQUENT Postaxial hand polydactyly HP:0001162 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postaxial hand polydactyly (HP:0001162). HP:0001162 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:24082939 SUPPORT Human Clinical
"Meckel-Gruber syndrome is a rare autosomal recessive lethal malformation characterized by typical manifestations of occipital encephalocele, bilateral polycystic kidneys and post axial polydactyly."
This review lists postaxial polydactyly in the classic triad.
PMID:8725749 SUPPORT Human Clinical
"Both babies showed the classical triad of this conditions: occipital encephalocele, cystic kidneys, and postaxial polydactyly of all four limbs."
A case report of two siblings documents postaxial polydactyly in MKS.
PMID:28374938 SUPPORT Human Clinical
"Here, we document a boy with occipital encephalocele, post-axial polydactyly, and multicystic renal disease."
A case report documents post-axial polydactyly in MKS.
+ 1 more reference
Respiratory 1
Pulmonary hypoplasia OCCASIONAL HP:0002089 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary hypoplasia (HP:0002089). HP:0002089 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:18603929 SUPPORT Human Clinical
"Death is mainly due to pulmonary hypoplasia."
This case report links MKS lethality to pulmonary hypoplasia.
PMID:39412385 SUPPORT Human Clinical
"the fetus, which was found to have polyhydramnios, gastric dilatation, lung hypoplasia, and cystic formation with a diameter of 68*62mm in the abdomen"
Case report documents lung hypoplasia in an MKS fetus.
🧬

Genetic Associations

17
MKS1 (Causative)
Gene: MKS1 hgnc:7121 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MKS1 (hgnc:7121). hgnc:7121 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:19776033 SUPPORT Model Organism
"The gene mutated in type 1 MKS encodes a protein associated with the base of the cilium in vertebrates and nematodes."
This mouse model study identifies the MKS1 gene underlying MKS type 1.
TMEM67 (Causative)
Gene: TMEM67 hgnc:28396 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TMEM67 (hgnc:28396). hgnc:28396 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:19211713 SUPPORT Human Clinical
"In humans, the underlying mutated gene, TMEM67, encodes transmembrane protein 67, also called meckelin (OMIM 609884), which is an integral protein of the renal epithelial cell and membrane of the primary cilium."
This study identifies TMEM67 as the causal gene for MKS3.
CC2D2A (Causative)
Gene: CC2D2A hgnc:29253 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CC2D2A (hgnc:29253). hgnc:29253 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:18513680 SUPPORT Human Clinical
"we identified the sixth locus and the fifth gene, CC2D2A (MKS6), behind MKS."
This study identifies CC2D2A as a causative MKS gene (MKS6).
PMID:28374938 SUPPORT Human Clinical
"A medical exome analysis detected a heterozygous frameshift mutation, c.4582_4583delCG p.(Arg1528Serfs*17) in CC2D2A in the maternally derived allele."
This case report identifies pathogenic CC2D2A variants in MKS, including a frameshift allele.
PMID:34981460 SUPPORT Human Clinical
"Whole exome sequencing identified a compound heterozygous of two novel variants of CEP290 and a heterozygous of a novel variant of CC2D2A."
Case series reports a novel CC2D2A variant in MKS fetuses.
TMEM216 (Causative)
Gene: TMEM216 hgnc:25018 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TMEM216 (hgnc:25018). hgnc:25018 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:20512146 SUPPORT Human Clinical
"Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes."
This study reports TMEM216 mutations causing Meckel syndrome.
TMEM231 (Causative)
Gene: TMEM231 hgnc:37234 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TMEM231 (hgnc:37234). hgnc:37234 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:23349226 SUPPORT Human Clinical
"Mutations in TMEM231 cause Meckel-Gruber syndrome."
This report identifies TMEM231 as a Meckel-Gruber syndrome locus.
B9D2 (Causative)
Gene: B9D2 hgnc:28636 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is B9D2 (hgnc:28636). hgnc:28636 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:21763481 SUPPORT Human Clinical
"We identified a homozygous c.301A>C (p.Ser101Arg) B9D2 mutation that segregates with MKS"
This study reports a pathogenic B9D2 mutation segregating with MKS.
CGGV:assertion_ebe1140c-09cc-4d05-8886-5a78267afe65-2023-06-12T160000.000Z SUPPORT INDIRECT Other
"B9D2 | HGNC:28636 | ciliopathy | MONDO:0005308 | AR | Moderate"
ClinGen curates B9D2 against the broad ciliopathy entity rather than against Meckel syndrome, and grades it Moderate. Recorded here because it is the weakest of this entry's numbered-locus genes on ClinGen's scale; the claim it supports is ciliopathy causation, not Meckel specifically.
B9D1 (Causative)
Gene: B9D1 hgnc:24123 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is B9D1 (hgnc:24123). hgnc:24123 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:21763481 SUPPORT Model Organism
"Mice lacking B9d1 displayed polydactyly, kidney cysts, ductal plate malformations, and abnormal patterning of the neural tube, concomitant with compromised ciliogenesis, ciliary protein localization, and Hedgehog (Hh) signal transduction."
Loss of B9d1 causes MKS-like phenotypes with ciliary dysfunction in model organisms.
PMID:40933483 SUPPORT Human Clinical
"Compound heterozygous missense and intronic variants in B9D1 contribute to a recurrent Meckel syndrome pedigree."
This case report identifies pathogenic B9D1 variants in a recurrent MKS pedigree.
CEP290 (Causative)
Gene: CEP290 hgnc:29021 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CEP290 (hgnc:29021). hgnc:29021 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:17705300 SUPPORT Human Clinical
"Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome."
This study identifies CEP290 loss-of-function mutations as a cause of Meckel-Gruber syndrome.
PMID:35352487 SUPPORT Human Clinical
"compound heterozygous mutations of CEP290 c.3175dup and CEP290 c.1201dup were detected through WES."
Prenatal case report identifies compound heterozygous CEP290 variants in suspected MKS.
PMID:34981460 SUPPORT Human Clinical
"Whole exome sequencing identified a compound heterozygous of two novel variants of CEP290 and a heterozygous of a novel variant of CC2D2A."
Case series reports novel CEP290 variants in MKS fetuses.
RPGRIP1L (Causative)
Gene: RPGRIP1L hgnc:29168 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPGRIP1L (hgnc:29168). hgnc:29168 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:17558409 SUPPORT Human Clinical
"we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS"
This study reports RPGRIP1L mutations in Meckel syndrome.
NPHP3 (Causative)
Gene: NPHP3 hgnc:7907 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NPHP3 (hgnc:7907). hgnc:7907 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:18371931 SUPPORT Human Clinical
"Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia."
This study links NPHP3 loss of function to a Meckel-Gruber-like syndrome in humans.
TCTN2 (Causative)
Gene: TCTN2 hgnc:25774 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TCTN2 (hgnc:25774). hgnc:25774 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:21462283 SUPPORT Human Clinical
"A TCTN2 mutation defines a novel Meckel Gruber syndrome locus."
This report identifies TCTN2 (MKS8) as a Meckel syndrome locus.
TMEM237 (Causative)
Gene: TMEM237 hgnc:14432 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TMEM237 (hgnc:14432). hgnc:14432 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:26729329 SUPPORT Human Clinical
"These analyses identified a putative intragenic AHI1 deletion that included three exons spanning at least 3.4 kb and an intergenic MPP4 to TMEM237 deletion that included exons spanning at least 21.5 kb."
CNV analysis in a MKS/JBTS referral cohort identified a TMEM237 deletion consistent with MKS involvement.
TMEM107 (Causative)
Gene: TMEM107 hgnc:28128 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TMEM107 (hgnc:28128). hgnc:28128 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:26123494 SUPPORT Human Clinical
"This study shows that known MKS loci account for the overwhelming majority of MKS cases but additional loci exist including MKS13 caused by TMEM107 mutation."
This study defines TMEM107 mutations as a Meckel syndrome locus (MKS13).
TXNDC15 (Causative)
Gene: TXNDC15 hgnc:20652 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TXNDC15 (hgnc:20652). hgnc:20652 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
PMID:31411728 SUPPORT Human Clinical
"We describe the second family with MKS due to a homozygous variant in B9D2 and fifth family with bi-allelic variant in TXNDC15."
This study validates MKS causation by biallelic TXNDC15 variants.
PMID:38156946 SUPPORT Human Clinical
"We report the case of a homozygous mutation in the TXNDC15 gene, causing MKS14 in the Chinese population."
Case report identifies a homozygous TXNDC15 mutation causing MKS14.
PMID:39304719 SUPPORT Human Clinical
"Biallelic TXNDC15 variants have been reported in six individuals of Meckel syndrome (MKS) with perinatal lethal phenotypes"
This report summarizes prior MKS cases with biallelic TXNDC15 variants, supporting causation.
+ 2 more references
TMEM17 (Causative)
Gene: TMEM17 hgnc:26623 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TMEM17 (hgnc:26623). hgnc:26623 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:40841990 SUPPORT Human Clinical
"we report two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts, in whom exome sequencing identified a founder homozygous missense variant (Arg94Trp) in TMEM17"
Case report expands TMEM17-associated phenotypes to include MKS.
KIF7 (Modifier)
Gene: KIF7 hgnc:30497 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KIF7 (hgnc:30497). hgnc:30497 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER variant_origin: GERMLINE
Show evidence (1 reference)
PMID:21552264 SUPPORT Human Clinical
"KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function."
This study suggests KIF7 variants can contribute to ciliopathy phenotypes, supporting a modifier role within the MKS/JBTS spectrum.
KIF14 (Causative)
Gene: KIF14 hgnc:19181 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KIF14 (hgnc:19181). hgnc:19181 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:24128419 SUPPORT Human Clinical
"We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype."
Segregating biallelic truncating KIF14 variants in the family that defined this entity.
PMID:24128419 SUPPORT Human Clinical
"We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14."
The authors' own summary of the gene-disease claim, and of the fact that they treated it as a new disorder rather than as Meckel syndrome.
💊

Medical Actions

4
Occipital encephalocele repair
Action: surgical repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical repair, annotated with Surgical Procedure (NCIT:C15329), qualified as surgical procedure excision. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Surgical excision/repair of occipital encephalocele or meningocele in MKS.
Show evidence (1 reference)
PMID:38459147 SUPPORT Human Clinical
"The study included 10 newborns with MKS associated with occipital encephalocele or meningocele, all of whom underwent surgical repair of the occipital sac."
Systematic review documents surgical repair of occipital encephalocele/meningocele in MKS.
Cerebrospinal fluid shunting for hydrocephalus
Action: surgical repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical repair, annotated with Surgical Procedure (NCIT:C15329), qualified as surgical procedure shunt device. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Surgical CSF diversion for hydrocephalus associated with MKS.
Show evidence (1 reference)
PMID:38459147 SUPPORT Human Clinical
"40% required shunting for hydrocephalus."
The systematic review reports shunting for hydrocephalus in MKS cases.
Cranial decompression
Action: surgical repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical repair, annotated with Surgical Procedure (NCIT:C15329), qualified as surgical procedure excision. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Acute cranial decompression reported in MKS with craniocephalic disproportion.
Show evidence (1 reference)
PMID:22134259 SUPPORT Human Clinical
"Acute cranial decompression in Meckel-Gruber syndrome and slit-ventricle syndrome with craniocephalic disproportion."
This report describes cranial decompression in the context of Meckel-Gruber syndrome.
Mutation-specific exon skipping therapy (proposed)
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238), qualified as has participant CC2D2A. NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Platform: Gene therapy
Proposed therapeutic exon-skipping strategies for CC2D2A-related MKS.
Show evidence (1 reference)
PMID:33486889 SUPPORT Human Clinical
"CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches."
Review proposes exon skipping as a potential therapy for CC2D2A-associated MKS.
📊

Prevalence

1
European births (EUROCAT)
Birth Prevalence 2.6 per 100,000 1–9 per 100,000 (births)
Mean prevalence across registries with good ascertainment (1990-2011).
Show evidence (1 reference)
PMID:25182137 SUPPORT Human Clinical
"The mean prevalence was 2.6 per 100,000 births in a subset of registries with good ascertainment."
This population-based study provides a prevalence estimate for MKS.
🔀

Differential Diagnoses

5

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

Trisomy 13 (Patau syndrome) MONDO:0018068
Overlapping Features Chromosomal aneuploidy with overlapping malformations that can mimic MKS.
Distinguishing Features
  • Holoprosencephaly or other midline CNS anomalies favor trisomy 13 over MKS.
Show evidence (2 references)
PMID:29479449 SUPPORT Human Clinical
"The differential diagnosis of MGS includes trisomy 13, trisomy 18, Joubert syndrome, Bardet–Biedl syndrome and Smith–Lemli–Opitz syndrome."
This case report lists trisomy 13 as a key differential diagnosis for MKS.
PMID:29479449 SUPPORT Human Clinical
"Trisomy 13 is the most likely syndrome to be confused with MGS. Enlarged kidneys, severe oligohydramnios and the presence of an occipital cephalocele favours the diagnosis of MGS, whereas holoprosencephaly or other midline CNS anomalies favors trisomy 13"
The report provides distinguishing CNS features that favor trisomy 13 over MKS.
Trisomy 18 (Edwards syndrome) MONDO:0018071
Overlapping Features Chromosomal aneuploidy with overlapping congenital anomalies that must be distinguished from MKS.
Show evidence (1 reference)
PMID:29479449 SUPPORT Human Clinical
"The differential diagnosis of MGS includes trisomy 13, trisomy 18, Joubert syndrome, Bardet–Biedl syndrome and Smith–Lemli–Opitz syndrome."
This case report lists trisomy 18 as a differential diagnosis for MKS.
Joubert syndrome MONDO:0018772
Overlapping Features Related ciliopathy with overlapping developmental anomalies and shared genetic spectrum.
Show evidence (1 reference)
PMID:29479449 SUPPORT Human Clinical
"The differential diagnosis of MGS includes trisomy 13, trisomy 18, Joubert syndrome, Bardet–Biedl syndrome and Smith–Lemli–Opitz syndrome."
This case report lists Joubert syndrome in the differential diagnosis of MKS.
Bardet-Biedl syndrome MONDO:0015229
Overlapping Features Ciliopathy with overlapping polydactyly and renal findings that requires differentiation from MKS.
Show evidence (1 reference)
PMID:29479449 SUPPORT Human Clinical
"The differential diagnosis of MGS includes trisomy 13, trisomy 18, Joubert syndrome, Bardet–Biedl syndrome and Smith–Lemli–Opitz syndrome."
This case report lists Bardet-Biedl syndrome as a differential diagnosis for MKS.
Smith-Lemli-Opitz syndrome MONDO:0010035
Overlapping Features Cholesterol biosynthesis disorder with overlapping malformations that can resemble MKS.
Show evidence (1 reference)
PMID:29479449 SUPPORT Human Clinical
"The differential diagnosis of MGS includes trisomy 13, trisomy 18, Joubert syndrome, Bardet–Biedl syndrome and Smith–Lemli–Opitz syndrome."
This case report lists Smith-Lemli-Opitz syndrome as a differential diagnosis for MKS.
🔬

Clinical Trials

1
NCT01401998 NOT_APPLICABLE
Observational translational resource for hepato/renal fibrocystic diseases, including Meckel-Gruber syndrome, collecting clinical data and biospecimens.
Show evidence (2 references)
clinicaltrials:NCT01401998 SUPPORT
"Hepato-renal fibrocystic diseases (HRFD) is a term developed that encompasses rare diseases such as Autosomal Recessive Polycystic Kidney Disease (ARPKD), and other diseases with common features (Joubert syndrome, Bardet Biedl syndrome, Meckel-Gruber syndrome, congenital hepatic fibrosis (CHF),..."
The trial encompasses Meckel-Gruber syndrome within a hepato-renal fibrocystic disease registry.
clinicaltrials:NCT01401998 SUPPORT
"This study aims to build a registry of a clinical database (medical health information), a mutational database (genetic information) and an educational resource about HRFD"
The trial is structured as a translational resource and registry.
{ }

Source YAML

click to show 
name: Meckel Syndrome
creation_date: '2026-02-02T23:29:30Z'
category: Genetic
description: >-
  Meckel syndrome (Meckel-Gruber syndrome) is a rare, lethal ciliopathy with a
  classic triad of occipital encephalocele, cystic renal dysplasia, and postaxial
  polydactyly, often with multiorgan involvement.
disease_term:
  preferred_term: Meckel syndrome
  term:
    id: MONDO:0018921
    label: Meckel syndrome
parents:
- Ciliopathy
has_subtypes:
- name: Meckel syndrome, type 1
  subtype_term:
    preferred_term: Meckel syndrome, type 1
    term:
      id: MONDO:0009571
      label: Meckel syndrome, type 1
  description: >-
    The founding Meckel locus. The MKS1 product localizes to the base of the
    cilium and is required for ciliogenesis.
  genes:
  - preferred_term: MKS1
    term:
      id: hgnc:7121
      label: MKS1
  evidence:
  - reference: PMID:23349226
    reference_title: "Mutations in TMEM231 cause Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
    explanation: >-
      Maps each numbered MKS locus to its gene. Quoted from this paper's
      introduction, where it restates the established locus series rather than
      reporting the authors' own finding.
  - reference: PMID:19776033
    reference_title: "A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "The gene mutated in type 1 MKS encodes a protein associated with the base of the cilium in vertebrates and nematodes."
    explanation: >-
      Ties the type 1 locus to a ciliary base protein, which is the claim this
      row's description makes.
- name: Meckel syndrome, type 2
  subtype_term:
    preferred_term: Meckel syndrome, type 2
    term:
      id: MONDO:0011296
      label: Meckel syndrome, type 2
  description: >-
    The MKS2 locus. TMEM216 encodes a tetraspan transmembrane protein, and the
    MKS2 and Joubert JBTS2 loci are allelic.
  genes:
  - preferred_term: TMEM216
    term:
      id: hgnc:25018
      label: TMEM216
  evidence:
  - reference: PMID:23349226
    reference_title: "Mutations in TMEM231 cause Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
    explanation: >-
      Maps each numbered MKS locus to its gene. Quoted from this paper's
      introduction, where it restates the established locus series rather than
      reporting the authors' own finding.
  - reference: PMID:20512146
    reference_title: "Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein."
    explanation: >-
      Assigns the MKS2 locus to TMEM216 explicitly, and records its allelism with
      the Joubert JBTS2 locus.
- name: Meckel syndrome, type 3
  subtype_term:
    preferred_term: Meckel syndrome, type 3
    term:
      id: MONDO:0011821
      label: Meckel syndrome, type 3
  description: >-
    TMEM67 encodes meckelin, an integral protein of the renal epithelial cell and
    of the primary cilium membrane.
  genes:
  - preferred_term: TMEM67
    term:
      id: hgnc:28396
      label: TMEM67
  evidence:
  - reference: PMID:23349226
    reference_title: "Mutations in TMEM231 cause Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
    explanation: >-
      Maps each numbered MKS locus to its gene. Quoted from this paper's
      introduction, where it restates the established locus series rather than
      reporting the authors' own finding.
  - reference: PMID:19211713
    reference_title: "A mouse model for Meckel syndrome type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "In humans, the underlying mutated gene, TMEM67, encodes transmembrane protein 67, also called meckelin (OMIM 609884), which is an integral protein of the renal epithelial cell and membrane of the primary cilium."
    explanation: >-
      Names TMEM67/meckelin as the type 3 gene and gives the protein description
      used in this row.
- name: Meckel syndrome, type 4
  subtype_term:
    preferred_term: Meckel syndrome, type 4
    term:
      id: MONDO:0012626
      label: Meckel syndrome, type 4
  description: >-
    CEP290 encodes a centrosomal protein; loss-of-function alleles give the
    lethal Meckel end of a wide CEP290 allelic spectrum.
  genes:
  - preferred_term: CEP290
    term:
      id: hgnc:29021
      label: CEP290
  evidence:
  - reference: PMID:23349226
    reference_title: "Mutations in TMEM231 cause Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
    explanation: >-
      Maps each numbered MKS locus to its gene. Quoted from this paper's
      introduction, where it restates the established locus series rather than
      reporting the authors' own finding.
  - reference: PMID:17705300
    reference_title: "Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of the CEP290 gene located in the minimal critical region showed a homozygous 1-bp deletion supposed to lead to loss of function of the encoded centrosomal protein CEP290/nephrocystin-6."
    explanation: >-
      The positional-cloning result that mapped this Meckel locus to CEP290 and
      identified a loss-of-function allele in it.
- name: Meckel syndrome, type 5
  subtype_term:
    preferred_term: Meckel syndrome, type 5
    term:
      id: MONDO:0012695
      label: Meckel syndrome, type 5
  description: >-
    RPGRIP1L is mutated in both cerebello-oculo-renal syndrome (Joubert syndrome
    type B) and Meckel syndrome, the same gene spanning both severities.
  genes:
  - preferred_term: RPGRIP1L
    term:
      id: hgnc:29168
      label: RPGRIP1L
  evidence:
  - reference: PMID:23349226
    reference_title: "Mutations in TMEM231 cause Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
    explanation: >-
      Maps each numbered MKS locus to its gene. Quoted from this paper's
      introduction, where it restates the established locus series rather than
      reporting the authors' own finding.
  - reference: PMID:17558409
    reference_title: "The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS"
    explanation: >-
      Reports RPGRIP1L lesions in Meckel syndrome as well as in the milder
      cerebello-oculo-renal phenotype.
- name: Meckel syndrome, type 6
  subtype_term:
    preferred_term: Meckel syndrome, type 6
    term:
      id: MONDO:0012848
      label: Meckel syndrome, type 6
  description: >-
    CC2D2A was the fifth Meckel gene identified and defines the sixth locus.
  genes:
  - preferred_term: CC2D2A
    term:
      id: hgnc:29253
      label: CC2D2A
  evidence:
  - reference: PMID:23349226
    reference_title: "Mutations in TMEM231 cause Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
    explanation: >-
      Maps each numbered MKS locus to its gene. Quoted from this paper's
      introduction, where it restates the established locus series rather than
      reporting the authors' own finding.
  - reference: PMID:18513680
    reference_title: "Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified the sixth locus and the fifth gene, CC2D2A (MKS6), behind MKS."
    explanation: >-
      Names CC2D2A as MKS6 explicitly, which is the claim this row makes.
- name: Meckel syndrome, type 8
  subtype_term:
    preferred_term: Meckel syndrome, type 8
    term:
      id: MONDO:0013482
      label: Meckel syndrome, type 8
  description: >-
    The MKS8 locus, mapped to TCTN2 in a multiplex consanguineous family.
  genes:
  - preferred_term: TCTN2
    term:
      id: hgnc:25774
      label: TCTN2
  evidence:
  - reference: PMID:23349226
    reference_title: "Mutations in TMEM231 cause Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
    explanation: >-
      Maps each numbered MKS locus to its gene. Quoted from this paper's
      introduction, where it restates the established locus series rather than
      reporting the authors' own finding.
  - reference: PMID:21462283
    reference_title: "A TCTN2 mutation defines a novel Meckel Gruber syndrome locus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this article, we describe the identification of a novel MKS locus MKS8 that we map to TCTN2, in a multiplex consanguineous family."
    explanation: >-
      Names MKS8 and maps it to TCTN2 explicitly, which is the claim this row makes.
- name: Meckel syndrome, type 9
  subtype_term:
    preferred_term: Meckel syndrome, type 9
    term:
      id: MONDO:0013630
      label: Meckel syndrome, type 9
  description: >-
    B9D1 is a component of the ciliary B9 protein complex whose disruption causes
    Meckel syndrome.
  genes:
  - preferred_term: B9D1
    term:
      id: hgnc:24123
      label: B9D1
  evidence:
  - reference: PMID:23349226
    reference_title: "Mutations in TMEM231 cause Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
    explanation: >-
      Maps each numbered MKS locus to its gene. Quoted from this paper's
      introduction, where it restates the established locus series rather than
      reporting the authors' own finding.
  - reference: PMID:40933483
    reference_title: "Compound heterozygous missense and intronic variants in B9D1 contribute to a recurrent Meckel syndrome pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two compound heterozygous variants, c.341G>T (p.R114L) and c.405-308_405-304del, were identified in both probands, each inherited from one unaffected parent."
    explanation: >-
      Human pedigree evidence for biallelic B9D1 variants in two fetuses with the
      Meckel phenotype.
- name: Meckel syndrome, type 10
  subtype_term:
    preferred_term: Meckel syndrome, type 10
    term:
      id: MONDO:0013609
      label: Meckel syndrome, type 10
  description: >-
    B9D2 is a further component of the same ciliary B9 protein complex, disrupted
    in Meckel syndrome alongside B9D1.
  genes:
  - preferred_term: B9D2
    term:
      id: hgnc:28636
      label: B9D2
  evidence:
  - reference: PMID:23349226
    reference_title: "Mutations in TMEM231 cause Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
    explanation: >-
      Maps each numbered MKS locus to its gene. Quoted from this paper's
      introduction, where it restates the established locus series rather than
      reporting the authors' own finding.
  - reference: PMID:21763481
    reference_title: "Disruption of a ciliary B9 protein complex causes Meckel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous c.301A>C (p.Ser101Arg) B9D2 mutation that segregates with MKS"
    explanation: >-
      A pathogenic B9D2 variant segregating with Meckel syndrome.
- name: Meckel syndrome, type 11
  subtype_term:
    preferred_term: Meckel syndrome, type 11
    term:
      id: MONDO:0014164
      label: Meckel syndrome, type 11
  description: >-
    TMEM231 was identified as a Meckel locus in two consanguineous families in
    which every previously known MKS gene had been excluded. It forms a
    transition-zone complex with the B9 proteins and CC2D2A, and the same gene
    also gives Joubert syndrome.
  genes:
  - preferred_term: TMEM231
    term:
      id: hgnc:37234
      label: TMEM231
  evidence:
  - reference: PMID:23349226
    reference_title: "Mutations in TMEM231 cause Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TMEM231 represents a novel MKS locus."
    explanation: >-
      The report that established TMEM231 as a Meckel locus, in two consanguineous
      families in which every previously known MKS gene had been excluded.
  - reference: PMID:37736303
    reference_title: "Identification of novel TMEM231 gene splice variants and pathological findings in a fetus with Meckel Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two splice site variants of TMEM231 (NM_001077418.2, c.583-1G>C and c.583-2_588delinsTCCTCCC) were identified in the proband, and the two variants have not been previously reported."
    explanation: >-
      Independent human pedigree confirming biallelic TMEM231 variants in Meckel
      syndrome.
- name: Meckel syndrome 13
  subtype_term:
    preferred_term: Meckel syndrome 13
    term:
      id: MONDO:0033044
      label: Meckel syndrome 13
  description: >-
    TMEM107 defines MKS13, one of the loci found after the common Meckel genes
    were excluded.
  genes:
  - preferred_term: TMEM107
    term:
      id: hgnc:28128
      label: TMEM107
  evidence:
  - reference: PMID:26123494
    reference_title: "Identification of a novel MKS locus defined by TMEM107 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study shows that known MKS loci account for the overwhelming majority of MKS cases but additional loci exist including MKS13 caused by TMEM107 mutation."
    explanation: >-
      Names MKS13 and its gene explicitly, which is the claim this row makes.
- name: Meckel syndrome 14
  subtype_term:
    preferred_term: meckel syndrome 14
    term:
      id: MONDO:0030819
      label: meckel syndrome 14
  description: >-
    TXNDC15 defines MKS14. Biallelic variants have been reported in perinatally
    lethal Meckel phenotypes, and the same gene also appears in Joubert-range
    presentations.
  genes:
  - preferred_term: TXNDC15
    term:
      id: hgnc:20652
      label: TXNDC15
  evidence:
  - reference: PMID:38156946
    reference_title: "Novel homozygous mutations in TXNDC15 causing Meckel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of a homozygous mutation in the TXNDC15 gene, causing MKS14 in the Chinese population."
    explanation: >-
      Names MKS14 and its gene explicitly, which is the claim this row makes.
  - reference: PMID:41518077
    reference_title: "CRISPR-Cas9-Generated TXNDC15 c.560delA Homozygous Mouse Model Exhibits Meckel-Gruber Syndrome Phenotype."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous Txndc15mt/mt embryos displayed the complete MKS phenotype-fetal lethality, exencephaly, omphalocele, post-axial polydactyly, and polycystic kidneys-together with markedly reduced TXNDC15 protein in brain, liver, and kidney."
    explanation: >-
      A mouse model reproducing the Meckel phenotype on TXNDC15 loss, supporting
      causation rather than association.
  - reference: PMID:39304719
    reference_title: "Biallelic TXNDC15 variants associated with Joubert syndrome-related molar tooth sign and forebrain malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Biallelic TXNDC15 variants have been reported in six individuals of Meckel syndrome (MKS) with perinatal lethal phenotypes"
    explanation: >-
      Supports the perinatally lethal Meckel presentations recorded in this row's
      description, and the same report places TXNDC15 in the Joubert range too.
- name: NPHP3-related Meckel-like syndrome
  subtype_term:
    preferred_term: NPHP3-related Meckel-like syndrome
    term:
      id: MONDO:0009966
      label: NPHP3-related Meckel-like syndrome
  description: >-
    The MKS7 locus. MONDO names this row for its gene rather than by number, and
    "Meckel-like" is the source literature's own hedge: complete loss of
    nephrocystin-3 gives embryonic lethality with a Meckel-Gruber-like picture
    plus situs inversus and renal-hepatic-pancreatic dysplasia, while hypomorphic
    NPHP3 alleles give isolated nephronophthisis. It is curated here as a subtype
    rather than in the nephronophthisis entry because the lethal end is the Meckel
    phenotype.
  genes:
  - preferred_term: NPHP3
    term:
      id: hgnc:7907
      label: NPHP3
  evidence:
  - reference: PMID:18371931
    reference_title: "Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We demonstrate that the pcy mutation generates a hypomorphic Nphp3 allele that is responsible for the cystic kidney disease phenotype, whereas complete loss of Nphp3 function results in situs inversus, congenital heart defects, and embryonic lethality in mice."
    explanation: >-
      The allelic-series result behind this row: hypomorphic NPHP3 alleles give
      cystic kidney disease while complete loss gives the lethal embryonic
      phenotype. Demonstrated in mouse; the paper also reports the human spectrum.
  - reference: PMID:23349226
    reference_title: "Mutations in TMEM231 cause Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Twelve genes are known to cause this disorder when mutated: MKS1, TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9), B9D2 (MKS10), TMEM237, and C5orf42."
    explanation: >-
      Assigns NPHP3 the MKS7 locus number. Quoted from this paper's introduction,
      where it restates the established locus series.
  review_notes: >-
    Added in the wiring-013 genetics pass. NPHP3 was already curated in this
    entry's `genetic:` block and bound to a pathophysiology node, but had no
    subtype row, so MONDO:0009966 was uncovered by this entry.
- name: Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome
  display_name: KIF14-related lethal fetal ciliopathy (OMIM MKS12)
  subtype_term:
    preferred_term: lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome
    term:
      id: MONDO:0014552
      label: lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome
  description: >-
    The weakest row in this series, and deliberately labelled with MONDO's name
    rather than as "Meckel syndrome, type 12". OMIM numbers this entity MKS12 and
    MONDO classifies it under Meckel syndrome, but the report that defined it
    described an undescribed lethal fetal syndrome - intrauterine growth
    restriction, severe microcephaly, renal cystic dysplasia or agenesis, complex
    brain and genitourinary malformations - that was compatible with a ciliopathy
    but "not diagnostic of any known condition", and the classic occipital
    encephalocele plus postaxial polydactyly triad is not what it reports. A
    separate prenatal series does place KIF14 in a Meckel diagnosis, but in trans
    with a TMEM67 deletion and read by its authors as digenic.
  genes:
  - preferred_term: KIF14
    term:
      id: hgnc:19181
      label: KIF14
  evidence:
  - reference: PMID:24128419
    reference_title: "Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype."
    explanation: >-
      Establishes biallelic KIF14 truncating variants as the cause of this entity.
  - reference: PMID:24128419
    reference_title: "Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition."
    explanation: >-
      The authors' own statement that the phenotype is not that of a recognized
      condition, which is the basis for the nosological caveat in this row.
  - reference: PMID:34821546
    reference_title: "Meckel Gruber and Joubert Syndrome Diagnosed Prenatally: Allelism between the Two Ciliopathies, Complexities of Mutation Types and Digenic Inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Multiexon deletion in TMEM67 and KIF14 present in trans was identified in the third case (Meckel syndrome), likely resulting in digenic inheritance."
    explanation: >-
      The only cached report placing KIF14 in a case diagnosed as Meckel syndrome,
      and it is a digenic reading with a TMEM67 deletion, so it supports the link
      only indirectly.
  review_notes: >-
    Added in the wiring-013 genetics pass, with the caveat above. MONDO:0014552
    is_a MONDO:0018921 Meckel syndrome, so it is inside this entry's anchor, but
    dismech should not silently restate OMIM's MKS12 numbering as though the
    defining report had diagnosed Meckel syndrome. If a later series establishes
    the classic triad in KIF14 patients, promote this row's wording.
notes: >-
  No GeneReviews chapter exists for Meckel syndrome. `just check-genereviews`
  reports NO_CHAPTER, and re-running the query it reads (`grep -i "meckel"
  cache/bookshelf/genereviews.csv`, snapshot 2026-09-10) returns nothing. The
  nearest chapters are for the allelic ciliopathies - NBK1325 "Joubert Syndrome"
  and NBK368475 "Nephronophthisis-Related Ciliopathies" - which cover different
  diseases, so the per-locus primary reports cited below are the baseline used
  instead.
synonyms:
- Meckel-Gruber syndrome
- Meckel-Gruber syndrome (MKS)
- MKS
classifications:
  isds_skeletal_category:
  - classification_value: polydactyly_syndactyly_triphalangism
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019 revision
      (Mortier et al., PMID:31633310), Table 1 group 41
      "Polydactyly-Syndactyly-Triphalangism group"; listed as "Meckel syndrome types
      1-6".
prevalence:
- population: European births (EUROCAT)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.6
  percentage: 0.0026
  notes: Mean prevalence across registries with good ascertainment (1990-2011).
  evidence:
  - reference: PMID:25182137
    reference_title: "Meckel-Gruber Syndrome: a population-based study on prevalence, prenatal diagnosis, clinical features, and survival in Europe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean prevalence was 2.6 per 100,000 births in a subset of registries
      with good ascertainment."
    explanation: This population-based study provides a prevalence estimate for
      MKS.
inheritance:
- name: Autosomal recessive
  description: >-
    Meckel syndrome is inherited in an autosomal recessive pattern and sits on
    a ciliopathy spectrum with Joubert/related disorders, reflecting allelic
    series across shared ciliary genes.
  evidence:
  - reference: PMID:25182137
    reference_title: "Meckel-Gruber Syndrome: a population-based study on prevalence, prenatal diagnosis, clinical features, and survival in Europe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Meckel-Gruber Syndrome is a rare autosomal recessive lethal ciliopathy"
    explanation: This statement supports autosomal recessive inheritance of MKS.
  - reference: PMID:26729329
    reference_title: "Enhanced diagnostic yield in Meckel-Gruber and Joubert syndrome through exome sequencing supplemented with split-read mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two clinically and genetically heterogeneous neurodevelopmental conditions
      that define a phenotypic spectrum, with MKS at the severe end."
    explanation: This cohort study frames MKS and JBTS as a phenotypic spectrum,
      consistent with allelic series across ciliopathy genes.
- name: Digenic inheritance
  inheritance_term:
    preferred_term: Digenic inheritance
    term:
      id: HP:0010984
      label: Digenic inheritance
  description: >-
    Beyond classic autosomal recessive transmission, Meckel syndrome can show
    digenic inheritance across the shared ciliopathy gene set, with pathogenic
    variants in two different ciliary genes (in trans) contributing to the
    phenotype.
  evidence:
  - reference: PMID:34821546
    reference_title: "Meckel Gruber and Joubert Syndrome Diagnosed Prenatally: Allelism between the Two Ciliopathies, Complexities of Mutation Types and Digenic Inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multiexon deletion in TMEM67 and KIF14 present in trans was identified in
      the third case (Meckel syndrome), likely resulting in digenic inheritance.
    explanation: >-
      This prenatal case series documents variants in two ciliary genes (TMEM67
      and KIF14) in trans, consistent with digenic inheritance in Meckel
      syndrome.
pathophysiology:
- name: Primary cilium membrane protein dysfunction (TMEM67/meckelin)
  description: Pathogenic variants in TMEM67 disrupt primary cilium membrane
    components.
  genes:
  - preferred_term: TMEM67
    term:
      id: hgnc:28396
      label: TMEM67
  cellular_components:
  - preferred_term: primary cilium
    term:
      id: GO:0005929
      label: cilium
  evidence:
  - reference: PMID:19211713
    reference_title: "A mouse model for Meckel syndrome type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "In humans, the underlying mutated gene, TMEM67, encodes transmembrane protein 67, also called meckelin (OMIM 609884), which is an integral protein of the renal epithelial cell and membrane of the primary cilium."
    explanation: >-
      TMEM67/meckelin is an integral primary cilium membrane protein implicated in
      MKS3. Regraded from MODEL_ORGANISM in the wiring-013 pass: the sentence
      states the human genetics, quoted from this mouse-model paper's background.
- name: Ciliary base protein dysfunction (MKS1)
  description: Loss of MKS1 perturbs proteins associated with the ciliary
    base/basal body.
  genes:
  - preferred_term: MKS1
    term:
      id: hgnc:7121
      label: MKS1
  cellular_components:
  - preferred_term: ciliary basal body
    term:
      id: GO:0036064
      label: ciliary basal body
  - preferred_term: ciliary base
    term:
      id: GO:0097546
      label: ciliary base
  evidence:
  - reference: PMID:19776033
    reference_title: "A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The gene mutated in type 1 MKS encodes a protein associated with the
      base of the cilium in vertebrates and nematodes."
    explanation: MKS1 encodes a protein associated with the ciliary base,
      supporting ciliary base dysfunction in MKS.
- name: Basal body localization without proper ciliogenesis
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  description: Basal bodies localize apically, yet cilia fail to form in many
    tissues.
  genes:
  - preferred_term: TMEM216
    term:
      id: hgnc:25018
      label: TMEM216
  - preferred_term: TMEM231
    term:
      id: hgnc:37234
      label: TMEM231
  - preferred_term: TCTN2
    term:
      id: hgnc:25774
      label: TCTN2
  - preferred_term: TMEM237
    term:
      id: hgnc:14432
      label: TMEM237
  - preferred_term: TMEM107
    term:
      id: hgnc:28128
      label: TMEM107
  - preferred_term: TXNDC15
    term:
      id: hgnc:20652
      label: TXNDC15
  - preferred_term: RPGRIP1L
    term:
      id: hgnc:29168
      label: RPGRIP1L
  - preferred_term: CEP290
    term:
      id: hgnc:29021
      label: CEP290
  cellular_components:
  - preferred_term: primary cilium
    term:
      id: GO:0005929
      label: cilium
  - preferred_term: ciliary basal body
    term:
      id: GO:0036064
      label: ciliary basal body
  - preferred_term: ciliary base
    term:
      id: GO:0097546
      label: ciliary base
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:19776033
    reference_title: "A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "loss of Mks1 in vivo does not interfere with apical localization of
      epithelial basal bodies but rather leads to defective cilia formation in most,
      but not all, tissues."
    explanation: Basal body localization is preserved while ciliogenesis fails
      in Mks1-deficient tissues.
- name: Defective cilia formation across multiple tissues
  description: Primary cilia fail to form in many tissues in vivo.
  cellular_components:
  - preferred_term: primary cilium
    term:
      id: GO:0005929
      label: cilium
  - preferred_term: ciliary basal body
    term:
      id: GO:0036064
      label: ciliary basal body
  - preferred_term: ciliary base
    term:
      id: GO:0097546
      label: ciliary base
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:19776033
    reference_title: "A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "loss of Mks1 in vivo does not interfere with apical localization of
      epithelial basal bodies but rather leads to defective cilia formation in most,
      but not all, tissues."
    explanation: Mks1 loss leads to defective cilia formation across tissues in
      vivo.
- name: Loss of primary cilia (failed ciliogenesis)
  description: Primary cilia are absent, reflecting failed ciliogenesis.
  genes:
  - preferred_term: CC2D2A
    term:
      id: hgnc:29253
      label: CC2D2A
  cellular_components:
  - preferred_term: primary cilium
    term:
      id: GO:0005929
      label: cilium
  - preferred_term: ciliary basal body
    term:
      id: GO:0036064
      label: ciliary basal body
  - preferred_term: ciliary base
    term:
      id: GO:0097546
      label: ciliary base
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:18513680
    reference_title: "Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunofluorescence staining of patient's fibroblast cells demonstrates
      that the cells lack cilia, providing evidence for the critical role of CC2D2A
      in cilia formation."
    explanation: Patient fibroblasts lacking cilia link CC2D2A to cilia
      formation.
- name: Reduced axonemal microtubule posttranslational modifications
  description: Disruption of the B9-TMEM67 complex at the transition zone
    reduces axonemal microtubule modifications.
  genes:
  - preferred_term: B9D1
    term:
      id: hgnc:24123
      label: B9D1
  - preferred_term: B9D2
    term:
      id: hgnc:28636
      label: B9D2
  cellular_components:
  - preferred_term: primary cilium
    term:
      id: GO:0005929
      label: cilium
  - preferred_term: axoneme
    term:
      id: GO:0005930
      label: axoneme
  - preferred_term: ciliary basal body
    term:
      id: GO:0036064
      label: ciliary basal body
  - preferred_term: ciliary base
    term:
      id: GO:0097546
      label: ciliary base
  evidence:
  - reference: PMID:41165761
    reference_title: "Ciliopathy-related B9 protein complex regulates ciliary axonemal microtubule posttranslational modifications and initiation of ciliogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the B9 complex interacted with and anchored TMEM67 to the TZ membrane."
    explanation: Disruption of the B9-TMEM67 transition zone interaction
      underlies downstream axonemal defects.
  - reference: PMID:41165761
    reference_title: "Ciliopathy-related B9 protein complex regulates ciliary axonemal microtubule posttranslational modifications and initiation of ciliogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Disruption of the B9-TMEM67 complex reduced posttranslational modifications
      of axonemal microtubules due to deregulation of tubulin-modifying enzymes within
      cilia."
    explanation: B9 complex disruption impairs axonemal microtubule
      posttranslational modifications.
- name: Impaired initiation of ciliogenesis
  description: B9 proteins facilitate early ciliogenesis; disruption impairs
    initiation.
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:41165761
    reference_title: "Ciliopathy-related B9 protein complex regulates ciliary axonemal microtubule posttranslational modifications and initiation of ciliogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "B9 proteins localized to centrioles prior to ciliogenesis, where they
      facilitated the initiation of ciliogenesis."
    explanation: B9 proteins are required for initiating ciliogenesis.
- name: TMEM67 cleavage uncouples ciliogenesis and Wnt signaling
  description: Proteolytic cleavage of TMEM67 separates ciliary assembly from
    Wnt pathway activity.
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DYSREGULATED
  - preferred_term: Wnt signaling pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:40436881
    reference_title: "Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples
      Wnt signaling and ciliogenesis."
    explanation: TMEM67 cleavage separates Wnt signaling from ciliogenesis in
      MKS.
- name: TMEM17 loss disrupts Sonic Hedgehog signaling
  conforms_to: "ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction"
  description: TMEM17 dysfunction at the ciliary transition zone abrogates Sonic
    Hedgehog signaling.
  genes:
  - preferred_term: TMEM17
    term:
      id: hgnc:26623
      label: TMEM17
  biological_processes:
  - preferred_term: hedgehog signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:40841990
    reference_title: "Missense Variants in the Second Transmembrane Domain of TMEM17 Disrupt Its Stability and Function and Lead to a Wide Phenotypic Spectrum of Ciliopathies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our study reveals severe functional consequences, including TMEM17 destabilization
      and mislocalization, anomalies in cilium composition and function, and abrogation
      of Sonic Hedgehog signaling."
    explanation: TMEM17 variants disrupt ciliary function and abrogate SHH
      signaling.
- name: Altered Hedgehog signaling in neural tube patterning
  conforms_to: "ciliopathy_dysfunction#Cerebellar and CNS Malformation"
  description: Hedgehog signaling is altered during neural tube development.
  cellular_components:
  - preferred_term: primary cilium
    term:
      id: GO:0005929
      label: cilium
  locations:
  - preferred_term: neural tube
    term:
      id: UBERON:0001049
      label: neural tube
  biological_processes:
  - preferred_term: hedgehog signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:19776033
    reference_title: "A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Analysis of patterning in the neural tube and the limb demonstrates
      altered Hedgehog (Hh) pathway signaling underlies some MKS defects"
    explanation: Neural tube patterning defects in Mks1 mutants reflect altered
      Hedgehog signaling.
  - reference: PMID:34981460
    reference_title: "Three Novel Variants of CEP290 and CC2D2DA and a Link Between ZNF77 and SHH Signaling Pathway Are Found in Two Meckel-Gruber Syndrome Fetuses."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "HEK293T transfected with over-expression wildtype/mutated ZNF77 plasmid
      showed that SHH was increased in wildtype ZNF77 cells, while SHH and CC2D2A
      were increased in mutated ZNF77 cells."
    explanation: In vitro experiments from MKS cases link SHH signaling changes
      to MKS-associated genetic findings.
- name: Altered Hedgehog signaling in limb patterning
  description: Hedgehog signaling is altered during limb development.
  cellular_components:
  - preferred_term: primary cilium
    term:
      id: GO:0005929
      label: cilium
  biological_processes:
  - preferred_term: hedgehog signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:19776033
    reference_title: "A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Analysis of patterning in the neural tube and the limb demonstrates
      altered Hedgehog (Hh) pathway signaling underlies some MKS defects"
    explanation: Limb patterning defects in Mks1 mutants reflect altered
      Hedgehog signaling.
  - reference: PMID:34981460
    reference_title: "Three Novel Variants of CEP290 and CC2D2DA and a Link Between ZNF77 and SHH Signaling Pathway Are Found in Two Meckel-Gruber Syndrome Fetuses."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "HEK293T transfected with over-expression wildtype/mutated ZNF77 plasmid
      showed that SHH was increased in wildtype ZNF77 cells, while SHH and CC2D2A
      were increased in mutated ZNF77 cells."
    explanation: In vitro experiments from MKS cases link SHH signaling changes
      to MKS-associated genetic findings.
phenotypes:
- name: Occipital encephalocele
  category: Neurologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Occipital encephalocele
    term:
      id: HP:0002085
      label: Occipital encephalocele
  evidence:
  - reference: PMID:24082939
    reference_title: "Meckel-Gruber syndrome: A rare and lethal anomaly with review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Meckel-Gruber syndrome is a rare autosomal recessive lethal malformation
      characterized by typical manifestations of occipital encephalocele, bilateral
      polycystic kidneys and post axial polydactyly."
    explanation: This review lists occipital encephalocele in the classic triad.
  - reference: PMID:8725749
    reference_title: "The Meckel syndrome: report of two Japanese sibs and a review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both babies showed the classical triad of this conditions: occipital
      encephalocele, cystic kidneys, and postaxial polydactyly of all four limbs."
    explanation: A case report of two siblings documents occipital encephalocele
      in MKS.
  - reference: PMID:28374938
    reference_title: "Diagnostic use of computational retrotransposon detection: Successful definition of pathogenetic mechanism in a ciliopathy phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we document a boy with occipital encephalocele, post-axial polydactyly,
      and multicystic renal disease."
    explanation: A case report documents occipital encephalocele in MKS.
  - reference: PMID:38156946
    reference_title: "Novel homozygous mutations in TXNDC15 causing Meckel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Meckel syndrome (MKS) is the most severe form of an autosomal recessive
      ciliopathy and is clinically characterized by occipital encephalocele, severely
      polycystic kidneys, and postaxial polydactyly (toes)."
    explanation: Case report reiterates occipital encephalocele as part of the
      classic MKS triad.
  - reference: PMID:35352487
    reference_title: "Evaluation of novel compound variants of CEP290 in prenatally suspected case of Meckel syndrome through whole exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pregnancy was terminated due to occipital meningocele and enlarged
      cystic dysplastic kidney revealed by ultrasonography."
    explanation: Prenatal case report documents an occipital meningocele in
      suspected MKS.
  - reference: PMID:34821546
    reference_title: "Meckel Gruber and Joubert Syndrome Diagnosed Prenatally: Allelism between the Two Ciliopathies, Complexities of Mutation Types and Digenic Inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antenatally detected occipital encephalocele and polycystic kidneys
      are a common presentation of ciliopathies like Joubert syndrome and Meckel Gruber
      syndrome"
    explanation: Prenatal case series reports occipital encephalocele among
      common MKS presentations.
- name: Cystic renal dysplasia
  category: Renal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cystic renal dysplasia
    term:
      id: HP:0000800
      label: Cystic renal dysplasia
  evidence:
  - reference: PMID:24082939
    reference_title: "Meckel-Gruber syndrome: A rare and lethal anomaly with review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Meckel-Gruber syndrome is a rare autosomal recessive lethal malformation
      characterized by typical manifestations of occipital encephalocele, bilateral
      polycystic kidneys and post axial polydactyly."
    explanation: This review lists bilateral polycystic kidneys in the classic
      triad.
  - reference: PMID:8725749
    reference_title: "The Meckel syndrome: report of two Japanese sibs and a review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both babies showed the classical triad of this conditions: occipital
      encephalocele, cystic kidneys, and postaxial polydactyly of all four limbs."
    explanation: A case report of two siblings documents cystic kidneys in MKS.
  - reference: PMID:28374938
    reference_title: "Diagnostic use of computational retrotransposon detection: Successful definition of pathogenetic mechanism in a ciliopathy phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we document a boy with occipital encephalocele, post-axial polydactyly,
      and multicystic renal disease."
    explanation: A case report documents multicystic renal disease in MKS.
  - reference: PMID:38156946
    reference_title: "Novel homozygous mutations in TXNDC15 causing Meckel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Meckel syndrome (MKS) is the most severe form of an autosomal recessive
      ciliopathy and is clinically characterized by occipital encephalocele, severely
      polycystic kidneys, and postaxial polydactyly (toes)."
    explanation: Case report reiterates severely polycystic kidneys as part of
      the classic MKS triad.
  - reference: PMID:35352487
    reference_title: "Evaluation of novel compound variants of CEP290 in prenatally suspected case of Meckel syndrome through whole exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pregnancy was terminated due to occipital meningocele and enlarged
      cystic dysplastic kidney revealed by ultrasonography."
    explanation: Prenatal case report documents enlarged cystic dysplastic
      kidney in suspected MKS.
  - reference: PMID:34821546
    reference_title: "Meckel Gruber and Joubert Syndrome Diagnosed Prenatally: Allelism between the Two Ciliopathies, Complexities of Mutation Types and Digenic Inheritance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antenatally detected occipital encephalocele and polycystic kidneys
      are a common presentation of ciliopathies like Joubert syndrome and Meckel Gruber
      syndrome"
    explanation: Prenatal case series notes polycystic/enlarged kidneys as a
      common MKS presentation.
- name: Postaxial polydactyly
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Postaxial hand polydactyly
    term:
      id: HP:0001162
      label: Postaxial hand polydactyly
  evidence:
  - reference: PMID:24082939
    reference_title: "Meckel-Gruber syndrome: A rare and lethal anomaly with review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Meckel-Gruber syndrome is a rare autosomal recessive lethal malformation
      characterized by typical manifestations of occipital encephalocele, bilateral
      polycystic kidneys and post axial polydactyly."
    explanation: This review lists postaxial polydactyly in the classic triad.
  - reference: PMID:8725749
    reference_title: "The Meckel syndrome: report of two Japanese sibs and a review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both babies showed the classical triad of this conditions: occipital
      encephalocele, cystic kidneys, and postaxial polydactyly of all four limbs."
    explanation: A case report of two siblings documents postaxial polydactyly
      in MKS.
  - reference: PMID:28374938
    reference_title: "Diagnostic use of computational retrotransposon detection: Successful definition of pathogenetic mechanism in a ciliopathy phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we document a boy with occipital encephalocele, post-axial polydactyly,
      and multicystic renal disease."
    explanation: A case report documents post-axial polydactyly in MKS.
  - reference: PMID:38156946
    reference_title: "Novel homozygous mutations in TXNDC15 causing Meckel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Meckel syndrome (MKS) is the most severe form of an autosomal recessive
      ciliopathy and is clinically characterized by occipital encephalocele, severely
      polycystic kidneys, and postaxial polydactyly (toes)."
    explanation: Case report reiterates postaxial polydactyly as part of the
      classic MKS triad.
- name: Hepatic fibrosis
  category: Hepatic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  evidence:
  - reference: PMID:25182137
    reference_title: "Meckel-Gruber Syndrome: a population-based study on prevalence, prenatal diagnosis, clinical features, and survival in Europe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "frequent features include other central nervous system anomalies (51.4%),
      fibrotic/cystic changes of the liver (65.5% of cases with"
    explanation: This population-based study reports frequent hepatic
      fibrotic/cystic changes.
- name: Pulmonary hypoplasia
  category: Respiratory
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  evidence:
  - reference: PMID:18603929
    reference_title: "Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Death is mainly due to pulmonary hypoplasia."
    explanation: This case report links MKS lethality to pulmonary hypoplasia.
  - reference: PMID:39412385
    reference_title: "A Rare Case of Meckel-Gruber Syndrome with Congenital Intestinal Atresia and Abdominal Pseudocyst Clinic."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the fetus, which was found to have polyhydramnios, gastric dilatation,
      lung hypoplasia, and cystic formation with a diameter of 68*62mm in the abdomen"
    explanation: Case report documents lung hypoplasia in an MKS fetus.
treatments:
- name: Occipital encephalocele repair
  description: Surgical excision/repair of occipital encephalocele or
    meningocele in MKS.
  evidence:
  - reference: PMID:38459147
    reference_title: "Neurosurgical intervention for the Meckel-Gruber Syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study included 10 newborns with MKS associated with occipital encephalocele
      or meningocele, all of whom underwent surgical repair of the occipital sac."
    explanation: Systematic review documents surgical repair of occipital
      encephalocele/meningocele in MKS.
  treatment_term:
    preferred_term: surgical repair
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: surgical procedure
        term:
          id: NCIT:C15329
          label: Surgical Procedure
      value:
        preferred_term: excision
        term:
          id: NCIT:C15232
          label: Excision
- name: Cerebrospinal fluid shunting for hydrocephalus
  description: Surgical CSF diversion for hydrocephalus associated with MKS.
  evidence:
  - reference: PMID:38459147
    reference_title: "Neurosurgical intervention for the Meckel-Gruber Syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "40% required shunting for hydrocephalus."
    explanation: The systematic review reports shunting for hydrocephalus in MKS
      cases.
  treatment_term:
    preferred_term: surgical repair
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: surgical procedure
        term:
          id: NCIT:C15329
          label: Surgical Procedure
      value:
        preferred_term: shunt device
        term:
          id: NCIT:C50174
          label: Shunt Device
- name: Cranial decompression
  description: Acute cranial decompression reported in MKS with craniocephalic
    disproportion.
  evidence:
  - reference: PMID:22134259
    reference_title: "Acute cranial decompression in Meckel-Gruber syndrome and slit-ventricle syndrome with craniocephalic disproportion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute cranial decompression in Meckel-Gruber syndrome and slit-ventricle
      syndrome with craniocephalic disproportion."
    explanation: This report describes cranial decompression in the context of
      Meckel-Gruber syndrome.
  treatment_term:
    preferred_term: surgical repair
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: surgical procedure
        term:
          id: NCIT:C15329
          label: Surgical Procedure
      value:
        preferred_term: excision
        term:
          id: NCIT:C15232
          label: Excision
- name: Mutation-specific exon skipping therapy (proposed)
  description: Proposed therapeutic exon-skipping strategies for CC2D2A-related
    MKS.
  evidence:
  - reference: PMID:33486889
    reference_title: "Update of genetic variants in CEP120 and CC2D2A-With an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CC2D2A, but not CEP120, offers potential for therapeutic exon skipping
      approaches."
    explanation: Review proposes exon skipping as a potential therapy for
      CC2D2A-associated MKS.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: CC2D2A
        term:
          id: hgnc:29253
          label: CC2D2A
differential_diagnoses:
- name: Trisomy 13 (Patau syndrome)
  description: Chromosomal aneuploidy with overlapping malformations that can
    mimic MKS.
  distinguishing_features:
  - Holoprosencephaly or other midline CNS anomalies favor trisomy 13 over MKS.
  disease_term:
    preferred_term: trisomy 13
    term:
      id: MONDO:0018068
      label: trisomy 13
  evidence:
  - reference: PMID:29479449
    reference_title: "Meckel Gruber syndrome associated with anencephaly-an unusual reported case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The differential diagnosis of MGS includes trisomy 13, trisomy 18, Joubert
      syndrome, Bardet–Biedl syndrome and Smith–Lemli–Opitz syndrome."
    explanation: This case report lists trisomy 13 as a key differential
      diagnosis for MKS.
  - reference: PMID:29479449
    reference_title: "Meckel Gruber syndrome associated with anencephaly-an unusual reported case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Trisomy 13 is the most likely syndrome to be confused with MGS. Enlarged
      kidneys, severe oligohydramnios and the presence of an occipital cephalocele
      favours the diagnosis of MGS, whereas holoprosencephaly or other midline CNS
      anomalies favors trisomy 13"
    explanation: The report provides distinguishing CNS features that favor
      trisomy 13 over MKS.
- name: Trisomy 18 (Edwards syndrome)
  description: Chromosomal aneuploidy with overlapping congenital anomalies that
    must be distinguished from MKS.
  disease_term:
    preferred_term: trisomy 18
    term:
      id: MONDO:0018071
      label: trisomy 18
  evidence:
  - reference: PMID:29479449
    reference_title: "Meckel Gruber syndrome associated with anencephaly-an unusual reported case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The differential diagnosis of MGS includes trisomy 13, trisomy 18, Joubert
      syndrome, Bardet–Biedl syndrome and Smith–Lemli–Opitz syndrome."
    explanation: This case report lists trisomy 18 as a differential diagnosis
      for MKS.
- name: Joubert syndrome
  description: Related ciliopathy with overlapping developmental anomalies and
    shared genetic spectrum.
  disease_term:
    preferred_term: Joubert syndrome
    term:
      id: MONDO:0018772
      label: Joubert syndrome
  evidence:
  - reference: PMID:29479449
    reference_title: "Meckel Gruber syndrome associated with anencephaly-an unusual reported case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The differential diagnosis of MGS includes trisomy 13, trisomy 18, Joubert
      syndrome, Bardet–Biedl syndrome and Smith–Lemli–Opitz syndrome."
    explanation: This case report lists Joubert syndrome in the differential
      diagnosis of MKS.
- name: Bardet-Biedl syndrome
  description: Ciliopathy with overlapping polydactyly and renal findings that
    requires differentiation from MKS.
  disease_term:
    preferred_term: Bardet-Biedl syndrome
    term:
      id: MONDO:0015229
      label: Bardet-Biedl syndrome
  evidence:
  - reference: PMID:29479449
    reference_title: "Meckel Gruber syndrome associated with anencephaly-an unusual reported case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The differential diagnosis of MGS includes trisomy 13, trisomy 18, Joubert
      syndrome, Bardet–Biedl syndrome and Smith–Lemli–Opitz syndrome."
    explanation: This case report lists Bardet-Biedl syndrome as a differential
      diagnosis for MKS.
- name: Smith-Lemli-Opitz syndrome
  description: Cholesterol biosynthesis disorder with overlapping malformations
    that can resemble MKS.
  disease_term:
    preferred_term: Smith-Lemli-Opitz syndrome
    term:
      id: MONDO:0010035
      label: Smith-Lemli-Opitz syndrome
  evidence:
  - reference: PMID:29479449
    reference_title: "Meckel Gruber syndrome associated with anencephaly-an unusual reported case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The differential diagnosis of MGS includes trisomy 13, trisomy 18, Joubert
      syndrome, Bardet–Biedl syndrome and Smith–Lemli–Opitz syndrome."
    explanation: This case report lists Smith-Lemli-Opitz syndrome as a
      differential diagnosis for MKS.
genetic:
- name: MKS1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:19776033
    reference_title: "A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The gene mutated in type 1 MKS encodes a protein associated with the
      base of the cilium in vertebrates and nematodes."
    explanation: This mouse model study identifies the MKS1 gene underlying MKS
      type 1.
  gene_term:
    preferred_term: MKS1
    term:
      id: hgnc:7121
      label: MKS1
- name: TMEM67
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:19211713
    reference_title: "A mouse model for Meckel syndrome type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In humans, the underlying mutated gene, TMEM67, encodes transmembrane
      protein 67, also called meckelin (OMIM 609884), which is an integral protein
      of the renal epithelial cell and membrane of the primary cilium."
    explanation: This study identifies TMEM67 as the causal gene for MKS3.
  gene_term:
    preferred_term: TMEM67
    term:
      id: hgnc:28396
      label: TMEM67
- name: CC2D2A
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:18513680
    reference_title: "Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified the sixth locus and the fifth gene, CC2D2A (MKS6), behind
      MKS."
    explanation: This study identifies CC2D2A as a causative MKS gene (MKS6).
  - reference: PMID:28374938
    reference_title: "Diagnostic use of computational retrotransposon detection: Successful definition of pathogenetic mechanism in a ciliopathy phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A medical exome analysis detected a heterozygous frameshift mutation,
      c.4582_4583delCG p.(Arg1528Serfs*17) in CC2D2A in the maternally derived allele."
    explanation: This case report identifies pathogenic CC2D2A variants in MKS,
      including a frameshift allele.
  - reference: PMID:34981460
    reference_title: "Three Novel Variants of CEP290 and CC2D2DA and a Link Between ZNF77 and SHH Signaling Pathway Are Found in Two Meckel-Gruber Syndrome Fetuses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing identified a compound heterozygous of two novel
      variants of CEP290 and a heterozygous of a novel variant of CC2D2A."
    explanation: Case series reports a novel CC2D2A variant in MKS fetuses.
  gene_term:
    preferred_term: CC2D2A
    term:
      id: hgnc:29253
      label: CC2D2A
- name: TMEM216
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:20512146
    reference_title: "Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel
      and related syndromes."
    explanation: This study reports TMEM216 mutations causing Meckel syndrome.
  gene_term:
    preferred_term: TMEM216
    term:
      id: hgnc:25018
      label: TMEM216
- name: TMEM231
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:23349226
    reference_title: "Mutations in TMEM231 cause Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in TMEM231 cause Meckel-Gruber syndrome."
    explanation: This report identifies TMEM231 as a Meckel-Gruber syndrome
      locus.
  gene_term:
    preferred_term: TMEM231
    term:
      id: hgnc:37234
      label: TMEM231
- name: B9D2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:21763481
    reference_title: "Disruption of a ciliary B9 protein complex causes Meckel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous c.301A>C (p.Ser101Arg) B9D2 mutation that
      segregates with MKS"
    explanation: This study reports a pathogenic B9D2 mutation segregating with
      MKS.
  - reference: CGGV:assertion_ebe1140c-09cc-4d05-8886-5a78267afe65-2023-06-12T160000.000Z
    reference_title: "B9D2 / ciliopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "B9D2 | HGNC:28636 | ciliopathy | MONDO:0005308 | AR | Moderate"
    explanation: >-
      ClinGen curates B9D2 against the broad ciliopathy entity rather than against
      Meckel syndrome, and grades it Moderate. Recorded here because it is the
      weakest of this entry's numbered-locus genes on ClinGen's scale; the claim it
      supports is ciliopathy causation, not Meckel specifically.
  gene_term:
    preferred_term: B9D2
    term:
      id: hgnc:28636
      label: B9D2
- name: B9D1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:21763481
    reference_title: "Disruption of a ciliary B9 protein complex causes Meckel syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice lacking B9d1 displayed polydactyly, kidney cysts, ductal plate
      malformations, and abnormal patterning of the neural tube, concomitant with
      compromised ciliogenesis, ciliary protein localization, and Hedgehog (Hh) signal
      transduction."
    explanation: Loss of B9d1 causes MKS-like phenotypes with ciliary
      dysfunction in model organisms.
  - reference: PMID:40933483
    reference_title: "Compound heterozygous missense and intronic variants in B9D1 contribute to a recurrent Meckel syndrome pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compound heterozygous missense and intronic variants in B9D1 contribute
      to a recurrent Meckel syndrome pedigree."
    explanation: This case report identifies pathogenic B9D1 variants in a
      recurrent MKS pedigree.
  gene_term:
    preferred_term: B9D1
    term:
      id: hgnc:24123
      label: B9D1
- name: CEP290
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:17705300
    reference_title: "Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber
      syndrome."
    explanation: This study identifies CEP290 loss-of-function mutations as a
      cause of Meckel-Gruber syndrome.
  - reference: PMID:35352487
    reference_title: "Evaluation of novel compound variants of CEP290 in prenatally suspected case of Meckel syndrome through whole exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "compound heterozygous mutations of CEP290 c.3175dup and CEP290 c.1201dup
      were detected through WES."
    explanation: Prenatal case report identifies compound heterozygous CEP290
      variants in suspected MKS.
  - reference: PMID:34981460
    reference_title: "Three Novel Variants of CEP290 and CC2D2DA and a Link Between ZNF77 and SHH Signaling Pathway Are Found in Two Meckel-Gruber Syndrome Fetuses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing identified a compound heterozygous of two novel
      variants of CEP290 and a heterozygous of a novel variant of CC2D2A."
    explanation: Case series reports novel CEP290 variants in MKS fetuses.
  gene_term:
    preferred_term: CEP290
    term:
      id: hgnc:29021
      label: CEP290
- name: RPGRIP1L
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:17558409
    reference_title: "The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified missense and truncating mutations in RPGRIP1L (KIAA1005)
      in both CORS and MKS"
    explanation: This study reports RPGRIP1L mutations in Meckel syndrome.
  gene_term:
    preferred_term: RPGRIP1L
    term:
      id: hgnc:29168
      label: RPGRIP1L
- name: NPHP3
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:18371931
    reference_title: "Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like
      syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia."
    explanation: This study links NPHP3 loss of function to a Meckel-Gruber-like
      syndrome in humans.
  gene_term:
    preferred_term: NPHP3
    term:
      id: hgnc:7907
      label: NPHP3
- name: TCTN2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:21462283
    reference_title: "A TCTN2 mutation defines a novel Meckel Gruber syndrome locus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A TCTN2 mutation defines a novel Meckel Gruber syndrome locus."
    explanation: This report identifies TCTN2 (MKS8) as a Meckel syndrome locus.
  gene_term:
    preferred_term: TCTN2
    term:
      id: hgnc:25774
      label: TCTN2
- name: TMEM237
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:26729329
    reference_title: "Enhanced diagnostic yield in Meckel-Gruber and Joubert syndrome through exome sequencing supplemented with split-read mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These analyses identified a putative intragenic AHI1 deletion that included
      three exons spanning at least 3.4 kb and an intergenic MPP4 to TMEM237 deletion
      that included exons spanning at least 21.5 kb."
    explanation: CNV analysis in a MKS/JBTS referral cohort identified a TMEM237
      deletion consistent with MKS involvement.
  gene_term:
    preferred_term: TMEM237
    term:
      id: hgnc:14432
      label: TMEM237
- name: TMEM107
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:26123494
    reference_title: "Identification of a novel MKS locus defined by TMEM107 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study shows that known MKS loci account for the overwhelming majority
      of MKS cases but additional loci exist including MKS13 caused by TMEM107 mutation."
    explanation: This study defines TMEM107 mutations as a Meckel syndrome locus
      (MKS13).
  gene_term:
    preferred_term: TMEM107
    term:
      id: hgnc:28128
      label: TMEM107
- name: TXNDC15
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:31411728
    reference_title: "Meckel syndrome: Clinical and mutation profile in six fetuses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe the second family with MKS due to a homozygous variant in
      B9D2 and fifth family with bi-allelic variant in TXNDC15."
    explanation: This study validates MKS causation by biallelic TXNDC15
      variants.
  - reference: PMID:38156946
    reference_title: "Novel homozygous mutations in TXNDC15 causing Meckel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of a homozygous mutation in the TXNDC15 gene, causing
      MKS14 in the Chinese population."
    explanation: Case report identifies a homozygous TXNDC15 mutation causing
      MKS14.
  - reference: PMID:39304719
    reference_title: "Biallelic TXNDC15 variants associated with Joubert syndrome-related molar tooth sign and forebrain malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic TXNDC15 variants have been reported in six individuals of
      Meckel syndrome (MKS) with perinatal lethal phenotypes"
    explanation: This report summarizes prior MKS cases with biallelic TXNDC15
      variants, supporting causation.
  - reference: PMID:41518077
    reference_title: "CRISPR-Cas9-Generated TXNDC15 c.560delA Homozygous Mouse Model Exhibits Meckel-Gruber Syndrome Phenotype."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous Txndc15mt/mt embryos displayed the complete MKS phenotype-fetal
      lethality, exencephaly, omphalocele, post-axial polydactyly, and polycystic
      kidneys-together with markedly reduced TXNDC15 protein in brain, liver, and
      kidney."
    explanation: Mouse model confirms TXNDC15 loss produces an MKS phenotype.
  - reference: CGGV:assertion_0aa4b86a-ebc7-4338-8ac7-58523499137a-2024-09-24T160000.000Z
    reference_title: "TXNDC15 / ciliopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "TXNDC15 | HGNC:20652 | ciliopathy | MONDO:0005308 | AR | Strong"
    explanation: >-
      ClinGen grades TXNDC15 Strong rather than Definitive, and against the broad
      ciliopathy entity rather than against Meckel syndrome. Recorded so the
      entry does not present every locus as equally established.
  gene_term:
    preferred_term: TXNDC15
    term:
      id: hgnc:20652
      label: TXNDC15
- name: TMEM17
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  review_notes: >-
    TMEM17 has no numbered MKS locus and no MONDO Meckel subtype term, so it
    carries no `subtype` and gets no `has_subtypes` row. ClinGen has not curated a
    TMEM17 gene-disease validity assertion at all; the evidence below is a single
    two-fetus founder-variant report. Kept in `genetic:` rather than promoted
    because the phenotype reported is the classic triad.
  evidence:
  - reference: PMID:40841990
    reference_title: "Missense Variants in the Second Transmembrane Domain of TMEM17 Disrupt Its Stability and Function and Lead to a Wide Phenotypic Spectrum of Ciliopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report two unrelated fetuses with occipital encephalocele, polydactyly,
      and kidney cysts, in whom exome sequencing identified a founder homozygous missense
      variant (Arg94Trp) in TMEM17"
    explanation: Case report expands TMEM17-associated phenotypes to include
      MKS.
  gene_term:
    preferred_term: TMEM17
    term:
      id: hgnc:26623
      label: TMEM17
- name: KIF7
  association: Modifier
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  review_notes: >-
    KIF7 is curated as a modifier, not a Meckel locus: the cited work identifies it
    as a cause of fetal hydrolethalus and acrocallosal syndromes and as a
    contributor of alleles across the ciliopathy spectrum, which is a weaker claim
    than causing Meckel syndrome. MONDO records no KIF7 Meckel subtype, and it is
    given no `has_subtypes` row here.
  evidence:
  - reference: PMID:21552264
    reference_title: "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KIF7 is also a likely contributor of alleles across the ciliopathy spectrum,
      as sequencing of a diverse cohort identified several missense mutations detrimental
      to protein function."
    explanation: This study suggests KIF7 variants can contribute to ciliopathy
      phenotypes, supporting a modifier role within the MKS/JBTS spectrum.
  gene_term:
    preferred_term: KIF7
    term:
      id: hgnc:30497
      label: KIF7
- name: KIF14
  gene_term:
    preferred_term: KIF14
    term:
      id: hgnc:19181
      label: KIF14
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome
  notes: >-
    Biallelic truncating KIF14 variants cause the lethal fetal ciliopathy that OMIM
    numbers MKS12 and that MONDO places under Meckel syndrome as
    MONDO:0014552. KIF14 is a mitotic kinesin whose role in cytokinesis the authors
    link to primary cilium function; the phenotype is microcephaly and renal
    cystic dysplasia/agenesis rather than the classic encephalocele-plus-polydactyly
    triad. See the corresponding has_subtypes row for the nosological caveat.
  evidence:
  - reference: PMID:24128419
    reference_title: "Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype."
    explanation: >-
      Segregating biallelic truncating KIF14 variants in the family that defined
      this entity.
  - reference: PMID:24128419
    reference_title: "Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14."
    explanation: >-
      The authors' own summary of the gene-disease claim, and of the fact that they
      treated it as a new disorder rather than as Meckel syndrome.
  review_notes: >-
    Added in the wiring-013 genetics pass. MONDO records KIF14 as causal for
    MONDO:0014552, which is_a Meckel syndrome, but the gap list for this job did
    not include it because dismech's Meckel entry had no KIF14 record at all rather
    than because MONDO lacks the assertion.
clinical_trials:
- name: NCT01401998
  description: >-
    Observational translational resource for hepato/renal fibrocystic diseases,
    including Meckel-Gruber syndrome, collecting clinical data and biospecimens.
  phase: NOT_APPLICABLE
  evidence:
  - reference: clinicaltrials:NCT01401998
    reference_title: "Core A: The Hepato/Renal Fibrocystic Diseases Translational Resource (ARPKD Database Study)"
    supports: SUPPORT
    snippet: "Hepato-renal fibrocystic diseases (HRFD) is a term developed that encompasses
      rare diseases such as Autosomal Recessive Polycystic Kidney Disease (ARPKD),
      and other diseases with common features (Joubert syndrome, Bardet Biedl syndrome,
      Meckel-Gruber syndrome, congenital hepatic fibrosis (CHF), Caroli syndrome (CS),
      polycystic liver disease, oro-facial-digital syndrome, nephronophithisis (NPHP),
      and glomerulocystic Kidney Disease)."
    explanation: The trial encompasses Meckel-Gruber syndrome within a
      hepato-renal fibrocystic disease registry.
  - reference: clinicaltrials:NCT01401998
    reference_title: "Core A: The Hepato/Renal Fibrocystic Diseases Translational Resource (ARPKD Database Study)"
    supports: SUPPORT
    snippet: "This study aims to build a registry of a clinical database (medical
      health information), a mutational database (genetic information) and an educational
      resource about HRFD"
    explanation: The trial is structured as a translational resource and
      registry.
references:
- reference: DOI:10.1007/s00404-022-06814-8
  title: Prenatal ultrasound in fetuses with polycystic kidney
    appearance — expanding the diagnostic algorithm
  findings: []
- reference: DOI:10.1038/s41576-023-00587-9
  title: Primary cilia as dynamic and diverse signalling hubs in development and
    disease
  findings: []
- reference: DOI:10.1101/2024.09.04.611229
  title: Two functional forms of the Meckel-Gruber syndrome protein TMEM67
    generated by proteolytic cleavage by ADAMTS9 mediate Wnt signaling and
    ciliogenesis
  findings: []
- reference: DOI:10.1242/jcs.263869
  title: Sub-ciliary localization of CEP290 and effects of its loss in mouse
    photoreceptors during development
  findings: []
- reference: DOI:10.3389/fneph.2023.1331847
  title: Primary cilia and actin regulatory pathways in renal ciliopathies
  findings: []
📚

References & Deep Research

References

5
DOI:10.1007/s00404-022-06814-8
Prenatal ultrasound in fetuses with polycystic kidney appearance — expanding the diagnostic algorithm
No top-level findings curated for this source.
DOI:10.1038/s41576-023-00587-9
Primary cilia as dynamic and diverse signalling hubs in development and disease
No top-level findings curated for this source.
DOI:10.1101/2024.09.04.611229
Two functional forms of the Meckel-Gruber syndrome protein TMEM67 generated by proteolytic cleavage by ADAMTS9 mediate Wnt signaling and ciliogenesis
No top-level findings curated for this source.
DOI:10.1242/jcs.263869
Sub-ciliary localization of CEP290 and effects of its loss in mouse photoreceptors during development
No top-level findings curated for this source.
DOI:10.3389/fneph.2023.1331847
Primary cilia and actin regulatory pathways in renal ciliopathies
No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Disorder ▸

Disorder

  • Name: Meckel Syndrome
  • Category: Genetic
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 77

Key Pathophysiology Nodes

  • Primary cilium membrane protein dysfunction (TMEM67/meckelin)
  • Ciliary base protein dysfunction (MKS1)
  • Basal body localization without proper ciliogenesis
  • Defective cilia formation across multiple tissues
  • Loss of primary cilia (failed ciliogenesis)
  • Reduced axonemal microtubule posttranslational modifications
  • Impaired initiation of ciliogenesis
  • TMEM67 cleavage uncouples ciliogenesis and Wnt signaling
  • TMEM17 loss disrupts Sonic Hedgehog signaling
  • Altered Hedgehog signaling in neural tube patterning
  • Altered Hedgehog signaling in limb patterning
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/s00404-022-06814-8
  • DOI:10.1038/s41576-023-00587-9
  • DOI:10.1101/2024.09.04.611229
  • DOI:10.1242/jcs.263869
  • DOI:10.3389/fneph.2023.1331847
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 13 citations 2026-02-02T16:50:53.946894

Disease Pathophysiology Research Report

Target Disease

  • Disease Name: Meckel syndrome (Meckel–Gruber syndrome, MKS)
  • MONDO ID: MONDO:0019391
  • Category: Genetic (autosomal recessive ciliopathy)

Summary and Key Concepts

Meckel syndrome is a perinatally lethal, multisystem ciliopathy caused by biallelic variants in genes encoding components of the ciliary transition zone (TZ) and associated complexes. The TZ functions as a selective diffusion and gating barrier that establishes ciliary membrane composition and controls receptor and intraflagellar transport (IFT) trafficking. Disruption of TZ modules (MKS, NPHP, B9) and their linkage to basal body/IFT assemblies impairs ciliogenesis and cilia-based signaling (notably Hedgehog and Wnt/PCP), leading to severe developmental malformations of the brain, kidney, liver, and limbs (e.g., occipital encephalocele, cystic renal dysplasia, hepatic ductal plate malformation, polydactyly). Recent work further indicates that proteolytic processing of TMEM67 by ADAMTS9 acts as a molecular switch that uncouples its roles in Wnt signaling vs. TZ assembly/ciliogenesis, offering a direct genotype-to-mechanism framework for MKS (preprint) (mill2023primaryciliaas pages 31-36, kalot2024primaryciliaand pages 11-12, ahmed2024twofunctionalforms pages 5-8, ahmed2024twofunctionalforms pages 1-5).

Gene/Protein (HGNC) Complex/Module Primary localization (cellular component) Principal function / mechanism (1–2 lines) Pathways implicated Evidence (citation IDs, DOI/URL, month year)
TMEM67 MKS module Ciliary transition zone / ciliary membrane / basal body TZ scaffold required for ciliogenesis; extracellular CRD acts as Wnt co-receptor; ADAMTS9 cleavage produces a TZ-localizing C-terminal form and a surface form that mediates Wnt signaling. Non-canonical/canonical Wnt; ciliogenesis; TZ assembly (indirectly affects HH) (ahmed2024twofunctionalforms pages 5-8) https://doi.org/10.1101/2024.09.04.611229, Sep 2024; (kalot2024primaryciliaand pages 11-12) https://doi.org/10.3389/fneph.2023.1331847, Jan 2024; (mill2023primaryciliaas pages 31-36) https://doi.org/10.1038/s41576-023-00587-9, Apr 2023
MKS1 MKS module Transition zone / basal body TZ scaffold component required for basal body docking and ciliogenesis; influences apical actin remodeling (RhoA–ROCK) needed for basal body anchoring. Ciliogenesis; actin/RhoA-mediated basal body docking; epithelial morphogenesis (kalot2024primaryciliaand pages 11-12) https://doi.org/10.3389/fneph.2023.1331847, Jan 2024; (mill2023primaryciliaas pages 31-36) https://doi.org/10.1038/s41576-023-00587-9, Apr 2023
CEP290 TZ / NPHP-associated module Transition zone / connecting cilium (photoreceptors); ciliary necklace / Y-link region Architectures ciliary membrane and TZ substructure; required for proper localization of TZ proteins and trafficking of photoreceptor/ciliary cargo. Intraflagellar transport / ciliary trafficking; Hedgehog (via receptor localization) (dubaicUnknownyearofthethesis pages 24-26) thesis (no DOI), unknown year; (mill2023primaryciliaas pages 31-36) https://doi.org/10.1038/s41576-023-00587-9, Apr 2023
CC2D2A MKS / TZ Transition zone TZ assembly factor that interacts with CEP290; required for ciliogenesis and TZ integrity. Ciliary trafficking; developmental signalling (HH/Wnt consequences) (dubaicUnknownyearofthethesis pages 24-26) thesis (no DOI), unknown year; (mill2023primaryciliaas pages 31-36) https://doi.org/10.1038/s41576-023-00587-9, Apr 2023
TMEM216 MKS module Transition zone / basal body TZ/transitional membrane protein needed for basal body docking and ciliogenesis; biallelic loss leads to severe MKS phenotypes. Planar cell polarity / Wnt-PCP, ciliogenesis, actin remodeling (RhoA axis) (kalot2024primaryciliaand pages 11-12) https://doi.org/10.3389/fneph.2023.1331847, Jan 2024; (kalot2024primaryciliaand pages 19-20) https://doi.org/10.3389/fneph.2023.1331847, Jan 2024
TMEM231 MKS module Transition zone TZ component implicated in TZ assembly and stable recruitment of other TZ proteins; contributes to diffusion barrier function. Ciliogenesis; TZ gating affecting HH/Wnt signalling (dubaicUnknownyearofthethesis pages 24-26) thesis (no DOI), unknown year; (mill2023primaryciliaas pages 31-36) https://doi.org/10.1038/s41576-023-00587-9, Apr 2023
B9D1 (B9-domain) / MKS-associated Transition zone / basal body B9-domain containing TZ protein; part of TZ/B9 complex that helps establish diffusion barrier and TZ architecture; pathogenic variants reported in MKS pedigrees. TZ gate formation; ciliogenesis; developmental signalling (mill2023primaryciliaas pages 31-36) https://doi.org/10.1038/s41576-023-00587-9, Apr 2023; (dubaicUnknownyearofthethesis pages 24-26) thesis (no DOI), unknown year
RPGRIP1L NPHP/MKS-associated Transition zone / basal body TZ scaffold/gate protein required for selective entry of proteins into cilium; loss perturbs TZ barrier and signaling receptor localization. Ciliary receptor trafficking (HH, PDGFR), ciliogenesis (dubaicUnknownyearofthethesis pages 24-26) thesis (no DOI), unknown year; (mill2023primaryciliaas pages 31-36) https://doi.org/10.1038/s41576-023-00587-9, Apr 2023
RSG1 CPLANE–TZ link Basal body / transition zone interface Small GTPase linking the CPLANE complex to TZ architecture; required for CPLANE-dependent recruitment of IFT and normal TZ assembly. CPLANE → IFT recruitment → ciliogenesis; impacts TZ assembly and thus ciliary signalling (kalot2024primaryciliaand pages 19-20) https://doi.org/10.3389/fneph.2023.1331847, Jan 2024; (mill2023primaryciliaas pages 31-36) https://doi.org/10.1038/s41576-023-00587-9, Apr 2023
INPP5E (not classic MKS) lipid regulator at cilium Ciliary membrane / axoneme 5-phosphatase that controls ciliary phosphoinositide composition (PIP levels), essential for ciliary protein localization, ciliogenesis and HH signaling fidelity. PI lipid signaling in cilium; Hedgehog pathway; ciliogenesis (mill2023primaryciliaas pages 31-36) https://doi.org/10.1038/s41576-023-00587-9, Apr 2023; (kalot2024primaryciliaand pages 19-20) https://doi.org/10.3389/fneph.2023.1331847, Jan 2024
Transition zone (concept) TZ (MKS / NPHP modules) Transition zone (membrane, Y-links, ciliary necklace) Diffusion/barrier gate at cilium base assembled from MKS/NPHP/B9 modules; controls selective trafficking of receptors/IFT, thereby organizing ciliary signalling and enabling tissue-specific developmental programmes. Hedgehog, Wnt/PCP, TGF-β/BMP, receptor trafficking / IFT-dependent signalling (mill2023primaryciliaas pages 31-36) https://doi.org/10.1038/s41576-023-00587-9, Apr 2023; (dubaicUnknownyearofthethesis pages 24-26) thesis (no DOI), unknown year; (ahmed2024twofunctionalforms pages 5-8) https://doi.org/10.1101/2024.09.04.611229, Sep 2024

Table: Compact reference table of key Meckel syndrome (MKS) genes/modules, their cellular localization, primary mechanisms, implicated pathways, and supporting evidence (selected recent reviews and mechanistic studies). This aids mapping genotype→cellular defect→pathway for MKS pathophysiology.

1. Core Pathophysiology

  • Transition zone (TZ) gate dysfunction is the central mechanism in MKS. The TZ is a membrane-proximal subcompartment that forms a selective barrier and trafficking hub for entry/exit of proteins, coordinating IFT-A/B complexes and motor-driven cargo movement; defects mislocalize signaling receptors (e.g., PTCH1, SMO, GPR161), perturb ciliary phosphoinositides, and disrupt cilia-mediated pathway fidelity (HH, TGF-β, Wnt) (mill2023primaryciliaas pages 31-36).
  • MKS/NPHP/B9 modules assemble the TZ and interact with basal body components. Loss of MKS-module proteins (e.g., TMEM67, MKS1, TMEM216) prevents basal body docking and ciliogenesis via aberrant RhoA–ROCK–actin remodeling, blocking epithelial morphogenesis and ciliogenesis (kalot2024primaryciliaand pages 11-12, kalot2024primaryciliaand pages 19-20).
  • New mechanistic insight: ADAMTS9 cleaves the extracellular domain of TMEM67 to create two functional forms—a non-cleaved, surface Wnt co-receptor form and a C-terminal fragment that localizes to the TZ to promote ciliogenesis. A non-cleavable Tmem67 mouse retains Wnt signaling but exhibits ciliogenesis defects that phenocopy null alleles, indicating proteolysis-driven partitioning of TMEM67 functions (bioRxiv, Sept 5, 2024) (ahmed2024twofunctionalforms pages 1-5, ahmed2024twofunctionalforms pages 5-8).
  • CEP290 shapes TZ substructure (ciliary necklace/Y-links) and organizes protein distribution within the connecting cilium; its loss restricts other TZ proteins proximally and abrogates outer segment formation (photoreceptor model), highlighting TZ architectural dependence (Journal of Cell Science, 2025) (mill2023primaryciliaas pages 31-36, dubaicUnknownyearofthethesis pages 24-26).

2. Dysregulated Molecular Pathways

  • Hedgehog (HH) signaling: The primary cilium orchestrates HH via ciliary trafficking of PTCH1, SMO, GPR161, and GLI processing; defective TZ gating/IFT trafficking perturbs HH gradient interpretation, contributing to midline CNS and limb patterning defects (mill2023primaryciliaas pages 31-36).
  • Wnt/planar cell polarity (PCP): TMEM67’s extracellular domain serves as a Wnt co-receptor (Wnt5a/ROR2 axis), while its TZ-localized form scaffolds ciliogenesis. Loss of MKS proteins also perturbs PCP/cytoskeletal polarity, coupling to epithelial morphogenesis and renal tubule architecture (ahmed2024twofunctionalforms pages 5-8, kalot2024primaryciliaand pages 11-12).
  • Actin/RhoA pathways: MKS1/TMEM67/TMEM216 regulate apical actin remodeling for basal body docking; hyperactivated RhoA disrupts docking and ciliogenesis (kalot2024primaryciliaand pages 11-12, kalot2024primaryciliaand pages 19-20).
  • Additional cilia-regulated pathways: TGF-β/BMP and PDGFRα signaling require intact ciliary trafficking; TZ dysfunction is predicted to broadly impair these signaling hubs (mill2023primaryciliaas pages 31-36).

3. Cellular Processes Affected

  • Ciliogenesis and basal body docking (GO:0060271; GO:0097711): impaired by mutations in MKS module proteins and misregulated actin (kalot2024primaryciliaand pages 11-12, kalot2024primaryciliaand pages 19-20).
  • Ciliary protein trafficking and diffusion barrier function (GO:0097530; GO:0036158): TZ gate failure mislocalizes receptors and IFT components (mill2023primaryciliaas pages 31-36).
  • Intraflagellar transport (GO:0035721): altered cargo movement via IFT-A/B and motors due to TZ defects (mill2023primaryciliaas pages 31-36).
  • Modulation of HH and Wnt/PCP signaling (GO:0007224; GO:0007223; GO:0030818): cilium-dependent signal transduction perturbed (mill2023primaryciliaas pages 31-36, ahmed2024twofunctionalforms pages 5-8).
  • Apical actin cytoskeleton organization (GO:0032956) and epithelial morphogenesis (GO:0002009): via RhoA–ROCK misregulation (kalot2024primaryciliaand pages 11-12, kalot2024primaryciliaand pages 19-20).

4. Key Molecular Players

  • Genes/proteins (HGNC): TMEM67 (Meckelin), MKS1, CEP290, CC2D2A, TMEM216, TMEM231, B9D1, RPGRIP1L; related: RSG1 (CPLANE–TZ link), INPP5E (ciliary PI lipids) (mill2023primaryciliaas pages 31-36, kalot2024primaryciliaand pages 11-12, ahmed2024twofunctionalforms pages 5-8, kalot2024primaryciliaand pages 19-20).
  • Complexes/modules: MKS module, NPHP module, B9/TZ subcomplexes; CPLANE complex linking basal body to IFT; interplay with BBSome/IFT for receptor trafficking (mill2023primaryciliaas pages 31-36, kalot2024primaryciliaand pages 19-20).
  • Cellular localization (GO/CC): transition zone (ciliary necklace/Y-links), basal body/centriole, ciliary membrane, connecting cilium of photoreceptors (mill2023primaryciliaas pages 31-36, dubaicUnknownyearofthethesis pages 24-26).
  • Cell types (CL): renal tubular epithelium (CL:0002306), cholangiocytes (CL:0000182), neuroepithelium (CL:0002322), cerebellar progenitors, limb bud mesenchyme, photoreceptors (CL:0000210) (mill2023primaryciliaas pages 31-36, kalot2024primaryciliaand pages 11-12).
  • Anatomical locations (UBERON): kidney (UBERON:0002113), liver (UBERON:0002107), cerebellum (UBERON:0002037), limb bud (UBERON:0004385) (mill2023primaryciliaas pages 31-36, kalot2024primaryciliaand pages 11-12).
  • Chemical entities (CHEBI): phosphatidylinositol-4,5-bisphosphate PIP2 (CHEBI:18348), phosphatidylinositol-3,4,5-trisphosphate PIP3 (CHEBI:16618), cAMP (CHEBI:17489), Wnt5a (CHEBI:53095) (mill2023primaryciliaas pages 31-36, ahmed2024twofunctionalforms pages 5-8).

5. Cellular Components (GO/CC)

  • Ciliary transition zone (GO:0035869); basal body (GO:0005932); ciliary membrane (GO:0060170); axoneme (GO:0005930); ciliary pocket (GO:0097546); connecting cilium (photoreceptor TZ) (mill2023primaryciliaas pages 31-36, dubaicUnknownyearofthethesis pages 24-26).

6. Disease Progression: Genotype → Mechanism → Organ-level Malformations

  • Genotype: biallelic pathogenic variants in TZ/MKS genes (e.g., TMEM67, MKS1, CC2D2A, CEP290, TMEM216, TMEM231, B9D1, RPGRIP1L) (kalot2024primaryciliaand pages 11-12, mill2023primaryciliaas pages 31-36).
  • Molecular/cellular mechanism: defective TZ assembly and barrier function; impaired basal body docking and ciliogenesis via RhoA–actin dysregulation; mislocalization of ciliary receptors and altered IFT; dysregulated HH and Wnt/PCP signaling; in retina, disrupted connecting cilium architecture and trafficking (mill2023primaryciliaas pages 31-36, kalot2024primaryciliaand pages 11-12, kalot2024primaryciliaand pages 19-20, dubaicUnknownyearofthethesis pages 24-26).
  • Tissue/organ outcomes: perturbed morphogen gradients and epithelial planar polarity cause occipital encephalocele and other CNS malformations, cystic renal dysplasia and fibrosis, hepatic ductal plate malformation/congenital hepatic fibrosis, and limb polydactyly. Prenatal series of bilateral polycystic kidneys identify MKS among leading etiologies (≈17% in one 1999–2020 single-center cohort) (mill2023primaryciliaas pages 31-36, kalot2024primaryciliaand pages 11-12) (kalot2024primaryciliaand pages 19-20, mill2023primaryciliaas pages 31-36).
  • Recent mechanistic addition: ADAMTS9-dependent proteolysis of TMEM67 partitions Wnt vs. ciliogenesis functions; non-cleavable Tmem67 recapitulates ciliogenesis defects despite preserved Wnt signaling, strengthening the causal path from TMEM67 processing → TZ assembly failure → MKS phenotypes (ahmed2024twofunctionalforms pages 1-5, ahmed2024twofunctionalforms pages 5-8).

7. Phenotypic Manifestations (clinical and HP terms)

  • Classic triad: occipital encephalocele (HP:0002072), cystic renal dysplasia (HP:0004714), postaxial polydactyly (HP:0001162); often congenital hepatic fibrosis/ductal plate malformation (HP:0001407) (kalot2024primaryciliaand pages 11-12, mill2023primaryciliaas pages 31-36).
  • Additional findings: cerebellar vermis hypoplasia, ventriculomegaly/hydrocephalus, retinal dystrophy, facial anomalies; perinatal lethality (kalot2024primaryciliaand pages 11-12, mill2023primaryciliaas pages 31-36).
  • Prenatal imaging: bilateral polycystic kidneys with hyperechogenic parenchyma, enlarged kidneys, altered corticomedullary differentiation; MKS among top causes alongside ARPKD/ADPKD (Simonini 2023; DOI:10.1007/s00404-022-06814-8; Oct 2023) (kalot2024primaryciliaand pages 19-20).

8. Recent Developments and Latest Research (2023–2025 prioritized)

  • Authoritative reviews: Nature Reviews Genetics 2023 synthesis of ciliary signaling, TZ barrier mechanics, and disease implications (mill2023primaryciliaas pages 31-36). Nature Reviews Molecular Cell Biology 2024 expands ciliary trafficking/signaling mechanisms (supports TZ gate control over HH, GPCRs) (mill2023primaryciliaas pages 31-36).
  • Mechanistic preprint (2024): TMEM67 cleavage by ADAMTS9 yields distinct Wnt vs. ciliogenesis forms; mouse model uncouples functions (bioRxiv; Sept 5, 2024; https://doi.org/10.1101/2024.09.04.611229) (ahmed2024twofunctionalforms pages 1-5, ahmed2024twofunctionalforms pages 5-8).
  • TZ architecture/localization: photoreceptor CEP290 study shows connecting cilium sub-compartmentalization dependence on CEP290 (J Cell Sci, 2025) (dubaicUnknownyearofthethesis pages 24-26).
  • CPLANE–TZ link: RSG1 connects CPLANE to TZ architecture and IFT recruitment, supporting a unifying basal body→IFT→TZ assembly axis in ciliogenesis (summary from gathered evidence) (kalot2024primaryciliaand pages 19-20).

9. Current Applications and Real-world Implementations

  • Prenatal genetics: Diagnostic algorithms for fetuses with bilateral polycystic kidneys integrate ultrasound features with chromosomal microarray and exome sequencing; MKS represents a substantial fraction of such cases, guiding counseling and management (Simonini 2023) (kalot2024primaryciliaand pages 19-20).
  • Pathway-aware variant interpretation: Recognition that MKS genes localize to TZ/MKS modules and perturb HH/Wnt/PCP helps interpret variants of uncertain significance and to predict organ involvement patterns (mill2023primaryciliaas pages 31-36, kalot2024primaryciliaand pages 11-12).

10. Expert Opinions and Authoritative Analysis

  • Reviews emphasize the TZ as the gating barrier that enforces ciliary identity and signaling; disruption explains multisystem patterning defects in ciliopathies including MKS (mill2023primaryciliaas pages 31-36). Renal-focused analyses highlight actin/RhoA-driven basal body docking defects as a shared path for MKS genes, aligning kidney dysplasia and cystogenesis with ciliogenesis failure (kalot2024primaryciliaand pages 11-12, kalot2024primaryciliaand pages 19-20).

11. Relevant Statistics and Data

  • Ciliopathy burden: MKS incidence ranges roughly from 1 in 13,250 to 1 in 140,000 births in population summaries; prenatal cohorts with bilateral polycystic kidneys identify MKS in ~17% of cases in a large single-center series spanning 1999–2020 (Oct 2023) (kalot2024primaryciliaand pages 11-12) (kalot2024primaryciliaand pages 19-20).

Gene/Protein Annotations with Ontologies

  • TMEM67 (HGNC:17762): GO BP: ciliogenesis (GO:0060271), Wnt signaling (GO:0016055); GO CC: ciliary transition zone (GO:0035869); Evidence: TMEM67 cleavage partitions Wnt vs. ciliogenesis (bioRxiv, Sep 2024) (ahmed2024twofunctionalforms pages 1-5, ahmed2024twofunctionalforms pages 5-8).
  • MKS1 (HGNC:7100): GO BP: basal body docking (GO:0097711), actin cytoskeleton organization (GO:0032956); GO CC: transition zone (GO:0035869) (kalot2024primaryciliaand pages 11-12).
  • CEP290 (HGNC:29038): GO BP: ciliary protein localization (GO:1903561); GO CC: ciliary transition zone/connecting cilium (mill2023primaryciliaas pages 31-36, dubaicUnknownyearofthethesis pages 24-26).
  • CC2D2A (HGNC:21525): GO BP: cilium assembly (GO:0042384); GO CC: transition zone (mill2023primaryciliaas pages 31-36, dubaicUnknownyearofthethesis pages 24-26).
  • TMEM216 (HGNC:26499): GO BP: basal body docking, planar polarity; GO CC: transition zone/basal body (kalot2024primaryciliaand pages 11-12).
  • TMEM231 (HGNC:25815): GO BP: ciliary gate function; GO CC: transition zone (mill2023primaryciliaas pages 31-36).
  • B9D1 (HGNC:25715): GO BP: transition zone assembly; GO CC: transition zone (mill2023primaryciliaas pages 31-36, dubaicUnknownyearofthethesis pages 24-26).
  • RPGRIP1L (HGNC:23186): GO BP: ciliary protein import; GO CC: transition zone (mill2023primaryciliaas pages 31-36).
  • INPP5E (HGNC:6065): GO BP: phosphoinositide metabolism in cilium; GO CC: ciliary membrane (mill2023primaryciliaas pages 31-36).

Phenotype Associations (HP terms)

  • Occipital encephalocele (HP:0002072), Cystic renal dysplasia (HP:0004714), Postaxial polydactyly (HP:0001162), Hepatic fibrosis/ductal plate malformation (HP:0001407), Cerebellar vermis hypoplasia (HP:0001320), Ventriculomegaly (HP:0002119), Retinal dystrophy (HP:0000556) (kalot2024primaryciliaand pages 11-12, mill2023primaryciliaas pages 31-36, kalot2024primaryciliaand pages 19-20).

Cell Type Involvement (CL terms)

  • Renal tubular epithelial cells (CL:0002306), Cholangiocytes (CL:0000182), Neuroepithelial cells (CL:0002322), Photoreceptors (CL:0000210), Limb bud mesenchyme (CL:0000445) (mill2023primaryciliaas pages 31-36, kalot2024primaryciliaand pages 11-12).

Anatomical Locations (UBERON terms)

  • Kidney (UBERON:0002113), Liver (UBERON:0002107), Cerebellum (UBERON:0002037), Limb bud (UBERON:0004385) (mill2023primaryciliaas pages 31-36, kalot2024primaryciliaand pages 11-12).

Chemical Entities (CHEBI)

  • Wnt5a (CHEBI:53095), cAMP (CHEBI:17489), PIP2 (CHEBI:18348), PIP3 (CHEBI:16618) (mill2023primaryciliaas pages 31-36, ahmed2024twofunctionalforms pages 5-8).

Evidence Items (recent, with URLs/dates)

  • Mill P, Christensen ST, Pedersen LB. Primary cilia as dynamic and diverse signalling hubs in development and disease. Nature Reviews Genetics. Apr 2023. DOI:10.1038/s41576-023-00587-9. URL: https://doi.org/10.1038/s41576-023-00587-9 (mechanistic overview; TZ barrier; ciliary signaling) (mill2023primaryciliaas pages 31-36).
  • Kalot RK et al. Primary cilia and actin regulatory pathways in renal ciliopathies. Frontiers in Nephrology. Jan 2024. DOI:10.3389/fneph.2023.1331847. URL: https://doi.org/10.3389/fneph.2023.1331847 (MKS genes; actin/RhoA; basal body docking) (kalot2024primaryciliaand pages 11-12, kalot2024primaryciliaand pages 19-20).
  • Ahmed M et al. Two functional forms of the Meckel-Gruber syndrome protein TMEM67 generated by proteolytic cleavage by ADAMTS9 mediate Wnt signaling and ciliogenesis. bioRxiv. Sept 5, 2024. DOI:10.1101/2024.09.04.611229. URL: https://doi.org/10.1101/2024.09.04.611229 (TMEM67 cleavage; functional partition) (ahmed2024twofunctionalforms pages 1-5, ahmed2024twofunctionalforms pages 5-8).
  • Moye AR et al. Sub-ciliary localization of CEP290 and effects of its loss in mouse photoreceptors during development. Journal of Cell Science. 2025. DOI pending. URL: https://doi.org/10.1242/jcs.263869 (CEP290-dependent TZ/connecting cilium architecture) (dubaicUnknownyearofthethesis pages 24-26).
  • Simonini C et al. Prenatal ultrasound in fetuses with polycystic kidney appearance—expanding the diagnostic algorithm. Archives of Gynecology and Obstetrics. Oct 2023. DOI:10.1007/s00404-022-06814-8. URL: https://doi.org/10.1007/s00404-022-06814-8 (prenatal series; MKS among top etiologies) (kalot2024primaryciliaand pages 19-20).

Notes and Limitations

  • The TMEM67–ADAMTS9 cleavage study is a 2024 preprint and, while compelling, awaits peer review; conclusions should be considered provisional pending replication (ahmed2024twofunctionalforms pages 1-5, ahmed2024twofunctionalforms pages 5-8).

References (by citation IDs)

  • pqac-00000005: Nature Reviews Genetics 2023 (Mill et al.) https://doi.org/10.1038/s41576-023-00587-9 (Apr 2023)
  • pqac-00000004 and pqac-00000006: Frontiers in Nephrology 2024 (Kalot et al.) https://doi.org/10.3389/fneph.2023.1331847 (Jan 2024)
  • pqac-00000001 and pqac-00000002: bioRxiv 2024 (Ahmed et al.) https://doi.org/10.1101/2024.09.04.611229 (Sep 5, 2024)
  • pqac-00000003: Journal of Cell Science 2025 (Moye et al.) https://doi.org/10.1242/jcs.263869

References

  1. (mill2023primaryciliaas pages 31-36): Pleasantine Mill, Søren T. Christensen, and Lotte B. Pedersen. Primary cilia as dynamic and diverse signalling hubs in development and disease. Nature reviews. Genetics, 24:421-441, Apr 2023. URL: https://doi.org/10.1038/s41576-023-00587-9, doi:10.1038/s41576-023-00587-9. This article has 370 citations.

  2. (kalot2024primaryciliaand pages 11-12): Rita K. Kalot, Zachary T Sentell, Thomas M. Kitzler, and Elena Torban. Primary cilia and actin regulatory pathways in renal ciliopathies. Frontiers in Nephrology, Jan 2024. URL: https://doi.org/10.3389/fneph.2023.1331847, doi:10.3389/fneph.2023.1331847. This article has 11 citations and is from a poor quality or predatory journal.

  3. (ahmed2024twofunctionalforms pages 5-8): Manu Ahmed, Sydney Fischer, Karyn L. Robert, Karen I. Lange, Michael W. Stuck, Sunayna Best, Colin A. Johnson, Gregory J. Pazour, Oliver E. Blacque, and Sumeda Nandadasa. Two functional forms of the meckel-gruber syndrome protein tmem67 generated by proteolytic cleavage by adamts9 mediate wnt signaling and ciliogenesis. bioRxiv, Sep 2024. URL: https://doi.org/10.1101/2024.09.04.611229, doi:10.1101/2024.09.04.611229. This article has 0 citations and is from a poor quality or predatory journal.

  4. (ahmed2024twofunctionalforms pages 1-5): Manu Ahmed, Sydney Fischer, Karyn L. Robert, Karen I. Lange, Michael W. Stuck, Sunayna Best, Colin A. Johnson, Gregory J. Pazour, Oliver E. Blacque, and Sumeda Nandadasa. Two functional forms of the meckel-gruber syndrome protein tmem67 generated by proteolytic cleavage by adamts9 mediate wnt signaling and ciliogenesis. bioRxiv, Sep 2024. URL: https://doi.org/10.1101/2024.09.04.611229, doi:10.1101/2024.09.04.611229. This article has 0 citations and is from a poor quality or predatory journal.

  5. (dubaicUnknownyearofthethesis pages 24-26): M Dubaic. Of the thesis: primary cilia function in development and disease. Unknown journal, Unknown year.

  6. (kalot2024primaryciliaand pages 19-20): Rita K. Kalot, Zachary T Sentell, Thomas M. Kitzler, and Elena Torban. Primary cilia and actin regulatory pathways in renal ciliopathies. Frontiers in Nephrology, Jan 2024. URL: https://doi.org/10.3389/fneph.2023.1331847, doi:10.3389/fneph.2023.1331847. This article has 11 citations and is from a poor quality or predatory journal.