Meckel Syndrome

Genetic MONDO:0018921 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.

Mappings

Definitions

Histopathology

Pathograph

Datasets

Models

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Inheritance

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.

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Subtypes

Meckel syndrome, type 1 MONDO:0009571

Meckel syndrome, type 2 MONDO:0011296

Meckel syndrome, type 3 MONDO:0011821

Meckel syndrome, type 4 MONDO:0012626

Meckel syndrome, type 5 MONDO:0012695

Meckel syndrome, type 6 MONDO:0012848

Meckel syndrome, type 8 MONDO:0013482

Meckel syndrome, type 9 MONDO:0013630

Meckel syndrome, type 10 MONDO:0013609

Meckel syndrome, type 11 MONDO:0014164

Meckel syndrome 13 MONDO:0033044

Meckel syndrome 14 MONDO:0030819

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References

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.

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Pathophysiology

Primary cilium membrane protein dysfunction (TMEM67/meckelin)

Pathogenic variants in TMEM67 disrupt primary cilium membrane components.

primary cilium link

Show evidence (1 reference)

PMID:19211713 SUPPORT Model Organism

"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.

Ciliary base protein dysfunction (MKS1)

Loss of MKS1 perturbs proteins associated with the ciliary base/basal body.

ciliary basal body link ciliary base link

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.

cilium assembly link ↕ DYSREGULATED

primary cilium link ciliary basal body link ciliary base link

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 link ↕ DYSREGULATED

primary cilium link ciliary basal body link ciliary base link

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.

cilium assembly link ↕ DYSREGULATED

primary cilium link ciliary basal body link ciliary base link

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.

primary cilium link axoneme link ciliary basal body link ciliary base link

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 link ↕ 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 link ↕ DYSREGULATED Wnt signaling pathway link ↕ 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.

hedgehog signaling pathway link ↕ 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 link ↕ DYSREGULATED

primary cilium link

neural tube link

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 link ↕ DYSREGULATED

primary cilium link

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.

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Phenotypes

Digestive 1

Hepatic fibrosis FREQUENT Hepatic fibrosis (HP:0001395)

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 Cystic renal dysplasia (HP:0000800)

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 Occipital encephalocele (HP:0002085)

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)

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 Pulmonary hypoplasia (HP:0002089)

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.

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Genetic Associations

MKS1 (Causative)

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)

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)

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)

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)

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)

Show evidence (1 reference)

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.

B9D1 (Causative)

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)

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)

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)

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)

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)

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)

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)

Show evidence (4 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.

+ 1 more reference

TMEM17 (Causative)

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)

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.

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Treatments

Occipital encephalocele repair

Action: surgical repair MAXO:0009072

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 repair MAXO:0009072

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 repair MAXO:0009072

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 therapy MAXO:0001001

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.

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Differential Diagnoses

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

Trisomy 13 (Patau syndrome) Not Yet Curated 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) Not Yet Curated 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.

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Clinical Trials

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.

📚

Literature Summaries

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

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

{ }

Source YAML

click to show

name: Meckel Syndrome
creation_date: '2026-02-02T23:29:30Z'
updated_date: '2026-02-17T21:53:14Z'
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
- name: Meckel syndrome, type 2
  subtype_term:
    preferred_term: Meckel syndrome, type 2
    term:
      id: MONDO:0011296
      label: Meckel syndrome, type 2
- name: Meckel syndrome, type 3
  subtype_term:
    preferred_term: Meckel syndrome, type 3
    term:
      id: MONDO:0011821
      label: Meckel syndrome, type 3
- name: Meckel syndrome, type 4
  subtype_term:
    preferred_term: Meckel syndrome, type 4
    term:
      id: MONDO:0012626
      label: Meckel syndrome, type 4
- name: Meckel syndrome, type 5
  subtype_term:
    preferred_term: Meckel syndrome, type 5
    term:
      id: MONDO:0012695
      label: Meckel syndrome, type 5
- name: Meckel syndrome, type 6
  subtype_term:
    preferred_term: Meckel syndrome, type 6
    term:
      id: MONDO:0012848
      label: Meckel syndrome, type 6
- name: Meckel syndrome, type 8
  subtype_term:
    preferred_term: Meckel syndrome, type 8
    term:
      id: MONDO:0013482
      label: Meckel syndrome, type 8
- name: Meckel syndrome, type 9
  subtype_term:
    preferred_term: Meckel syndrome, type 9
    term:
      id: MONDO:0013630
      label: Meckel syndrome, type 9
- name: Meckel syndrome, type 10
  subtype_term:
    preferred_term: Meckel syndrome, type 10
    term:
      id: MONDO:0013609
      label: Meckel syndrome, type 10
- name: Meckel syndrome, type 11
  subtype_term:
    preferred_term: Meckel syndrome, type 11
    term:
      id: MONDO:0014164
      label: Meckel syndrome, type 11
- name: Meckel syndrome 13
  subtype_term:
    preferred_term: Meckel syndrome 13
    term:
      id: MONDO:0033044
      label: Meckel syndrome 13
- name: Meckel syndrome 14
  subtype_term:
    preferred_term: meckel syndrome 14
    term:
      id: MONDO:0030819
      label: meckel syndrome 14
synonyms:
- Meckel-Gruber syndrome
- Meckel-Gruber syndrome (MKS)
- MKS
prevalence:
- population: European births (EUROCAT)
  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.
pathophysiology:
- name: Primary cilium membrane protein dysfunction (TMEM67/meckelin)
  description: Pathogenic variants in TMEM67 disrupt primary cilium membrane
    components.
  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: MODEL_ORGANISM
    snippet: "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.
- name: Ciliary base protein dysfunction (MKS1)
  description: Loss of MKS1 perturbs proteins associated with the ciliary
    base/basal body.
  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
  description: Basal bodies localize apically, yet cilia fail to form in many
    tissues.
  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.
  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.
  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
  description: TMEM17 dysfunction at the ciliary transition zone abrogates Sonic
    Hedgehog signaling.
  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
  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: MAXO:0009072
      label: surgical repair
    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: MAXO:0009072
      label: surgical repair
    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: MAXO:0009072
      label: surgical repair
    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.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      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
  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
  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
  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
  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
  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
  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.
  gene_term:
    preferred_term: B9D2
    term:
      id: hgnc:28636
      label: B9D2
- name: B9D1
  association: Causative
  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
  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
  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
  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
  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
  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
  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
  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.
  gene_term:
    preferred_term: TXNDC15
    term:
      id: hgnc:20652
      label: TXNDC15
- name: TMEM17
  association: Causative
  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
  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
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
    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
    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: []