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MKS1 Gene Curation

MKS1 Gene Curation

Owned by Andrea Oza
2024-02-22
3 min read

Gene-disease assertions not curated here (add link or write note): Meckel and Joubert syndromes were lumped together given the phenotypic overlap and no difference in mechanism found (LOF established for both). Bardet-Biedl is curated as limited by Invitae in GenCC, but it also has phenotype overlap, so it is unclear whether this is a separate entity.

Disease

MKS1- Related disorders

(Meckel syndrome, Joubert syndrome)

Disease

MKS1- Related disorders

(Meckel syndrome, Joubert syndrome)

Inheritance

Autosomal recessive

Prevalence

Orphanet

Medline Plus Genetics

 Meckel Gruber syndrome is 1 in 13,250 to 1 in 140,000 live births according to PMID: 24082939

Source:

Rapid or full curation?

Rapid
Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - dosage (curation status = reopened). GenCC - Strong for Meckel and Joubert syndrome (invitae), limited for Bardet-Biedl. BabySeq - strong for Meckel syndrome (PMID: 6486167, 17377820, 16415886, 17397051, 18327255, 17437276)

Clinical Validity Scoring Notes and points

Using BabySeq citations listed above.

Clinical Validity Points Total

N/A

Clinical Validity Classification

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Strong

Source: 6486167, 17377820, 16415886, 17397051, 18327255, 17437276

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function

Sources: 17397051, 19466712, 23351400, 26490104, 33193692

Meckel

  1. c.184_190delACTGCCA p.(Thr62Valfs*14) PMID: 17397051

  2. c.392_393delCT p.(Ser131*) PMID: 19466712

  3. c.811delC p.(His271Thrfs*29) PMID: PMID: 23351400

 

Joubert

  1. c.381delC p.(Tyr128Thrfs*17) PMID: 26490104

  2. c.1058delG p.(Gly353Glufs*2) PMID: 33193692

  3. c.157dupG p.D53Gfs*6 PMID: 26490104

 

Penetrance

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

 

Source:

Age of Onset

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Congenital

Severity

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

Severe/Lethal

Clinical Features

 

Sources:

HPO Terms

https://hpo.jax.org/app/

 

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

The MKS1 gene is associated with autosomal recessive MKS1-related disorders, which include Meckel syndrome and autosomal recessive Joubert syndrome; these syndromes share overlapping clinical features including central nervous system malformation, renal/liver disease, and polydactyly (PMID: 34359301, 24886560,19466712). Loss of function variants have been reported in both syndromes (PMID: 17397051, 19466712, 23351400, 26490104, 33193692). Joubert syndrome is characterized by cerebellar vermis hypoplasia, cystic kidney disease, liver fibrosis, polydactyly, and retinal dystrophy, intellectual disability, developmental delay, endocrine abnormalities, obesity, ataxia, typical facial features, congenital heart defects, and other findings (PMID: 20301500). Meckel syndrome is a severe/lethal disease characterized by occipital encephalocele, cystic renal dysplasia, and postaxial polydactyly.

Case ID, Curator name, Date, Jira ticket link

Andrea Oza, 02.22.2024 D-180314734-BH-4039-P-A

 

 

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