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Gene-disease assertions not curated here (add link or write note):

Disease

Orofaciodigital syndrome

Inheritance

Autosomal recessive

Prevalence

 <1 / 1 000 000

Source: ORPHA:2919

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

CLINGEN - NONE. GENCC - Strong (Invitae). BabySeq - none. HGMD curation below.

Clinical Validity Scoring Notes and points

PMID: 34008892

  • NM_001031725.6:c.[751T>C]; [1597-6T>G], p.(Ser251Pro) variants in supplement table 2, found via WES, in trans, but they only give a MIM phenotype. In case 8006. No specific phenotype info. Not scoring either variant.

PMID: 28289185

  • Homozygous c.754G>A p.Gly252Arg (absent gnomAD) in case 1. Per table S1, this is a patient w/ cleft lip, abnormal frenuale, lobulated tongue, Post-axial polydactyly, LSE: low-set ears, PrP: Pre-axial polydactyly, syndactyly. 0.5x0.5 points = 1 POINT.

PMID: 38693247

  • In supplement, compound het variants NM_001031725:exon3:c.G953A:p .R318H; exon2:c.26delT:p.I9Tfs*16 . No specific phenotype given, this is a cerebral palsy cohort. No evidence awarded for the OFD syndrome

PMID: 23972372

  • c.1100T>G; NP_001026895.2: p.V367G, absent gnomAD,

  • 2 large consanguineous Arab families with OFD syndrome. They state that the “variants survived the test of segregation” but it isn’t very clear which individuals had testing done on. I’m going to assume that the affected individuals were tested, but could consider downgrading segregations here.

    • Family 1 with c.1100T>G; NP_001026895.2: p.V367G, absent gnomAD. 3 affected individuals total, 2 affected segregations. 0.5x2 = 1 POINT VARIANT, 2 SEGS

    • Family 2 had c.1600G>A p.Gly534Arg. In gnomAD but very low, only 3 alleles. 4 affected individuals and 3 AR segregations. 0.5x2 = 1 POINT VARIANT, 3 SEGS

    • Ddx59 expressed in developing palate and limb buds of mouse embryos. EXPRESSION - 1 POINT

    • Immunoblot analysis of patient fibroblasts revealed marked reduction in protein abundance compared to controls

PMID: 32552793 and 37644014- author overlap with 23972372, homozygous in table S3 in 32552793 and table S1 in 37644014, assuming it is the same patient. No points awarded.

PMID: 38160027

  • c.1450A>G p.R484G, only 2 alleles in gnomAD v4. Phenotype is a little different in this proband, with microcephaly, tongue hamartoma. Variant found via WES. 0.5x2 = 1 point

PMID: 28711741

PMID: 29127725

  • c.185delT p.(Phe62Serfs*14) -7/1180048 European non-Finnish chr in gAD v4. homozygous in a family with OFD syndrome, including microcephaly, ID, DD, epilepsy. Variant segregated in an affected sib. 2x1 = 4 POINT, 1 AR SEG

  • A Drosophila model using a homolog of DDX59 had shortened lifespan and abnormalities in neuronal structures (fig 2.). Since this is a homolog, I’m reducing points for animal model to 1 POINT

SEGREGATION EVIDENCE - 6 SEGS, 2 POINTS

Source:

Clinical Validity Points Total

14

Source:

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

DEFINITIVE

Source: 28289185, 23972372, 38160027, 28711741, 29127725,

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Suspected Loss of function (not enough evidence yet)

Marina scored using the new ClinGen framework: and arrived at Likely LOF https://docs.google.com/document/d/18Z_SPWFiG80NzoZpbWZp7foYRTQjRamC6vi3fWcm2RQ/edit?tab=t.0

Variants/LOF evidence:

  • PMID: 29127725 (see scoring above)

  • could potentially score Bahrain case 2106077007 SM-MPQ1T D-091113270-BH-4161-P-A; however, an unaffected sibling is also HOM for the variant.

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

 Options

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.

Clinical Features

Postaxial polydactyly

microcephaly, intellectualdisability, epilepsy, and white matter signal abnormalities associated with cortical and subcortical ischemic events (PMID: 29127725)

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

 Examples

- 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 DDX59 gene is associated with autosomal recessive orofaciodigital syndrome. Clinical features include cleft palate/uvula, lobulated tongue, frontal bossing, hypertelorism, postaxial polydactyly, and impaired intellectual development (PMID 28711741).

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 01/14/25 CASE: 2106077007 SM-MPQ1T D-091113270-BH-4161-P-A

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