Inheritance

Autosomal recessive

Prevalence

 <1 / 1 000 000

Source: ORPHA:2919

Rapid or full curation?

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. Het in both parents, no sibs to look for penetrance/segregation info. 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. No evidence of non-segregation presented, or reduced penetrance.

  • 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. No evidence of nonsegregations/reduced penetrance and PP1_Strong is awarded in S1 of PMID:37644014, so more confident of the segregations counted above in paper PMID: 23972372.

PMID: 38160027

• c.1450A>G p.R484G, only 2 alleles in gnomAD v4. Phenotype - microcephaly, tongue hamartoma. No siblings in this paper. Variant found via WES. 0.5x2 = 1 point

PMID: 28711741

• c.1859G>T p.(620Leuext22) - variant in 0.00008338 (11/73202) S. Asian chromosomes in gAD v4, https://gnomad.broadinstitute.org/variant/1-200644255-C-A?dataset=gnomad_r4 extension variant found via autozygosity and WES found HOM in 2 families with consanguinity with OFD syndrome. Variant segregates in family 1, it doesn’t look like any testing done in family 2, no unaffected family members tested. Scoring as a non-NMD variant. Phenotype includes lobulated tongues, cleft palate, developmental delay and polydactyly 1x2 = 2 points.

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. Found via duo WES (two affected sibs), no nonsegregations, 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

DEFINITIVE

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

Molecular Mechanism

Suspected Loss of function (not enough evidence yet)

Marina scored using the new ClinGen framework: and arrived at Suspected 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

(list source/PMID)

Unknown

Published sources show no nonsegregations, but a potential internal case 2106077007 SM-MPQ1T D-091113270-BH-4161-P-A had homozygous c.130dup p.Ala44GlyfsTer45 which was also found in sib reported to be unaffected

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Postaxial polydactyly, syndactyly, clinodactyly

lobulated tongue, bifid tongue tip, bifid uvula, cleft palate, high-arched palate, oral hamartomas

microcephaly, intellectual disability, 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

The DDX59 gene is associated with autosomal recessive orofaciodigital syndrome. Clinical features include cleft palate, bifid 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