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Intellectual disability

Gene: DDX59

Green List (high evidence)

DDX59 (DEAD-box helicase 59)
EnsemblGeneIds (GRCh38): ENSG00000118197
EnsemblGeneIds (GRCh37): ENSG00000118197
OMIM: 615464, Gene2Phenotype
DDX59 is in 14 panels

2 reviews

Catherine Snow (Genomics England)

Green List (high evidence)

Expert review by Konstantinos Varvagiannis on DDX59. Biallelic mutations in DDX59 cause Orofaciodigital syndrome V, 174300.

PMID: 23972372 reports on 6 individuals from 2 consanguineous Arab families. All 6 presented with the disease phenotype and ID. Two variants identified, family one were homozygous for Val367Gly (NM_001031725.4:c.1100T>G) variant and the second family were homozygous for Gly534Arg.

PMID: 28711741 describes 3 further patients (from two consanguineous Pakistani families), presenting the cardinal features of orofaciodigital syndrome and also DD. Affected individuals from both families were homozygous for a SNV leading to loss of a stop codon, thus extending the reading frame by 21 codons.

PMID: 29127725 reports on two sibs with a diagnosis of orofaciodigital syndrome born to non-consanguineous parents. Both siblings had a homozygous frameshift deletion in DDX59 (c.185del: p.Phe62fs*13) ID was a feature in both.

Therefore although the disease description in G2P relates to the perdominant phenotype of orofaciodigital syndrome as all individuals have DD/ID and there is a sufficient number of cases, DDX59 can be classified as a Green gene.

Created: 14 May 2019, 10:24 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Orofaciodigital syndrome V 174300

Publications

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Biallelic mutations in DDX59 cause Orofaciodigital syndrome V, 174300.

PMID: 23972372 reports on 6 individuals from 2 consanguineous Arab families. All 6 presented with palatal anomalies (cleft palate or bifid uvula), lobulated tongue, facial anomalies (frontal bossing and hypertelorism) as well as intellectual disability.

Individuals from the first family were homozygous for the Val367Gly (NM_001031725.4:c.1100T>G) variant while those from the second were homozygous for Gly534Arg (NM_001031725.4:c.1600G>A), both predicted to be pathogenic in silico. Immunoblot demonstrated reduced levels of the Val367Gly variant in patient fibroblasts (the other variant was probably not tested). Ddx59 was shown to be expressed in lips, palatal shelves and developing limb buds of mouse embryos.

PMID: 28711741 describes 3 further patients (from two consanguineous Pakistani families), presenting the cardinal features of orofaciodigital syndrome (though polydactyly was only reported in one of the three). Developmental delay was reported in all (in the first family one of the sibs had more severe delay with no speech at the age of 7 years, in the patient from the other family speech was limited to 2 words at school age). Affected individuals from both families were homozygous for a SNV leading to loss of a stop codon, thus extending the reading frame by 21 codons.

PMID: 29127725 reports on two sibs with a diagnosis of orofaciodigital syndrome born to non-consanguineous parents. ID was a feature in both. These individuals were homozygous for a frameshift variant. Reverse transcription PCR/semiquantitative PCR demonstrated reduction of the mutant transcript compared to the levels in wt controls (suggestive of incomplete NMD). Functional studies showed possible perturbation of the Sonic Hedgehog pathway. DDX59 expression in CNS from control post-mortem human brains was confirmed to be high (based on data generated in a previous study). Studies in Drosophila suggest reduced lifespan and neuronal defects secondary to mutations in mahe (the Drosophila homolog of DDX59).

As a result this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature, Expert Review
Created: 27 Nov 2018, 4:31 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Orofaciodigital syndrome V, 174300

Publications

History Filter Activity

25 Jul 2019, Gel status: 3

Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to DDX59. Added phenotypes Orofaciodigital syndrome V, 174300 for gene: DDX59 Publications for gene DDX59 were changed from 23972372; 28711741; 29127725 to 28711741; 29127725; 23972372; 30914295 Rating Changed from No List (delete) to Green List (high evidence)

27 Nov 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: DDX59 was added gene: DDX59 was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: DDX59 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DDX59 were set to 23972372; 28711741; 29127725 Phenotypes for gene: DDX59 were set to Orofaciodigital syndrome V, 174300 Penetrance for gene: DDX59 were set to Complete Review for gene: DDX59 was set to GREEN