Confirmation that mutations in DDX59 cause an autosomal recessive form of oral-facial-digital syndrome: Further delineation of the DDX59 phenotype in two new families

Abstract

We report three probands from two unrelated consanguineous families of South Asian origin who all carry the same rare novel homozygous variant within the dead box helicase gene DDX59 in association with features of oral-facial-digital syndrome (OFDS). DDX59 variants have been reported previously in an unclassified, autosomal recessive form of OFDS; clinically associated with features including tongue lobulation, cleft palate, frontal bossing, hypertelorism and postaxial polydactyly. All three probands had lobulated tongues with tongue hamartomas, abnormal tongue tip, developmental delay and microcephaly, with just one proband demonstrating polydactlyly. The novel DDX59 variant was identified through autozygosity studies followed by sequencing of homozygous regions identified. It affects a stop codon, extending the protein product and is therefore predicted to be pathogenic. It is only the third reported DDX59 mutation associated with OFDS reported so far.

Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation

“…LoF variants in another member of this helicase family, DDX59, have also been reported to cause an autosomal-recessive form of ID with features of oral-facial-digital syndrome. [53][54][55] Interestingly, the phenotypic traits observed in our DDX6 cohort align well with the syndromes described in individuals with pathogenic variants in DDX3X and DHX30. [50][51][52] These include ID, DD, gait abnormalities, cardiac anomalies, and corpus callosum hypoplasia, as well as dysmorphic facial features (high forehead, a bulbous nasal tip, hypertelorism, and arched eyebrows).…”

A loss-of-function homozygous mutation in DDX59 implicates a conserved DEAD-box RNA helicase in nervous system development and function

“…They both presented small OFC since birth, similarly to the patients recently reported by Faily et al. (). Proband II.1 presented since early adulthood diffuse white matter signal abnormalities associated with subcortical ischemic changes, Proband II.2 showed brain MRI features similar to her brother and EMG features of mild peripheral (axonal) neuropathy.…”

“…() were missense variants (c.1100T > G: p.Val367Gly; c.1600G > A: p.Gly534Arg) and the mutation recently described by Faily et al. () affected a stop codon (c.1859G > T: p.*620Leuext*22) extending the protein product, whereas the homozygous mutation we identified in the present study lead to an early truncation of the protein, likely explaining the more severe phenotype including the complex heterogeneous neurological involvement. Interestingly, our functional analysis of the Drosophila model clearly showed that mahe null embryos exhibit highly disorganized neuron clusters and axonal projections, loss or incomplete ventral nerve cord, and also show shortened lifespan.…”

“…The c.185del of a single T nucleotide results in a frameshift at amino‐acid residue 62, generating a premature stop codon 13 amino acids downstream and a truncated protein with the helicase ATP‐ binding and C‐terminal domains (and the evolutionary conserved active motifs PTRELA, TPGR, and DEAD) being omitted (Figure E and F). Homozygous mutations in DDX59 were reported in only two studies so far, with two Arab and two Pakistani families presenting an orofaciodigital syndrome phenotype (with distinctive facial features and digital and midline abnormalities) associated with ID (Faily, Perveen, Urquhart, Chandler, & Clayton‐Smith, ; Shamseldin et al., ). The functional analysis in the original study from Shamseldin et al.…”

Tectonic Proteins Are Important Players in Non-Motile Ciliopathies

“…So far, 8 causative genes have been identified for OFD syndrome [57,58]. Among these genes, TCTN3 is also reported to be a causative gene of OFD syndrome.…”