Molecular Genetic Testing

Because the phenotype of DDX3X-NDD is indistinguishable from many other genetic disorders with intellectual disability, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of DDX3X, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability (ID) or hypotonia (for young children) multigene panel that includes DDX3X and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, some panels for ID may not (yet) include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
  Exome array (when clinically available) may be considered if exome sequencing is non-diagnostic. Copy number variation in DDX3X has not been studied in detail, but deletions are found in females and duplications in both genders (see Decipher Database).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

DDX3X-Related Neurodevelopmental Disorder in Females

Developmental delay/disability. All females with DDX3X-NDD reported to date (within the limits of ascertainment) likely meet criteria for ID (or developmental delays when too young for the diagnosis of a disability), ranging from mild to severe [Snijders Blok et al 2015, Wang et al 2018, Lennox et al 2020].

Systematic IQ testing has not been published for females with DDX3X-NDD, so in most instances the term ID is inferentially chosen from parentally reported delayed milestones. In one report four categories were identified: 10/38 individuals with mild or moderate ID, 10/38 with moderate or moderate to severe ID, 15/38 with severe ID, and 3/38 with developmental delay (DD) who were younger than age five years [Snijders Blok et al 2015].

In another study, in which the parents of 53 affected girls used the Vineland Adaptive Behavior Scales (VABS) to self-report their child's adaptive behavioral skills, the mean composite standard score was 56.6, which is significantly below the mean score of 100 (SD 15) in the neurotypical population.

In addition, affected individuals with polymicrogyria (PMG) were more delayed developmentally, with an average VABS of 43.8 versus 57.5 in those without PMG (p<0.05) [Lennox et al 2020].

Speech/language delays or disorders are common: After age five years, 52% of females with DDX3X-NDD were nonverbal [Lennox et al 2020]. While a systematic review of progression of milestones has not been reported, in one report a female age 47 years was reported to have learned to sit at age two years, walk at age eight years, and say simple words [Wang et al 2018]. Data on the use of sign language or alternative communication methods have not been reported.

Behavioral issues include autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD) and hyperactivity, self-injurious behavior, poor impulse control, aggression, and other inappropriate behaviors [Snijders Blok et al 2015, Wang et al 2018, Lennox et al 2020]. In one study of 42 individuals, scores on the Social Communication Questionnaire completed by parents/caregivers indicated that 67% were above the at-risk threshold for ASD [Lennox et al 2020].

Tone abnormalities included either isolated hypotonia or a mixture of hypertonia and hypotonia in which truncal tone is lower and limb tone is increased.

Movement disorders are present at a young age and can include dyskinesia, ataxia, and dystonia, sometimes expressed as a stiff-legged or wide-based gait. One female was reported to have striking dystonic episodes [Beal et al 2019].

Seizure types include myoclonic-atonic seizures (episodes of brief shock-like jerks of a muscle or group of muscles as well as drop attacks), infantile spasms, focal partial seizures, or generalized absence spells. Seizures are more common in females with polymicrogyria [Lennox et al 2020].

Microcephaly is more frequent in persons with polymicrogyria (6/9) [Lennox et al 2020], nearly all of whom had an occipital frontal circumference 2 to 3 SDs below the mean.

Ophthalmologic problems include refractive errors, cortical visual impairment, optic atrophy, coloboma (type not specified in 4/92 individuals in Lennox et al), nystagmus, and strabismus (25/92, or 27%) [Wang et al 2018, Lennox et al 2020].

Respiratory problems can include obstructive sleep apnea, tachypnea, and chronic respiratory failure [Wang et al 2018].

Cardiac abnormalities, in addition to those included in Table 2, include atrial septal defect (ASD), patent ductus arteriosus (PDA), and patent foramen ovale (PFO) [Nicola et al 2019], ASD and VSD (ventricular septal defect) [Dikow et al 2017], and (in 1 of 6 females) a VSD [Beal et al 2019].

Skeletal. Scoliosis is likely secondary to hypotonia. In one report 37% (14/38) of individuals had joint laxity [Snijders Blok et al 2015].

Hearing impairment can be conductive, sensorineural, or both. Age of onset is unknown; whether hearing loss is progressive or not is unknown.

Precocious puberty (defined as onset of pubertal changes before age 8 years in girls and age 9 years in boys). While observed in a minority of females [Snijders Blok et al 2015, Lennox et al 2020], the real frequency may be higher, as both cohorts include females younger than the average age at which precocious puberty is observed.

Other

• Gastrointestinal manifestations reported include feeding problems, gastroesophageal reflux, and constipation. There are isolated cases of anal atresia or stenosis, esophagitis, intestinal volvulus, and cyclic vomiting [Dikow et al 2017; Lennox et al 2020].
• Cleft lip, palate or uvula is reported in a few individuals [Snijders Blok et al 2015, Fieremans et al 2016].
• Malignancy. It is currently unclear whether the risk for specific malignancies is increased in children with germline DDX3X pathogenic variants.
  Neuroblastoma has been observed in three females ages 4-7 months [Lennox et al 2020; Sherr, personal communication]. In two of the three, neuroblastoma was detected incidentally (while obtaining spine MRIs). All three were disease free at annual follow ups [Sherr & Johnson-Kerner, personal communication].
  A pilocytic astrocytoma, incidentally found on head imaging, was reported in a female age eight years [Scala et al 2019].

DDX3X-Related Neurodevelopmental Disorder in Males

To date, males from at least ten different families have been reported with a hemizygous DDX3X variant [Snijders Blok et al 2015, Kellaris et al 2018, Wang et al 2018]. While data are insufficient to characterize a detailed phenotype, all males had intellectual disability, ranging from mild to severe.

In one report, two of five males had a head circumference less than 2 SD below the mean [Snijders Blok et al 2015]. In another report, two brothers had macrocephaly – the significance of which is unknown as it was also present in the otherwise asymptomatic father and sister [Kellaris et al 2018].

Additional features similar to those reported in affected females included behavioral problems, spasticity, tremor, hypotonia, vision problems, congenital heart disease, and delayed puberty [Snijders Blok et al 2015, Nicola et al 2019]. Brain MRI anomalies include corpus callosum abnormalities, ventriculomegaly, and white matter abnormalities.