VIP Summary #11: Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID

van Bon et al. – Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID (2016)

In their research on the DYRK1A gene, van Bon and his colleagues aimed to understand how changes in DYRK1A can affect the medical, developmental, and behavioral traits of someone who has this genetic change. The research team identified eight patients with DYRK1A, diagnosed with intellectual disability (ID), epilepsy, and/or ASD as well as one additional patient with the DYRK1A gene change with microcephaly (small head size). These nine patients had undergone genetic testing and had been identified as having de novo (non-inherited)mutations in the DYRK1A gene, meaning that the genetic change was only identified in the patient’s DNA and not in either parent’s DNA. Of these nine identified patients, only five had undergone complete medical evaluations. These evaluations were combined with those of ten other DYRK1A individuals who were previously described in the literature and had had in-depth clinical evaluations.

A Breakdown of the Study Participants

 

 

Because the clinical evaluations of all fifteen individuals were done at different times and measured different things, not all individuals were evaluated for the same 24 characteristics listed in the chart below. The percentages denote the relative prevalence of each characteristic among this DYRK1A population. All fifteen individuals who had undergone clinical evaluation had microcephaly (after birth or in the first months after birth), showed varying degrees of intellectual disability (mild, mild-moderate, moderate, severe, or global), impaired speech, and neonatal feeding problems. Ten out of ten individuals had some type of foot abnormality, of which having a short fifth toe and/or having partial syndactyly (two to four toes are partially fused together) were the most common abnormal features.

 

Most individuals had facial and skeletal (craniofacial) features that were atypical for their developmental stage. In infancy and during childhood, facial characteristics observed included:

 

  • deep-set eyes
  •  mild upslanting of the regions where the eyelids meet (regions called the palpebral fissures)
  •  a short nose with a broad tip  
  • short lower jaw (called retrognathia)
  • broad chin

 

 

 

 

In adulthood, the features become slightly different: the nasal bridge becomes high and the nostrils shorten, giving the nose a more prominent appearance.

 

Febrile seizures, convulsions triggered by fever in young children, were reported in 77% of individuals in childhood, but epilepsy (recurrent seizures) was only seen in 33% (five individuals) at a later age. Nine individuals had an abnormal gait and eight individuals had hypertonia (increased muscle tone making mobility difficult). The level of intellectual disability varied in these individuals with DYRK1A, but the majority (80%) had moderate to severe ID.

 

Based on their clinical evaluation, van Bon and colleagues concluded that a specific type of change in the DYRK1A gene, called truncating mutations, leads to an identifiable syndromatic form of ASD and ID, with the most common features being a specific facial differences, microcephaly, lack of speech, seizures, neonatal feeding problems, hypertonia, and gait irregularities.  The team recommends that evaluations for cardiac and ophthalmologic (eye) abnormalities should be completed in all affected individuals because the occurrence rates were found to be increased for individuals in the study.

 

Several individuals in the study were recruited because of their involvement in registry-based studies similar to Simons VIP. It is through active participation that researchers are able to develop profiles of the common clinical features of a genetic change. We thank Simons VIP families for helping further our knowledge of these genetic changes.