Deep phenotyping in 3q29 deletion syndrome: recommendations for clinical care

Abstract

Purpose: To understand the consequences of the 3q29 deletion on medical, neurodevelopmental, psychiatric, brain structural, and neurological sequalae by systematic evaluation of affected individuals. To develop evidence-based recommendations using these data for effective clinical care.

Methods: Thirty-two individuals with the 3q29 deletion were evaluated using a defined phenotyping protocol and standardized data collection instruments.

Results: Medical manifestations were varied and reported across nearly every organ system. The most severe manifestations were congenital heart defects (25%) and the most common were gastrointestinal symptoms (81%). Physical examination revealed a high proportion of musculoskeletal findings (81%). Neurodevelopmental phenotypes represent a significant burden and include intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), and graphomotor weakness (78%). Psychiatric illness manifests across the lifespan with psychosis prodrome (15%), psychosis (20%), anxiety disorders (40%), and attention deficit-hyperactivity disorder (ADHD) (63%). Neuroimaging revealed structural anomalies of the posterior fossa, but on neurological exam study subjects displayed only mild or moderate motor vulnerabilities.

Conclusion: By direct evaluation of 3q29 deletion study subjects, we document common features of the syndrome, including a high burden of neurodevelopmental and neuropsychiatric phenotypes. Evidence-based recommendations for evaluation, referral, and management are provided to help guide clinicians in the care of 3q29 deletion patients.

Fig. 1. Z-scores for height, weight, and frontal occipital circumference (FOC) as a function of age, for males (blue, left panels) and females (red, right panels).

These data indicate the 3q29 deletion has an impact toward diminished height, weight, and FOC, and this is more pronounced at younger ages.

Fig. 2. Percent of 3q29 deletion participants who qualify for neurodevelopmental and neuropsychiatric diagnoses after direct evaluation by our team.

19% of study subjects qualified for a diagnosis of psychosis; 14% had features of schizophrenia prodrome (light blue). ADHD attention deficit–hyperactivity disorder, ASD autism spectrum disorder, ID intellectual disability, VMI graphomotor weakness.

Fig. 3. Midsagittal T1-weighted images acquired from N = 24 patients with 3q29 deletion (3q29Del) syndrome.

A representative T1-weighted image from a healthy control is provided in the first panel for comparison (red dashed lines indicate normative anatomical boundaries of the posterior fossa). T1-weighted patient images are displayed in ascending chronological age, with participant demographics (sex, age in years) provided below each scan. Posterior fossa abnormalities (indicated by red arrows) were observed in N = 17 (70.83%) patients. Note that midline sagittal images were selected to provide optimal visualization of the cerebellar vermis and retrocerebellar arachnoid cysts. Presence of cerebellar hemispheric hypoplasia was determined via anatomical inspection of the adjacent cerebellar hemispheres in the coronal and horizontal planes, which were not included in this figure due to space limitations.