Development and Adaptive Function in Individuals With -Related Disorders.

BACKGROUND AND OBJECTIVES

Developmental impairment is common in individuals with -related disorders, although descriptions are limited. We aimed to determine trajectories and outcomes of development and adaptive function.

METHODS

This was a mixed retrospective cross-sectional study of individuals from an international Natural History Study, who had neurologic/neurodevelopmental disorders due to an variant. Individuals with intragenic variants were grouped into early-onset (EO) and late-onset (LO) phenotypic groups; those with -containing 2q24.3 copy number variants (CNVs) were considered separately. We collected medical and developmental history from parents/caregivers and medical records. Adaptive function and behavior were characterized using functional classification system levels and Vineland Adaptive Behavior Scales-3 (VABS-3) Parent/Caregiver Form. We repeated analyses on individuals with variants known to result in gain-of-function (GOF, typically EO phenotypes) or loss-of-function (LOF, typically LO phenotypes).

RESULTS

A total of 100 individuals (age 0.1-21.9 years, 39% female) were studied. Phenotypic groups were EO (n = 44), LO (n = 48), and 2q24.3 CNV (n = 8). Developmental delay/intellectual disability was present in 91 of 100, and 23 of 80 individuals (29%) older than 2 years had autism spectrum disorder. Of people older than the typical age for skill attainment, 59 of 95 (62%) could sit and 48 of 88 (55%) could walk. In addition, 27 of 86 individuals (31%) spoke more than 1-5 single words, and 24 of 74 (32%) followed two-step commands. Median VABS-3 Adaptive Behavior Composite (ABC) scores were as follows: the EO phenotypic group had a score of 56 (range 21-110), the LO phenotypic group had a score of 45 (range 20-89), and 5 of 6 with a 2q24.3 CNV had an ABC score of <45. The EO phenotypic group had 3 distinct subgroups, consistent with "benign," "intermediate," and "severe" definitions previously published. The LO phenotypic group showed a continuum of severity, without distinct clusters. However, clinically relevant differences in motor function were evident when subgrouped by seizure-onset age; a lower proportion with earlier seizure onset (age <18 months) were independently ambulant than those with later onset or no seizures (5/15 [33%] vs 10/12 [83%] vs 14/15 [93%], < 0.01). Analyses of individuals with confirmed GOF/LOF variants (n = 57) showed similar results to the EO/LO analyses.

DISCUSSION

The spectrum of developmental impairments and adaptive function in -related disorders is extremely broad. Phenotypic subgroups provide prognostic information and critically inform clinical trial design.