Clinical phenotype of the recurrent 1q21.1 copy-number variant

Abstract

Purpose: To characterize the clinical phenotype of the recurrent copy-number variation (CNV) at 1q21.1, we assessed the psychiatric and medical phenotypes of 1q21.1 deletion and duplication carriers ascertained through clinical genetic testing and family member cascade testing, with particular emphasis on dimensional assessment across multiple functional domains.

Methods: Nineteen individuals with 1q21.1 deletion, 19 individuals with the duplication, and 23 familial controls (noncarrier siblings and parents) spanning early childhood through adulthood were evaluated for psychiatric, neurologic, and other medical diagnoses, and their cognitive, adaptive, language, motor, and neurologic domains were also assessed. Twenty-eight individuals with 1q21.1 CNVs (15 deletion, 13 duplication) underwent structural magnetic resonance brain imaging.

Results: Probands with 1q21.1 CNVs presented with a range of psychiatric, neurologic, and medical disorders. Deletion and duplication carriers shared several features, including borderline cognitive functioning, impaired fine and gross motor functioning, articulation abnormalities, and hypotonia. Increased frequency of Autism Spectrum Disorder (ASD) diagnosis, increased ASD symptom severity, and increased prevalence of macrocephaly were observed in the duplication relative to deletion carriers, whereas reciprocally increased prevalence of microcephaly was observed in the deletion carriers.

Conclusions: Individuals with 1q21.1 deletions or duplications exhibit consistent deficits on motor and cognitive functioning and abnormalities in head circumference.Genet Med 18 4, 341-349.

Figure 1:. Dimensional Assessment of Participants.

(a) Histogram revealing smaller mean standardized head circumference for deletion carriers (red) relative to duplication carriers (blue) collected during clinical site visits. Head circumference was collected from a total of 19 deletion carriers and 18 duplication carriers. (b) Mean performance across domains of functioning for individuals with deletions, individuals with duplication, and familial noncarrier controls. Cognitive ability is represented as nonverbal and verbal IQ, and adaptive functioning is reflected by an overall adaptive composite. IQ and adaptive functioning estimates have a mean of 100 and standard deviation of 15. Mean values for motor ability, defined by Purdue T scores, phonological processing, defined by a nonword repetition task, and autism severity, defined by the comparison score, have been re-scaled to a mean of 100 and standard deviation of 15. Greater comparison scores signify increased autism severity. *Significant difference between deletion and duplication carriers.

Figure 2:. Dimensional Assessment of Participants.

Relationship between overall cognitive ability, proband status, and age in the cohort showing that the proband children in both the deletion and duplication groups had a greater range of cognitive abilities that extended into the impaired range, whereas the adults, identified through cascade testing, had cognitive abilities that spanned the average to above average range.