Defining the Clinical Phenotype of Recurrent Copy Number Variation at Chromosome 1q21.1

Background: Copy number variation (CNV) at chromosomal region 1q21.1 is associated with a range of phenotypes, including autism spectrum disorder (Mefford et al, 2008; Girirajan et al, 2013). Given the variability of the phenotype, the limited sample sizes of previous studies, and the lack of comparison cohorts with which to more precisely refine the behavioral phenotype, characterization of the phenotype and commonly associated features are needed for deletions and duplications at 1q21.1.

Objectives: To describe the psychiatric and behavioral phenotype of 1q21.1 deletion and duplications and identify shared and distinct features of between deletions and duplications carriers.

Methods: Participants included 36 individuals (19 children) with a confirmed 1q21.1 deletion or duplication (19 deletion; 17 duplication) ascertained through the Simons VIP connect online portal. Detailed medical history was collected through interview and medical records review. Standardized diagnostic and detailed neuropsychologic assessment was conducted at one of three participating Simons VIP clinical sites and included ADOS and ADI, as well as cognitive, language, behavioral and adaptive skills assessment. Multivariate ANOVA was used to examine differences in phenotypic presentation of individuals with deletions and duplications.

Results: Of the 19 deletion patients, 9 were children. Of the 17 duplication patients, 10 were children. All but one of the children was the initially identified patient.  In the deletion cohort anxiety/mood disorders (31%), developmental coordination disorder (19%), ASD (12%) and intellectual disability (12%), were the most common psychiatric disorders.  In the duplication cohort, the most common diagnoses were ASD (44%), ADHD (31%), intellectual disability (31%), and developmental coordination disorder (25%). Deletion carriers generally reported a higher frequency of some medical manifestations than duplications carriers: cataracts (17% vs 0%), seizures (17% vs 0%), short stature (25% vs 0%), hypothyroidism (17% vs 0%), genito-urinary problems (17% vs 9%), and microcephaly (34% vs 0%). Similar frequencies of hypotonia (58% vs 54%) and lower rates of macrocephaly (0% vs 27%) and congenital heart disease (0% vs 18%) were reported in deletions relative to duplications. For deletions and duplications, the children were more impaired than the adults in cognitive ability, adaptive functioning, and parent report of ASD symptoms. For adults average nonverbal IQ, verbal IQ, adaptive functioning, and ASD symptomatology were in the normal range, while for children nonverbal IQ, verbal IQ, and adaptive ability fell in the borderline low normal range and ASD symptomatology fell in the clinical ASD range. In both adults and children, deletion carriers did not significantly differ from duplication carriers in cognitive and adaptive ability or ASD symptom severity. When only the initially identified probands were compared, there were no differences between deletion and duplication carriers in cognitive and adaptive functioning, but duplication carriers showed significantly greater ASD symptom severity (ADOS CSS F(1,14)=6.3, p=.02).

Conclusions: Psychiatric and other medical disorders were common in both individuals with the 1q21.1 deletion and duplication. While deletion and duplication carriers shared some nonspecific traits (e.g. borderline cognitive functioning), there was a high and increased frequency of ASD in 44% of duplication carriers relative to 12% of deletion carriers.