Proximal microdeletions and microduplications of 1q21.1 contribute to variable abnormal phenotypes

Abstract

Chromosomal band 1q21.1 can be divided into two distinct regions, proximal and distal, based on segmental duplications that mediate recurrent rearrangements. Microdeletions and microduplications of the distal region within 1q21.1, which are susceptibility factors for a variety of neurodevelopmental phenotypes, have been more extensively studied than proximal microdeletions and microduplications. Proximal microdeletions are known as a susceptibility factor for thrombocytopenia-absent radius (TAR) syndrome, but it is unclear if these proximal microdeletions have other phenotypic consequences. Therefore, to elucidate the clinical significance of rearrangements of the proximal 1q21.1 region, we evaluated the phenotypes in patients identified with 1q21.1 rearrangements after referral for clinical microarray testing. We report clinical information for 55 probands with copy number variations (CNVs) involving proximal 1q21.1: 22 microdeletions and 20 reciprocal microduplications limited to proximal 1q21.1 and 13 microdeletions that include both the proximal and distal regions. Six individuals with proximal microdeletions have TAR syndrome. Three individuals with proximal microdeletions and two individuals with larger microdeletions of proximal and distal 1q21.1 have a 'partial' TAR phenotype. Furthermore, one subject with TAR syndrome has a smaller, atypical deletion, narrowing the critical deletion region for the syndrome. Otherwise, phenotypic features varied among individuals with these microdeletions and microduplications. The recurrent, proximal 1q21.1 microduplications are enriched in our population undergoing genetic testing compared with control populations. Therefore, CNVs in proximal 1q21.1 can be a contributing factor for the development of abnormal phenotypes in some carriers

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

“…There is little information in the published cases regarding dimensional assessment of functioning, rendering comparison to our findings difficult. Previously reported duplication cases have similar rates as deletion cases of ASD diagnosis 6 and developmental delay, 1,2 suggesting, at least at the categorical level, the deleterious impact of both CNVs is sufficient to cross diagnostic thresholds and neither emerges as more impairing.…”

“…The observed high frequency of ASD and other associated developmental abnormalities in the duplication cases is consistent with previous findings. 2,6,12 In the 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.…”

“…1,3,8 Although both deletions and duplications have been reported in individuals with schizophrenia and ASD, deletions have been more strongly associated with schizophrenia than duplications [9][10][11][12] and duplications more strongly associated with ASD/autistic features than deletions. 2,3,6,8 Most studies of 1q21.1 have reported on individuals ascertained through disease-specific series, e.g., work performed by The International Schizophrenia Consortium (2008) and Levinson et al 9,12 Studies of patients ascertained from genetics clinics [1][2][3]6 provide a broader understanding of the full range of the clinical phenotype but are limited in the availability of standardized, dimensionally assessed behavioral and psychiatric features.…”

“…This is due, in part, to the rarity of specific CNVs limiting sample sizes, and also because of differing ascertainment approaches, rendering equivalent comparisons impossible. The detailed characterization of , LeeAnne Green Snyder, PhD 6,10 , Sarah Spence, MD 11 , Melissa B. Ramocki, MD 12 , David W. Evans, PhD 13 , John E. Spiro, PhD 10 , Christa L. Martin, PhD 13,14 , David H. Ledbetter, PhD 13,14 and Wendy K. Chung, MD 15,16 ; on behalf of the Simons VIP consortium.…”

“…Deletions and duplications at the 1q21.1 locus are more frequent in clinical series of individuals with intellectual disability, developmental delay, schizophrenia, and autism spectrum disorder (ASD) compared with controls. [1][2][3][4][5][6][7] Phenotypes associated with 1q21.1 also include other psychiatric diagnoses such as learning disabilities, attention-deficit hyperactivity disorder (ADHD), bipolar disorder, anxiety, and depression. 1,3,8 Although both deletions and duplications have been reported in individuals with schizophrenia and ASD, deletions have been more strongly associated with schizophrenia than duplications [9][10][11][12] and duplications more strongly associated with ASD/autistic features than deletions.…”