Disorders Associated With Diverse, Recurrent Deletions and Duplications at 1q21.1.

Hui Pang,Young Mi Kim,Jianing Yin,Hongcang Gu,Jeremy K Jinkins,Shibo Li,Xiaowei Yu,Xianfu Wang

doi:10.3389/fgene.2020.00577

Abstract

The subchromosomal region 1q21.1 is one of the hotspots in the human genome for deletions and reciprocal duplications, owing to the existence of hundreds of segmental duplications. Recurrent deletions and duplications in this region are thought to be causative in patients with variable clinical manifestations. Based on the genomic locations, deletions and duplications at the 1q21.1 locus have been associated with distinguishable syndromes: chromosome 1q21.1 deletion syndrome, chromosome 1q21.1 duplication syndrome, and thrombocytopenia-absent radius (TAR) syndrome, which is partially due to deletions at the proximal 1q21.1 region. We report here diverse, recurrent deletions and duplications at the 1q21.1 locus in 36 patients from a cohort of 5,200 individuals. Among the 36 patients, 18 patients carry 1q21.1 deletions, nine individuals have reciprocal duplications at 1q21.1, two patients share an identical short deletion, and the remaining seven possess variable sizes of duplications at the proximal 1q21.1 region. Furthermore, we provide cytogenetic characterization and detailed clinical features for each patient. Notably, duplications at the proximal 1q21.1 region have not been associated with a defined disorder in publications. However, recurrent duplications at the proximal 1q21.1 region among the seven patients strongly suggested that the variants are likely pathogenic. The common phenotypical features of those disorders are also summarized to facilitate clinical diagnoses and genetic counseling.

Highlights

Chromosomal breakpoints (BPs) in patients with 1q21.1deletions and duplications have been exclusively mapped to the four segmental duplication blocks, designated as BP1–BP4 according to the orientation from centromere to telomere (Brunetti-Pierri et al, 2008; Rosenfeld et al, 2012)
To better understand the disorders associated with deletions and duplications at the 1q21.1 locus, we investigated more than 5,200 clinical tests conducted in the last 10 years at our laboratory that has been accredited by the College of American Pathologist (CAP) since 2000
The applications of Chromosomal microarray (CMA) technologies have led to the discovery of pathogenicity in many patients with developmental delay (Sharp et al, 2006), intellectual disabilities (IDs), congenital heart defects (Christiansen et al, 2004), autism (Sebat et al, 2007; Marshall et al, 2008), and schizophrenia (International Schizophrenia Consortium, 2008; Stefansson et al, 2008)

Summary

Introduction

Recurrent deletions and duplications at the subchromosomal region 1q21.1 (GRCh37/hg, chr1:144.0–149.5 Mb) have been reported in patients with diverse clinical features (Brunetti-Pierri et al, 2008; Mefford et al, 2008; Cooper et al, 2011; Girirajan et al, 2012). As hundreds of individuals possessing the 1q21.1 deletions or the reciprocal duplications manifest phenotypic abnormalities, documentation and categorization of three syndromes have been included in the Online Mendelian Inheritance in Man (OMIM). Those rare disorders include chromosome 1q21.1 deletion syndrome (MIM 612474), chromosome 1q21.1 duplication syndrome (MIM 612475), and TAR syndrome (MIM 274000). The class I deletions and reciprocal duplications typically occur at the 1q21.1 distal region between BP3 and BP4 with a size range of 800 kb– 2 Mb, and the class II deletions and reciprocal duplications commonly reside between BP1/BP2 and BP4 with relatively bigger sizes of ∼3 Mb or larger (Brunetti-Pierri et al, 2008; Cooper et al, 2011)

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Conclusion