Clinical and genomic delineation of the new proximal 19p13.3 microduplication syndrome

Abstract

A small but growing body of scientific literature is emerging about clinical findings in patients with 19p13.3 microdeletion or duplication. Recently, a proximal 19p13.3 microduplication syndrome was described, associated with growth delay, microcephaly, psychomotor delay and dysmorphic features. The aim of our study was to better characterize the syndrome associated with duplications in the proximal 19p13.3 region (prox 19p13.3 dup), and to propose a comprehensive analysis of the underlying genomic mechanism. We report the largest cohort of patients with prox 19p13.3 dup through a collaborative study. We collected 24 new patients with terminal or interstitial 19p13.3 duplication characterized by array‐based Comparative Genomic Hybridization (aCGH). We performed mapping, phenotype–genotype correlations analysis, critical region delineation and explored three‐dimensional chromatin interactions by analyzing Topologically Associating Domains (TADs). We define a new 377 kb critical region (CR 1) in chr19: 3,116,922–3,494,377, GRCh37, different from the previously described critical region (CR 2). The new 377 kb CR 1 includes a TAD boundary and two enhancers whose common target is PIAS4. We hypothesize that duplications of CR 1 are responsible for tridimensional structural abnormalities by TAD disruption and misregulation of genes essentials for the control of head circumference during development, by breaking down the interactions between enhancers and the corresponding targeted gene.

A familial rearrangement resulting in pure duplication of distal 19p13.3

“…The ClinVar database (ClinVar, 2021) lists at least 4 similar entries with a pathogenic or likely pathogenic classification (VCV000059078.1, VCV000146110.2, VCV000057357.1, VCV000145542.2); however, the clinical features are broad or not provided making comparison difficult. Recently, Jouret et al ., (2022) collected the largest series of 19p13.3 duplications ever published and proposed a new critical region CR1 ([GRCh38] chr19: 3 116 924–3 494 379) in addition to the previously described critical region, CR2 ([GRCh38] chr19: 3 979 570–4 093 037) described by Tenorino and Nevado (Nevado et al ., 2015; Tenorio et al ., 2020). Both CR1 at and CR2 at are located more proximally than our duplication (Fig.…”

“…Genes with an increased probability of triplosensitvity (pTriplo score ≥ 0.68, OR ≥ 2) included: DOT1L, APC2, BTBD2, NDUFS7, LMNB2, MEX3D, HCN2, and REXO1. By comparing the overlap between our duplication and excluding genes within benign intervals described in the Database of Genomic Variants (MacDonald et al, 2014) and elsewhere (Jouret et al, 2022) we were able to determine regions of interest encompassing two genes: MBD3 (OMIM *603573), and LMNB2 (OMIM *150341). DOT1L (OMIM *607375) contained a small amount of overlap with published benign duplications, however, it was also considered a gene of interest due to widespread expression and its role in embryonic development.…”