The pleiotropic spectrum of proximal 16p11.2 CNVs

Abstract

Recurrent genomic rearrangements at 16p11.2 BP4-5 represent one of the most common causes of genomic disorders. Originally associated with increased risk for autism spectrum disorder, schizophrenia, and intellectual disability, as well as adiposity and head circumference, these CNVs have since been associated with a plethora of phenotypic alterations, albeit with high variability in expressivity and incomplete penetrance. Here, we comprehensively review the pleiotropy associated with 16p11.2 BP4-5 rearrangements to shine light on its full phenotypic spectrum. Illustrating this phenotypic heterogeneity, we expose many parallels between findings gathered from clinical versus population-based cohorts, which often point to the same physiological systems, and emphasize the role of the CNV beyond neuropsychiatric and anthropometric traits. Revealing the complex and variable clinical manifestations of this CNV is crucial for accurate diagnosis and personalized treatment strategies for carrier individuals. Furthermore, we discuss areas of research that will be key to identifying factors contributing to phenotypic heterogeneity and gaining mechanistic insights into the molecular pathways underlying observed associations, while demonstrating how diversity in affected individuals, cohorts, experimental models, and analytical approaches can catalyze discoveries.

Keywords: multi-system disorder; penetrance; pleiotropy; proximal 16p11.2 BP4-5 CNV; structural variant; variable expressivity.

Graphical abstract

Figure 1

Genomic landscape of the 16p11.2 region (A) Overview of 16p11.2 cytoband (GRCh38), with the minimal 16p11.2 BP4-5 region highlighted in blue. Upper track: exonic structure of protein-coding genes overlapping the region colored according to GnomAD v.2.1.1 loss-of-function observed over expected upper bound fraction (LOEUF) score. Small LOEUF (<0.35) indicates selection against loss-of-function variants in the gene, i.e., evolutionary constraint. Genes with no LOEUF score are in gray. Tagged genes: ° indicates Online Mendelian Inheritance in Man (OMIM) morbid genes; ^∗ have a new HGNC symbol since the GnomAD v.2.1.1 release (SGF29 [MIM: 613374] was CCDC101 and TLCD3B [MIM: 615175] was FAM57B). Middle track: segmental duplications colored according to similarity degree, ranging from 90% to ≥99%. These form the breakpoints (BP) for recurrent copy-number variants (CNVs). Lower track: density of CNVs reported in the Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER; accessed December 12^th, 2020) colored according to CNV count. While rearrangements of the BP4-5 interval are the most common, rearrangements between other BPs have been described, e.g., the second most common CNV in the region spans a 220 kb interval between the BP2-3 (MIM: 613444). (B) ClinGen coordinates for the minimal region affected by the 16p11.2 BP4-5 rearrangements in three human reference genome builds. Coordinates in GRCh37 were lifted over with the University of California Santa Cruz (UCSC) LiftOver tool. Because breakpoints might occur at several locations within the segmental duplication region, exact coordinates and length might vary across individuals.

Figure 2

Pleiotropy of the 16p11.2 BP4-5 region in the UK Biobank (A) Most common copy-number states for the 16p11.2 BP5-4 locus, including the copy-neutral state (2 copies; white), deletion (1 copy; red), and duplication (3 copies; blue), which typically arise through non-allelic homologous recombination (NAHR). (B) Schematic representation of the phenotypic distribution, shown as boxplots, of individuals with different 16p11.2 BP5-4 copy-number states according to four dosage mechanisms, with one example phenotype: an additive mirror mechanism wherein deletion and duplication affect the phenotype in opposite direction, a U-shape mechanism wherein any deviation from the copy-neutral state affects the phenotype in the same direction, and a duplication-only or deletion-only mechanism wherein only duplication or deletion carrier individuals deviate from the copy-neutral phenotypic distribution, respectively. For the two last models, deletion and duplication carrier individuals (semi-transparent) are not assessed to obtain the effect of the duplication and deletion, respectively. (C) Effect sizes (beta; y axis) with 95% confidence interval (CI) of the 16p11.2 BP4-5 deletion (red) and duplication (blue) on 46 complex traits and diseases that were significantly (p ≤ 0.05/117 = 4.3 × 10⁻⁴) associated with the region’s copy-number in the UK Biobank through at least one of four tested association models in (B), ordered by physiological system (x axis). Data from Auwerx et al. Effect sizes are in standard deviation units of the outcome (quantitative traits) or logarithms of the odds ratio of a logistic regression (disease traits). Associations that fail to reach the significance threshold upon conditioning on body mass index (BMI) or involve traits highly correlated with BMI (>0.7) are semi-transparent (BMI-dependent) while the others are opaque (BMI-independent).

Figure 3

Model of phenotypic variability among CNV carrier individuals Schematic view on a holistic approach to understanding phenotypic heterogeneity. Top: distribution of the global health burden among copy-neutral (gray) and CNV carrier (black) individuals. CNV carrier individuals from population cohorts tend to be sampled from the left side of the CNV carrier distribution, while CNV carrier individuals from clinical cohorts tend to be sampled from the right side of that distribution. Bottom: liability to diseases affecting different physiological systems for five individuals sampled from the above distributions. The red mark represents the liability threshold that needs to be exceeded for an individual to be diagnosed with a disease. The threshold is lower for common diseases and individuals that are near the threshold might present with subclinical features, e.g., the first individual is overweight without meeting diagnostic criteria for obesity (orange). The dark-colored area represents the contribution of the CNV to disease liability, which in the absence of epistasis or gene-environment interactions is constant across CNV carrier individuals but variable across diseases. Typically, contribution is stronger for rare disorders, but usually not sufficient to pass the threshold. The light-colored area represents the contribution of various other factors to disease liability, which will determine whether the individual reaches the disease threshold or not. Importantly, contribution of these factors is variable across both diseases and individuals, resulting in phenotypic heterogeneity across CNV carrier individuals.

Figure 4

GWAS Catalog associations at 16p11.2 BP4-5 Top: 290 single-nucleotide variants associations mapping to the 16p11.2 BP4-5 CNV region (GRCh38) reported in the GWAS Catalog (accessed March 14^th, 2024). The negative logarithm of the association p value (P; left y axis) is plotted against the genomic position (x axis). The dashed red line represents the threshold for genome-wide significance, p < 5 × 10⁻⁸. Associations are plotted from the suggestive p value of p < 7 × 10⁻⁶. p values for three signals, depicted as upward-facing triangles, were truncated. Associations are colored according to physiological systems. Number of signals for each category and subcategory is reported (n). The GRCh38 recombination rate in cM/Mb is depicted in blue (right left axis) and was downloaded from the Eagle software webpage. Bottom: exonic structure of protein-coding genes overlapping the region. ° indicates Online Mendelian Inheritance in Man (OMIM) morbid genes.