Human Genetics (2018) 137:961–970 https://doi.org/10.1007/s00439-018-1960-6 ORIGINAL INVESTIGATION Chromosome 18 gene dosage map 2.0 Jannine D. Cody1,2 · Patricia Heard1 · David Rupert1 · Minire Hasi‑Zogaj1 · Annice Hill1 · Courtney Sebold1 · Daniel E. Hale1,3 Received: 9 August 2018 / Accepted: 14 November 2018 / Published online: 17 November 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract In 2009, we described the first generation of the chromosome 18 gene dosage maps. This tool included the annotation of each gene as well as each phenotype associated region. The goal of these annotated genetic maps is to provide clinicians with a tool to appreciate the potential clinical impact of a chromosome 18 deletion or duplication. These maps are continually updated with the most recent and relevant data regarding chromosome 18. Over the course of the past decade, there have also been advances in our understanding of the molecular mechanisms underpinning genetic disease. Therefore, we have updated the maps to more accurately reflect this knowledge. Our Gene Dosage Map 2.0 has expanded from the gene and phenotype maps to also include a pair of maps specific to hemizygosity and suprazygosity. Moreover, we have revamped our classification from mechanistic definitions (e.g., haplosufficient, haploinsufficient) to clinically oriented classifications (e.g., risk factor, conditional, low penetrance, causal). This creates a map with gradient of classifications that more accurately represents the spectrum between the two poles of pathogenic and benign. While the data included in this manuscript are specific to chro- mosome 18, they may serve as a clinically relevant model that can be applied to the rest of the genome. Introduction possible consequences, the genetics community has gener- ally attempted to classify genomic imbalances on a gradient The rapidly increasing use of molecular diagnostics is identi- between benign and pathogenic using a scale based on the fying a growing number of people with both small and large strength of the evidence for pathogenicity (Richards et al. genomic copy number changes. However, data regarding 2015). The implication is that once all evidence is “very the clinical implications of these imbalances lag far behind. strong” all genomic copy number variations (CNVs) will Without linking genotype to phenotype, the utility of molec- be either pathogenic or benign. Such a dichotomous clas- ular diagnostics is limited. While some genomic imbalances sification fails to capture the full breadth of the biology. For may have no clinical implications, others may have a serious example, the data could be very strong that hemizygosity of impact. In between these two extremes lies a wide spectrum gene A is benign; however, it is causative of disease in the of potential outcomes. However, despite this wide range of presence of a loss-of-function mutation in gene B. Or, gene A hemizygosity is causative of disease only with exposure to a particular drug. In both cases, gene A hemizygosity alone Electronic supplementary material The online version of this is benign yet has clinically actionable implications. Con- article (https ://doi.org/10.1007/s0043 9-018-1960-6) contains veying the potential consequences is particularly important, supplementary material, which is available to authorized users. because the end goal for each genomic change is the knowl- * Jannine D. Cody edge of the biological consequences of that change and the [email protected] potential for rectifying those that are adverse. We are particularly attuned to both genotypic and pheno- 1 Department of Pediatrics, The Chromosome 18 Clinical Research Center, University of Texas Health Science Center typic variation due to the non-recurrent nature of most of the at San Antonio, 7703 Floyd Curl Drive, San Antonio, chromosome 18 conditions. The vast majority of individuals TX 78229, USA with chromosome 18 genomic copy number changes have 2 The Chromosome 18 Registry and Research Society, unique regions of genomic variation. This is not a popula- San Antonio, TX 78229, USA tion of people with recurrent CNVs. For example, no two 3 Department of Pediatrics, Penn State Milton S. Hershey unrelated people with a simple 18q deletion have the same Medical Center, Hershey, PA 17033, USA Vol.:(0123456789)1 3 962 Human Genetics (2018) 137:961–970 region of hemizygosity, and half of those with 18p deletions consequences of abnormal gene dosage has informed the have unique deletions (Heard et al. 2009; Hasi-Zogaj et al. creation of a more nuanced and clinically relevant gene dos- 2015). This means that accurately predicting the clinical age map for chromosome 18 to serve as a model for the rest consequences of an individual’s unique deletion or dupli- of the genome. cation must be based on the genes involved in the imbal- ance and not merely the chromosome arm within which it lies (e.g., 18q- or 18p-). For this reason, we have created a Materials and methods gene dosage map which annotates each of the known 263 genes on chromosome 18 as well as identifies each region The Chromosome 18 Gene Dosage Maps are visualized of the chromosome linked to specific phenotypes. The first as custom tracks within the University of California Santa edition was published in 2009 (Cody et al. 2009a) and is Cruz Genome Browser. The information used to create and updated annually. The original map included four categories update these maps is derived from multiple sources. We uti- that were mechanistically defined; haplosufficient, haploin- lize the genotype and phenotype data from our cohort of sufficient, conditionally haploinsufficient, and haplolethal. over 650 individuals with chromosome 18 genomic copy However, we now recognize that this classification scheme number changes. This longitudinal study, now in its 27th is as limiting as the dichotomous classifications of benign year, has been approved by the University of Texas Health and pathogenic. In addition, the mechanistic response to a Science Center at San Antonio’s Institutional Review Board. dosage imbalance does not necessarily translate into clinical All study participants are involved in the informed consent relevance. For example, mice with a deletion of the Slc14a1 process which is appropriately documented. The molecu- gene have a urea transport deficiency yet they do not suffer larly defined chromosome 18 copy number changes for each any clinical syndrome, suggesting the existence of compen- participant were determined by high resolution microarray satory mechanisms (Jiang et al. 2017). While hemizygosity as previously described (Heard et al. 2009).The clinical of the SLC14A1 gene may result in haploinsufficiency in consequences and genotype–phenotype correlations have humans at a physiological level the clinical outcome is not been described in numerous publications and were recently significant. reviewed (Hasi-Zogaj et al. 2015; Sebold et al. 2015; Carter The difficulty in determining where to draw the line et al. 2015; O’Donnell et al. 2015; Cody et al. 2015). In addi- between haplosufficient and haploinsufficient; or even tion, we use data derived from scientific publications and between pathogenic and benign became increasingly prob- public databases to inform our classifications. Of particular lematic. Is a gene in hemizygosity that causes an abnormal importance is the Database of Genomic Variation (DGV) phenotype benign when this phenotype is 49% penetrant and (MacDonald et al. 2014) which identifies regions of CNV pathogenic when it is 51% penetrant? Or is it the severity of in control populations thereby eliminating them from high the phenotype itself that defines the terminology? Is a gene penetrance classifications. in hemizygosity that causes short stature benign but another Like the original version, there are two types of data one that causes deafness pathogenic? Or is it the age of onset in this second version of the chromosome 18 gene dosage of the abnormal phenotype that is the determining factor? maps: genes and phenotype regions. Each gene on chromo- For example is a gene in hemizygosity that causes an adult some 18 has been classified into one of the seven classes for onset cancer benign but one that causes congenital cataracts hemizygosity and six for suprazygosity. We use the term pathogenic? These are the questions that prompted us to re- suprazygosity to combine data on individuals with trisomy think and re-categorize the terminology and designations 18 as well as tetrasomy 18p. In addition, phenotypes linked from our original gene dosage maps. to specific regions are classified into five hemizygosity We have modified and expanded the classifications of classes and four suprazygosity classes. Phenotype regions the consequences of abnormal gene dosage to emphasize are those regions of the chromosome linked to a specific penetrance and the probability of an abnormal clinically disease or phenotype but for which the causative gene(s) relevant phenotype. This moves away from the binary clas- has not yet been identified. These regions range from SNPs sification of pathogenic or benign towards a classification to 24 Mb in size. system that more adequately reflects the biologic variability. The classifications for the gene and phenotype regions These changes make the second generation genome dosage and the data sources and rationale for each one are shown map more clinically relevant to patients and their healthcare below. Data from human studies carries more weight than providers. those from animal studies. In particular, data from our own In addition to describing a more nuanced classification studies provides the most definitive data especially with scheme of genomic variants, we will also present several regard to defining phenotype regions. Recognizing that examples of re-evaluation of disease mechanisms in the some conditions have variable expressivity, the presence of context of our own data. The updated information on the any aspect of the associated phenotype is considered to be 1 3 Human Genetics (2018) 137:961–970 963 evidence of the condition in question.