TABLE 1.

Glossary table

Term	Definition
Aneuploidy	The presence of an abnormal number of chromosomes in a cell. Examples are Down syndrome and monosomy X (Turner syndrome).
Anthropometric trait	A trait that describes body dimensions, such as head circumference, height, weight, girth, or body fat composition.
Array comparative genomic hybridization (aCGH)	A molecular cytogenetic method to detect copy number variants (CNVs) by comparing large fragments of DNA from a test individual to those from a reference sample.
Breakpoints (BP), chromosomal	A specific site of breakage, usually associated with a recurrent chromosomal abnormality. As in 16p11.2 distal CNV BP2‐BP3, where BP2‐BP3 refers to BP 2 to BP 3. For some CNVs, several low copy repeats (LCRs) in the region allow for multiple such BPs.
Copy number variant (CNV)	A type of structural genomic variation (Figure 1) that includes insertions, inversions, and translocations (Sharp, Cheng, & Eichler, 2006) in which segments of the genome are either deleted or duplicated. “Pathogenic” recurrent CNVs are of vastly different sizes and can span many genes (up to 90 for 22q11.2; McDonald‐McGinn et al., 2015) or just one (as in the case of NRXN1 CNVs; Lowther et al., 2017). Differences in BPs within the same locus add to the complexity of CNVs (e.g., in the 16p11.2 or 1q21.1 regions). In addition to recurrent CNVs, numerous ultra‐rare nonrecurrent, “one‐hit,” or single CNVs may also disrupt normal function.
CNV ‐ naming	A CNV is named based on its locus, that is, its specific position on the chromosome. The shorter arm of a chromosome is termed the p‐arm (petite = French for small), while the longer arm is the q‐arm. For example, the 16p11.2:16 = chromosome 16; p = p‐arm; 11 = region 1, band 1; 2 = sub‐band 2. Distal and proximal are used when two CNVs are present at the same locus (e.g., the 16p11.2 distal and proximal CNVs)—Distal is situated farther away from the centre of the chromosome (called the centromere) than the proximal which is closer to the centromere.
de novo	A genomic variation that occurs spontaneously in the offspring and thus is not inherited from the parents.
Fluorescence in situ hybridization (FISH)	A targeted molecular cytogenetic method used to detect and localize a chromosomal deletion or duplication using fluorescent probes corresponding to the DNA sequence targeted.
Gene dosage effect	The relationship between the number of copies of a gene and, for example, gene expression or brain volume.
Gene dose response	The effect of altering the amount of genetic material in a region/the magnitude of the response of an organism to changes in gene presence.
Genome assembly/build	A reference genome assembly is a string of digital ATCG nucleotides representing the complete set of genes from an organism. It is assembled through a consensus of the genomes of different donors. The most recent human genome assembly, termed GRCh38 (also called “build 38”), was released in 2013 and is derived from 13 anonymous donors. Earlier human reference genome versions include: GRCh37 or hg19 (2009), NCBI36 or hg18 (2006), NCBI35 or hg17 (2004), and NCBI34 or hg16 (2003)
Genetics‐first approach	A strategy used in epidemiological studies to associate specific genotypes (such as a specific CNV) with apparent clinical phenotypes of a complex disease or trait. Also called “genotype‐first.”
Genotyping	The process of determining differences in the genetic make‐up (genotype) of an individual by examining the individual's DNA sequence using biological assays. The term is often used to refer to the identification of SNPs through (SNP) genotyping arrays.
Genetic heterogeneity	The same or similar phenotypes caused by different genetic mechanisms.
Idiopathic	Any disease or condition for which the cause is unknown.
Insertion	A structural variant that involves a mutation through the addition of genetic material to a chromosome.
Inversion	A structural variant in which a segment of a chromosome is reversed end to end.
Low copy repeats (LCRs)	Highly homologous sequence elements within the eukaryotic genome arising from segmental duplication and predisposing the genome to nonallelic homologous recombination (NAHR). LCRs mediate many of the chromosomal rearrangements that underlie genomic disorders by predisposition to recombination errors.
Multiplex ligation‐dependent probe amplification (MLPA)	A molecular cytogenetic method used to identify copy number variants. It is a variation of the multiplex polymerase chain reaction that permits amplification of multiple targets with only a single primer pair.
Nonallelic homologous recombination (NAHR)	A form of homologous recombination that occurs in two pieces of DNA that have similar sequences, often as a result of the presence of low copy repeats (LCRs). NAHR can occur within the same LCR or in an alternative LCR, and can result in a variety of chromosomal rearrangements, including deletion, duplication, translocation, and inversion. The presence of LCRs and resultant NAHR is believed to play a key role in molecular evolution in primates, as a mechanism involved in rapidly changing gene dosage (which may be advantageous) and even in the creation of new genes.
Noncarrier	In the context of CNVs, this is usually defined as an individual who does not carry the particular CNV being studied.
Penetrance	The proportion of people with a particular genotype/CNV who have any signs or symptoms of the disease.
Pleiotropy	The phenomenon whereby one allele (or a pair of alleles) influences multiple, independent phenotypes.
Polygenic trait	A phenotype that is influenced by multiple genetic variants at different genomic sites.
Rare CNV	Typically defined as a CNV with <1% frequency in the population.
Reciprocal CNVs	Deletions and duplications that occur at the same locus, usually flanked by LCRs.
Recurrent CNVs	CNVs that occur as spontaneous de novo events at the same sites in the genome repeatedly in unrelated individuals due to the presence of flanking low copy repeats, or LCRs) (Hastings, Lupski, Rosenberg, & Ira, 2009). In other words, they occur de novo in the first individual, and hence are not observed in the CNV carrier's parents but are potentially inherited in subsequent generations.
Single nucleotide polymorphism (SNP)	The substitution of a single base (A, T, C, or G) for another base at a specific genetic location that occurs in at least 1% of the population. A SNP may or may not have functional consequences on gene expression.
SNP genotyping array	DNA microarray used to detect SNPs within a population.
Somatic disease	A disease relating to the body, especially as distinct from the mind.
Translocation	A structural variant in which a portion of a chromosome breaks from its original location and reattaches to a different location in the genome.