Table 1.

Glossary.

Coisogenic mouse—developed in embryonic stem cells of a mouse strain and bred with the same mouse line to maintain the genetic background of wild-type and mutant mice as identical.

Congenic mouse—backcrossing an F2 generation mouse to the breeder for more than 10 generations to saturate the genetic background with alleles of the breeder, thereby minimizing the systematic difference in the flanking regions between wild-type and mutant mice.

Copy number variant (CNV)—a deviation of the number of alleles (typically 2n for autosomes) of genomic sequence (ranging from a few to several millions of basepairs in length). A deletion refers to the loss of one allele (1n), a duplication refers to an increase in copies (3n).

Df1/+ mouse—a common 22q11.2 mouse model with a hemizygous deletion of the Dgs-i-Ufd1l (Df1) region. This is the second largest deletion model in the homologous murine chromosome 16; Df1/+ mice show cardiovascular anomalies like those seen in humans with 22q11.2 deletions, as well as hyperactivity and deficits in prepulse inhibition.

Df(h22q11)/+ mouse—another common 22q11.2 mouse model with a hemizygous deletion of the region containing Dgcr2-Hira genes. Similar phenotype to the Df1/+ mouse above.

DGCR8—DiGeorge syndrome critical region gene 8 is a microprocessor complex subunit in the 22q11.2 locus that is involved in microRNA processing, which regulates gene expression by binding messenger RNAs to silence their translation. DGCR8 mutations in mice disrupt neuronal morphogenesis, synaptic plasticity, and cognitive performance.

LgDel/+ mouse—well-established 22q11.2 mouse model with the largest deletion in the homologous murine chromosome 16.  LgDel mice have a hemizygous deletion from Idd to Hira, a region containing 24 genes (5 more genes than the Df1/+ mice). They show similar phenotypes to 22q11DS in humans, including cardiac and parathyroid defects, and deficits in prepulse inhibition and in a visual reversal-learning task.

Penetrance—categorically, penetrance can be defined as the prevalence of a given phenotype among individuals with the same pathogenic genetic variant. For example, the penetrance of schizophrenia for 22q11DS is estimated to be 25%. Alternatively, the dimensional assessment of penetrance is a quantitative measure of phenotypic deviation from the population mean. For example, the effect on intellectual ability of 22q11DS can be expressed as an average left shift of ~30 IQ points, or ~2 standard deviations (SD) compared to the IQ distribution in the general population.

Pleiotropy—phenomenon in which a single genetic locus (or mutation) is associated with more than one phenotypic trait/disorder. For example, certain genes increase risk for both ASD and congenital cardiac malformations. Here, we use the term pleiotropy broadly to refer to the range of phenotypic manifestations of the 22q11.2 deletion.

PRODH—proline dehydrogenase (or proline oxidase) is a mitochondrial enzyme in the 22q11.2 locus that catalyzes proline degradation, which is converted to glutamate. PRODH mutations in humans result in hyperprolinemia and are associated with seizures, motor and cognitive delay, aggression, hyperactivity, stereotypic behaviors, and sleep disturbances.

Research Domain Criteria (RDoC)—this alternative approach to psychiatric nosology posits that measures based on dimensions and observable behaviors (both within and across disease diagnoses) may be more informative than our current diagnostic system about mechanisms underlying neuropsychiatric disorders.

SEPT5—Septin 5 is a gene located in the 22q11.2 locus; it is a member of the septin gene family of nucleotide-binding proteins that is implicated in cytoskeletal organization.

Stochastic influences- variation as an intrinsic feature of biological developmental processes. As a result of stochastic variation, the impact of a genetic variant on a brain developmental program may lead to more than one outcome if given a chance to run more than once.

TBX1—T-Box transcription factor 1 is in the 22q11.2 locus and encodes transcription factors involved in regulating developmental processes. Mutation is believed sufficient to cause most of the physical features of 22q11DS.

Variable expressivity—refers to the variability in the severity of a phenotype when present as a result of a pathogenic genetic variant.

ZDHHC8—zinc finger DHHC-type palmitoyltransferase 8 is a gene in the 22q11.2 locus thought to modulate neurotransmitter systems, including activity-dependent plasticity at glutamate synapses, via palmitoylation.