Developmental trajectories in 22q11.2 deletion

Abstract

Chromosome 22q11.2 deletion syndrome (22q11.2DS), a neurogenetic condition, is the most common microdeletion syndrome affecting 1 in 2,000-4,000 live births and involving haploinsufficiency of ∼50 genes resulting in a multisystem disorder. Phenotypic expression is highly variable and ranges from severe life-threatening conditions to only a few associated features. Most common medical problems include: congenital heart disease, in particular conotruncal anomalies; palatal abnormalities, most frequently velopharyngeal incompetence (VPI); immunodeficiency; hypocalcemia due to hypoparathyroidism; genitourinary anomalies; severe feeding/gastrointestinal differences; and subtle dysmorphic facial features. The neurocognitive profile is also highly variable, both between individuals and during the course of development. From infancy onward, motor delays (often with hypotonia) and speech/language deficits are commonly observed. During the preschool and primary school ages, learning difficulties are very common. The majority of patients with 22q11.2DS have an intellectual level that falls in the borderline range (IQ 70-84), and about one-third have mild to moderate intellectual disability. More severe levels of intellectual disability are uncommon in children and adolescents but are more frequent in adults. Individuals with 22q11.2DS are at an increased risk for developing several psychiatric disorders including attention deficit with hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anxiety and mood disorders, and psychotic disorders and schizophrenia. In this review, we will focus on the developmental phenotypic transitions regarding cognitive development in 22q11.2DS from early preschool to adulthood, and on the changing behavioral/psychiatric phenotype across age, on a background of frequently complex medical conditions.

Keywords: 22q11.2 deletion; Di George; chromosome 22; developmental trajectories.

Figure 1

Low copy repeats, represented here as A, B, C, and D, bracket the 22q11.2 deletion and define the breakpoints with the standard ∼3Mb 22q11.2 deletion extending from A–D. Atypical nested deletions include A–B, A–C, B–C, B–D, and C–D. Notable genes within the deleted regions of chromosome 22q11.2 include PRODH, TBX1 and COMT within A–B and SNAP 29 and CRKL1 within C–D. Note that FISH probes D22S75 (N25) and HIRA (TUPLE1) are located within A–B and would be present in those patients with nested deletions excluding the A–B region.

Figure 2

Most common indications for 22q11.2 deletion testing varies by age.

Figure 3

Developmental cognitive trajectories in 22q11 DS.