22q11.2 Deletion, Duplication Linked to Opposing Changes in White Matter

3D color medical concept of human brain white matter

Deletions or duplication at the 22q11.2 chromosomal locus are associated with high rates of neuropsychiatric disorders. Individuals with 22q11.2 deletion (22q-del) have an increased risk of autism spectrum disorder, attention deficit–hyperactivity disorder, and anxiety, and up to 25% develop psychosis. 22q11.2 duplication (22q-dup) carriers may have a normal or near-normal phenotype, or present with potential psychiatric manifestations that partially overlap those reported for 22q-del. However, 22q-dup is not associated with a higher risk of psychosis, with some studies suggesting that the psychosis risk is lower than in the general population.

Ofer Pasternak, PhD, an associate professor in the Department of Psychiatry at Brigham and Women’s Hospital, Johanna Seitz-Holland, MD, PhD, investigator and instructor in the department, and colleagues from Brigham and Women’s Hospital and from the University of California, Los Angeles, conducted the first study to compare white matter (WM) in 22q-del and 22q-dup.

In Translational Psychiatry, they report finding opposing abnormalities that might indicate distinct WM pathologies in 22a-del and 22q-dup.


Twenty-six individuals with 22q-del, 19 carriers of 22q-dup and 18 healthy controls underwent diffusion-weighted magnetic resonance imaging (dwMRI). This imaging technique can assess the microstructure of WM by measuring the direction and extent of water molecule diffusion in the brain. Diffusion was quantified using the fractional anisotropy (FA) index, and additional advanced dwMRI analyses.

FA Analyses

  • Individuals with 22q-del had significantly higher FA than controls (in 41% of WM) or 22q-dup carriers (in 66% of WM)
  • 22q-dup carriers, conversely, had significantly lower FA than controls in 37% of WM

Additional Analyses

The researchers applied advanced dwMRI analyses to determine mechanisms that might drive FA alterations.

In individuals with 22q-del, the higher FA was accompanied by higher fiber fractions and less extracellular space than in controls, as well as greater volumes of cerebrospinal fluid and smaller WM volumes than in either controls or 22-dup carriers. These results suggest WM may be abnormally densely packed in people with 22q-del.

In 22q-dup carriers, the lower FA was accompanied by lower fiber fractions and greater extracellular space than in controls. Similar patterns have been observed in many behaviorally defined neuropsychiatric disorders, including psychosis, mood disorders, obsessive-compulsive disorder and dementia. In contrast to 22q-del, the microstructural changes were not associated with volumetric changes.

Interpreting the Findings

Opposing effects of copy number variation on WM architecture have been detected in imaging studies of other loci related to neuropsychiatric disease, including 15q11.2 (as reported in Human Brain Mapping) and 16p11.2 (as reported in Biological Psychiatry). The authors of both papers speculated their findings indicate a “gene dosage effect” on brain structure.

Additional research is needed, but the results of this study do not appear to support a direct gene dosage effect on WM. The lower FA in 22q-dup carriers could be related to less myelin, but the higher FA observed in individuals with 22q-del is unlikely to result from abnormally increased myelination, judging from previous postmortem studies and the severe functional abnormalities associated with 22q-del.

Instead, this study suggests microstructural WM changes are related to macrostructural volume changes in individuals with 22q-del and not those with 22q-dup. Postmortem and animal studies will be needed to determine why this is so. Clinically, an intriguing possibility is that longitudinal human studies might identify changes in dwMRI measures that could predict the onset of psychosis in individuals with 22q-del.

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