A patient with a de novo distal 22q11.2 microdeletion and anxiety disorder

Abstract

We report on a young female with normal intelligence evaluated for long-term anxiety. Her history includes prematurity, neonatal feeding problems, surgical correction of congenital heart defects, recurrent upper airway and urinary tract infections, and delayed motor and developmental milestones. Physical examination disclosed small stature and minor dysmorphisms. Chromosome analysis, 22q11.2 FISH analysis, and subtelomeric MLPA testing did not detect any abnormalities. Genome wide SNP Array analysis showed a de novo deletion in 22q11.21q11.22, the so-called distal 22q11 microdeletion that involves the MAPK1 gene. A diagnosis of panic disorder was made and the patient was successfully treated with a daily dose of 20 mg citalopram. To our knowledge, this is the first adolescent patient with a long history of complaints about anxiety and a distal 22q11 microdeletion. We speculate that genes from the deleted region, especially MAPK1, increase the neurobiological susceptibility to anxiety disorders that may be a part of the psychopathological phenotype of the distal 22q11.2 microdeletion syndrome.

The recurrent distal 22q11.2 microdeletions are often de novo and do not represent a single clinical entity: a proposed categorization system

“…DD and/or ID have been reported in more than 80% of distal 22q11.2 microdeletion patients described in the literature to date and tend to be relatively mild to moderate in severity. [7][8][9][10][11][12][13][14][15][16][17][18] Taken together, global DD and ID seem to be key components of the distal 22q11.2 microdeletions phenotype irrespective of the size and position of the deletion. Behavioral and neurological problems were also quite common in our patients in all deletion types.…”

“…[7][8][9][10][11][12][13][14][15][16][17][18] These deletions are mediated by nonallelic homologous recombination between the five telomeric LCR22s (LCR22-D to -H) in the distal portion of the 22q11.2 region (Figure 2). 10 Distal 22q11.2 microdeletions that span the LCR22-F to -G interval encompassing the tumor suppressor SMARCB1 gene (also called INI1) have been reported to manifest many of the presenting features mentioned above but also have high incidence of malignant rhabdoid tumors in infancy and early childhood, predominantly in the kidneys and central nervous system, which necessitates tumor surveillance in these patients.…”

“…[7][8][9][10][11][12][13][14][15][16][17][18] Moreover, some patients present with cleft lip and/or cleft palate. Although some of our patients manifested some of these features, the majority of them presented with nonspecific, nondiagnostic features that were quite variable, as shown in the Results section.…”

“…6 Recently, others and we demonstrated that the five telomeric LCR22s, namely LCR22-D to H, at the distal portion of 22q11.2 are causally implicated in the recurrent distal 22q11.2 microdeletion-associated phenotype(s) (OMIM 611867), and their reciprocal microduplications in the region immediately distal to the DG/VCFs typically deleted region (Figure 2). [7][8][9][10][11][12][13][14][15][16][17][18] The structure of the LCR22-D, -E, and -F has been studied and was shown to contain the BCRL module in each LCR22, suggesting that the distal 22q11.2 microdeletions/microduplications are mediated by nonallelic homologous recombination. 10 To date, the distal 22q11.2 microdeletions have been grouped together as a single clinical entity despite the fact that these deletions are variable in size and position depending on the Purpose: The five segmental duplications (LCR22-D to -H) at the distal region of chromosome 22 band q11.2 in the region immediately distal to the DiGeorge/velocardiofacial syndrome deleted region have been implicated in the recurrent distal 22q11.2 microdeletions.…”

Disrupted ERK Signaling during Cortical Development Leads to Abnormal Progenitor Proliferation, Neuronal and Network Excitability and Behavior, Modeling Human Neuro-Cardio-Facial-Cutaneous and Related Syndromes

“…It is possible that these changes may contribute to the behavioral deficits seen in these mice, specifically the anxiety phenotype, which has not been previously observed. In fact, in patients, microdeletion of 22q11.21-22, which encompasses the ERK2 gene, MAPK1 was found to be associated with developmental abnormalities and profound anxiety (Verhoeven et al, 2011). Significantly, copy number variations in ERK1 gene, MAPK3, have been genetically linked with autism and mental retardation (Sanders et al, 2011).…”