Chromosome 22q13 Duplication Syndrome

A number sign (#) is used with this entry because of evidence that this hyperkinetic neuropsychiatric disorder is caused by heterozygous interstitial duplication in chromosome 22q13 (Chr22:49.5-49.7 Mb, NCBI36) involving the SHANK3 gene (606230).

Clinical Features

On the basis of the phenotype of Shank3-overexpressing mice (see ANIMAL MODEL), Han et al. (2013) hypothesized that SHANK3 overexpression may have a role in hyperkinetic neuropsychiatric disorders in humans. Han et al. (2013) sought and identified 2 patients with small duplications within chromosome 22q13 involving the SHANK3 gene. One patient was an 11-year-old girl diagnosed with ADHD, combined type, who also had developmental delays and learning problems, kleptomania, destructive behavior, auditory overstimulation, and hyperphagia. She experienced 2 generalized tonic-clonic seizures at the age of 2 years without associated fever or other precipitants. Physical exam was significant for minor dysmorphic features including upslanting palpebral fissures, epicanthus inversus, and a pinched nose with anteverted nares. Brain MRI performed at age 2 was normal. Treatment with Adderall resulted in only minimal improvement. The second patient was a 35-year-old male with a longstanding history of bipolar disorder and epilepsy. He had generalized tonic-clonic seizures in childhood, with several episodes of status epilepticus. Levetiracetam provided excellent seizure control. He had significant learning problems and received special education during school. He did graduate from high school at 20 years of age. During adolescence he was diagnosed with bipolar disorder and anger management problems. He had had several inpatient psychiatric hospitalizations and suicide attempts.

Cytogenetics

The 2 patients with hyperkinetic disorders reported by Han et al. (2013) carried the smallest 22q13 duplications spanning the SHANK3 gene reported to that time. The female patient carried a small interstitial duplication of 22q13.33, with a minimal size of 64 kb (chr22:49,461,602-49,525,130, NCBI36) and a maximal size of 240 kb (chr22:49,451,468-49,691,432, NCBI36). This duplication included the entire SHANK3 gene and part of the ACR gene (102480), which encodes a protease expressed in sperm with no known expression or function in the brain. The duplication in the male patient spanned a minimal size of 115 kb (chr22:51,063,071-51,178,264, GRCh37) and a maximal size of 302 kb (chr22:51,002,394-51,304,566, GRCh37) and included all of the SHANK3 gene, part of the ACR gene, and part of the ARSA gene (607574).

Animal Model

Han et al. (2013) found that mice with overexpression of Shank3 had manic-like behaviors with increased locomotion, hypersensitivity to amphetamine, and abnormal circadian rhythms. The mice also ad altered synaptic excitatory/inhibitory bounds with spontaneous seizures. The manic-like behavior of mice with Shank3 overexpression responded to valproate, but not to lithium.