Angelman syndrome (AS) is caused by a lack of expression of the maternally 
inherited UBE3A gene in the brain. However, about 10% of individuals with a 
clinical diagnosis of AS do not have an identifiable molecular defect. It is 
likely that most of those individuals have an AS-like syndrome that is 
clinically and molecularly distinct from AS. These AS-like syndromes can be 
broadly classified into chromosomal microdeletion and microduplication 
syndromes, and single-gene disorders. The microdeletion/microduplication 
syndromes are now easily identified by chromosomal microarray analysis and 
include Phelan–McDermid syndrome (chromosome 22q13.3 deletion), MBD5 
haploinsufficiency syndrome (chromosome 2q23.1 deletion), and KANSL1 
haploinsufficiency syndrome (chromosome 17q21.31 deletion). The single-gene 
disorders include Pitt–Hopkins syndrome (TCF4), Christianson syndrome (SLC9A6), 
Mowat–Wilson syndrome (ZEB2), Kleefstra syndrome (EHMT1), and Rett (MECP2) 
syndrome. They also include disorders due to mutations in HERC2, 
adenylosuccinase lyase (ADSL), CDKL5, FOXG1, MECP2 (duplications), MEF2C, and 
ATRX. Although many of these single-gene disorders can be caused by chromosomal 
microdeletions resulting in haploinsufficiency of the critical gene, the 
individual disorders are often caused by intragenic mutations that cannot be 
detected by chromosomal microarray analysis. We provide an overview of the 
clinical features of these syndromes, comparing and contrasting them with AS, in 
the hope that it will help guide clinicians in the diagnostic work-up of 
individuals with AS-like syndromes.