The majority of the genomic disorders identified before 2006 were characterized by developmental delay, learning disability and/or mental retardation (MR). Interestingly, the genetic basis for MR is still unknown in well over 50% of clinical cases. Therefore, many studies have been aimed at identifying submicroscopic copy number changes in this population [14
], and it is now estimated that large microdeletions and microduplications underlie >15% of MR. We note that many potential pathogenic copy number changes are non-recurrent (i.e. private mutations seen only once) and likely occur by a mechanism other than NAHR since segmental duplications have not been found at the junctions. Although significant in the aggregate, the pathogenicity for any one specific event can be difficult to prove. Here, we focus on those genomic disorders mediated by segmental duplications where the pathogenic significance is unambiguous. Sixteen of the eighteen new genomic disorders identified since 2005 are associated with MR (). Several of these appear to be highly penetrant with recognizable syndromic features.
In 2006, three groups simultaneously reported recurrent microdeletions of chromosome 17q21.31 detected by array CGH [15
], kicking off a flurry of discovery of novel genomic disorders. The 17q21.31 microdeletion, with an estimated prevalence of 1 in 16,000, fits the definition of a classic genomic disorder: the microdeletion has breakpoints in flanking segmental duplications, is always de novo
in affected individuals and has never been seen in controls, and patients harboring 17q21.31 microdeletions have very similar phenotypes () [15
]. Notably, within the same genomic region is an inversion of ~900 kb observed in approximately 20% of individuals of European ancestry [35
]. Further emphasizing the importance of regional genomic architecture, the inversion has been found in every parent who transmits a de novo
deletion to an affected child and appears to be a prerequisite to facilitate microdeletion [34
]. The reciprocal duplication has also been reported in one patient with severe psychomotor delay and craniofacial dysmorphism [37
]; whether individuals with the reciprocal duplication have syndromic features will require the identification of additional patients.
Reports of recurrent microdeletions in individuals with developmental delay or mental retardation continued steadily throughout 2007 and 2008. Microdeletions of 15q24, although rare, are also highly penetrant. To date, five individuals with overlapping deletions [38
] and one patient with autism and a larger but overlapping deletion [22
] have been reported. As with 17q21.31, all deletions appear to be de novo
, and affected individuals have similar facial features in addition to developmental delays (). Another rare but recognizable syndrome involves deletions of chromosome 16p11.2–p12.2. Ballif and colleagues [40
] reported four individuals (from 8789 analyzed) with severe developmental delays and similar facial features; each had a large deletion sharing the same distal breakpoint at 16p12.2, ranging from 7.1 to 8.7 Mb in size. Deletions of a large hotspot region on chromosome 10q22–q23 are also rare but recurrent. Two families with inherited deletions and one individual with an overlapping deletion have been reported; deletion carriers have varying degrees of cognitive and behavioral abnormalities [41
The long arm of chromosome 22 is rich with segmental duplications, some of which are responsible for recurrent rearrangements seen in velocardiofacial syndrome, reciprocal 22q11 duplications and cat-eye syndrome [9
]. More recently, recurrent deletions distal to the velocardiofacial syndrome region were reported [44
]; most affected individuals had developmental and growth delays and were born prematurely (). Reciprocal duplications have also been reported and tend to result in milder, more variable phenotypes [45
]. Because of the number and density of segmental duplications on 22q, there are several possible rearrangements due to NAHR; many appear to be associated with disease, but collecting information on individuals with the same events is critical to determine features associated with each. Two additional regions for which reciprocal deletions and duplications have been recently reported include 3q29 [46
] and 16p13.11 [49
]. Deletions of 3q29 are associated with mild to moderate MR, microcephaly, mild dysmorphic features and possibly autism; duplications may also be associated with MR but with decreased penetrance. Deletions of 16p13.11 are highly (though not fully) penetrant and have been seen in individuals with autism, mental retardation, dysmorphic features and brain abnormalities. Individuals harboring duplications tended to have mental retardation, autism and/or behavioral problems, but the duplication is also seen rarely in controls suggesting decreased penetrance and/or variable expressivity ().