Microduplication 22q11.2, an Emerging Syndrome: Clinical, Cytogenetic, and Molecular Analysis of Thirteen Patients

Abstract

Chromosome 22, particularly band 22q11.2, is predisposed to rearrangements due to misalignments of low-copy repeats (LCRs). DiGeorge/velocardiofacial syndrome (DG/VCFS) is a common disorder resulting from microdeletion within the same band. Although both deletion and duplication are expected to occur in equal proportions as reciprocal events caused by LCR-mediated rearrangements, very few microduplications have been identified. We have identified 13 cases of microduplication 22q11.2, primarily by interphase fluorescence in situ hybridization (FISH). The size of the duplications, determined by FISH probes from bacterial artificial chromosomes and P(1) artificial chromosomes, range from 3-4 Mb to 6 Mb, and the exchange points seem to involve an LCR. Molecular analysis based on 15 short tandem repeats confirmed the size of the duplications and indicated that at least 1 of 15 loci has three alleles present. The patients' phenotypes ranged from mild to severe, sharing a tendency for velopharyngeal insufficiency with DG/VCFS but having other distinctive characteristics, as well. Although the present series of patients was ascertained because of some overlapping features with DG/VCF syndromes, the microduplication of 22q11.2 appears to be a new syndrome.

Karyotype Versus Microarray Testing for Genetic Abnormalities After Stillbirth

“…The phenotype of both syndromes is variable, with shared clinical anomalies that include heart defects, urogenital abnormalities, and velopharyngeal insufficiency. [27][28][29] The incidence of the DiGeorge syndrome is estimated to be 1 case in 4000 births. 30 The 22q11.2 microduplication syndrome appears to be less prevalent.…”

Severe intellectual disability and autistic features associated with microduplication 2q23.1

“…However, it has been shown that the clinical presentations due to microduplications of a given genomic segment can be significantly different from those seen in the corresponding microdeletion syndrome. [10][11][12][13][14][15] Furthermore, microduplications that are responsible for clinical phenotypes may be inherited from apparently unaffected carrier parents. [25][26][27] Repnikova et al 28 have reported a patient with a 600-kb duplication in chromosome 2q23.1 that included MBD5 and EPC2.…”

“…A well-known example is the duplication of chromosome region 17p12 that causes CharcotMarie-Tooth disease type 1A syndrome and the corresponding deletion that causes hereditary neuropathy with liability to pressure palsies. 9 Other examples include duplications reciprocal to the recurrent deletions associated with Willams-Beuren syndrome, 10 velo-cardio-facial syndrome, 11 Smith-Magenis syndrome, 12 neurofibromatosis I, 13 Sotos syndrome, 14 and Rett syndrome. 15 Duplications of chromosome region 2q23.1 have not been described to date and the clinical consequences are currently not known.…”

A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion

“…Such deletions are a known cause of human disease; identifying the reciprocal duplications and documenting their role in generating specific phenotypes is one of the challenges of modern human genetics. Duplications reciprocal to the recurrent deletions associated with velo-cardio-facial syndrome, 4 the Williams-Beuren syndrome 5 and the Smith-Magenis syndrome 6 have been documented. In addition, newly described phenotypes associated with deletions and duplications in regions of the genome previously not known to be causative of human disease [7][8][9][10][11][12] have arisen.…”