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Genotypic and phenotypic variability of 22q11.2 microduplications – an institutional experience

Alexander Yu

University of Texas Medical Branch


Introduction: Chromosome 22q11.2 harbors 8 low-copy repeat regions termed LCR22A-H. Duplications within these LCRs result in the rare 22q11.2 duplication syndrome. Patients with this syndrome present with a variety of phenotypes including facial, cardiac, and neurological abnormalities as summarized in Online Mendelian Inheritance in Man. However, the penetrance and expressivity of this syndrome is variable. These combined with the rarity of the syndrome necessitate continued reporting of cases to elucidate possible genotype-phenotype contributions of 22q11.2 duplicated regions. Methods: Chromosomal microarray (CMA) was performed using patient peripheral blood and examined with Cytoscan HD microarray. Genomic DNA was extracted and purified from whole blood sample using Gentra Puregene Blood Kit. Procedures for DNA digestion, adapter ligation, PCR, amplicon DNA fragmentation, labeling and hybridization of the arrays were performed according to manufacturer’s instructions. Results were investigated using the Chromosome Analysis Suite and interpreted based on published literature, publicly available databases, and by investigating gene content following practice guidelines. From March 2013 to March 2018, 1,200 germline CMA results were generated with 9 patients positive for 22q11.2 duplications. We performed chart review of these 9 patients using University of Texas Medical Branch ’s electronic medical record. The study was approved by University of Texas Medical Branch institutional review board. Results: There were 4 AD, 1 AC, 1 CD, 1 FG, and 2 GI duplications flanked by LCR22G and a distal LCR that we termed LCR22I. Shared features among the AD patients included small secundum atrial septal defects (2/4), speech/gross motor delays (2/4) and recovered head circumference (3/4) within 28 months after birth. In addition, a novel 2,3 syndactyly was associated with 2 patients harboring CD regions. Moreover, we report a possible second lethal case associated with the CD region sharing features of thoracic heterotaxia and abdominal situs inversus consistent with a previous lethal 22q11.2 duplication report. In addition, 1 asymptomatic adult harbored a GI duplication, 1 neonate harbored an underlying AC duplication in addition to Trisomy 18, and 1 patient harboring an FG duplication presented with severe microcephaly. Conclusion: We report that 22q11.2 duplications vary in penetrance and expressivity. Furthermore, we elucidate genotype-phenotype associations specific to 22q11.2 duplications.

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