Open Access Highly Accessed Research article

Genotype-phenotype correlation in 22q11.2 deletion syndrome

Elena Michaelovsky12, Amos Frisch127*, Miri Carmel12, Miriam Patya12, Omer Zarchi13, Tamar Green134, Lina Basel-Vanagaite125, Abraham Weizman126 and Doron Gothelf13

Author Affiliations

1 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

2 Felsenstein Medical Research Center, Petah Tikva, Israel

3 The Child Psychiatry Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel

4 Nes-Ziyyona-Beer Yaakov Mental Health Center, Beer Yaakov, Israel

5 Pediatric Genetics Schneider Children’s Medical Center of Israel and Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, Israel

6 Geha Mental-Health Center, Petah Tikva, Israel

7 Felsenstein Medical Research Center (FMRC), Sackler Faculty of Medicine, Tel Aviv University, Rabin Medical Center, 49100, Petah Tikva, Israel

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BMC Medical Genetics 2012, 13:122  doi:10.1186/1471-2350-13-122

Published: 17 December 2012



The 22q11.2 deletion syndrome (22q11.2DS) is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations. We explored the genotype-phenotype relationship in a relatively large 22q11.2DS cohort treated and monitored in our clinic using comprehensive clinical evaluation and detailed molecular characterization of the deletion.


Molecular analyses in 142 subjects with 22q11.2DS features were performed by FISH and MLPA methods. Participants underwent clinical assessment of physical symptoms and structured psychiatric and cognitive evaluation.


Deletions were found in 110 individuals including one with an atypical nested distal deletion which was missed by the FISH test. Most subjects (88.2%) carried the 3Mb typically deleted region and 11.8% carried 4 types of deletions differing in size and location. No statistically significant genotype-phenotype correlations were found between deletion type and clinical data although some differences in hypocalcemia and cardiovascular anomalies were noted.

Analysis of the patient with the distal nested deletion suggested a redundancy of genes causing the physical and neuropsychiatric phenotype in 22q11.2DS and indicating that the psychiatric and cognitive trajectories may be governed by different genes.


MLPA is a useful and affordable molecular method combining accurate diagnosis and detailed deletion characterization. Variations in deletion type and clinical manifestations impede the detection of significant differences in samples of moderate size, but analysis of individuals with unique deletions may provide insight into the underlying biological mechanisms.

Future genotype-phenotype studies should involve large multicenter collaborations employing uniform clinical standards and high-resolution molecular methods.

Velocardiofacial syndrome (VCFS); Multiplex ligation probe amplification (MLPA); Copy number variation (CNV); Molecular diagnosis; Neuropsychiatric disorders