Genotype-phenotype correlation in 22q11.2 deletion syndrome

Elena Michaelovsky,Doron Gothelf,Tamar Green,Omer Zarchi,Miri Carmel,Lina Basel-Vanagaite,Miriam Patya,Abraham Weizman,Amos Frisch

doi:10.1186/1471-2350-13-122

Abstract

BackgroundThe 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.MethodsMolecular 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.ResultsDeletions 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.ConclusionsMLPA 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.

Highlights

The 22q11.2 deletion syndrome (22q11.2DS) is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations
The majority (90%) of the 22q11.2 deletions are of 3Mb occurring between low copy repeats (LCR) A and LCR D and often referred to as typically deleted region (TDR) while 8% are 1.5Mb in size (~28 genes) (LCR A-B)
We evaluated the utility of multiplex ligation probe amplification (MLPA) as an alternative to fluorescent in situ hybridization (FISH) in diagnosing 142 Israeli individuals who had been referred to our clinic with the initial suspicion of 22q11.2DS and as a tool for characterizing the deletion size and location

Summary

Introduction

The 22q11.2 deletion syndrome (22q11.2DS) is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations. The classic molecular diagnostic procedure used for detection of deletions and duplications at 22q11.2 is chromosomal analysis coupled with fluorescent in situ hybridization (FISH) using a single fluorescent probe (N25 or TUPLE1) located in the proximal part of the typically deleted region. In recent years several new methods for detecting the 22q11.2 deletion have been developed: comparative genomic hybridization (CGH) [6,7], multiplex ligation probe amplification (MLPA) [8,9], multiplex quantitative real-time PCR [10,11] and high-resolution SNP microarray analysis [10,12]. The MLPA method uses multiple probes to achieve a good resolution combined with the practicality and affordability of a commercial kit, which is rapidly and performed in any experienced laboratory

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