Association between phenotype and deletion size in 22q11.2 microdeletion syndrome: systematic review and meta-analysis

M Fernanda Rozas,Luis León,Felipe Benavides,Gabriela M Repetto

doi:10.1186/s13023-019-1170-x

M Fernanda Rozas, Luis León + Show 2 more

Open Access

https://doi.org/10.1186/s13023-019-1170-x

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Abstract

BackgroundChromosome 22q11.2 microdeletion syndrome, a disorder caused by heterozygous loss of genetic material in chromosome region 22q11.2, has a broad range of clinical symptoms. The most common congenital anomalies involve the palate in 80% of patients, and the heart in 50–60% of them. The cause of the phenotypic variability is unknown. Patients usually harbor one of three common deletions sizes: 3, 2 and 1.5 Mb, between low copy repeats (LCR) designated A-D, A-C and A-B, respectively. This study aimed to analyze the association between these 3 deletion sizes and the presence of congenital cardiac and/or palatal malformations in individuals with this condition. A systematic review and meta-analysis were conducted, merging relevant published studies with data from Chilean patients to increase statistical power.ResultsEight articles out of 432 were included; the data from these studies was merged with our own, achieving a total of 1514 and 487 patients to evaluate cardiac and palate malformations, respectively. None of the compared deleted chromosomal segments were statistically associated with cardiac defects (ORAB v/s AC-AD: 0.654 [0.408–1.046]; OR AD v/s AB-AC: 1.291 [0.860–1.939]) or palate anomalies (ORAB v/s AC-AD: 1.731 [0.708–4.234]; OR AD v/s AB-AC: 0.628 [0.286–1.382]).ConclusionsThe lack of association between deletion size and CHD or PA found in this meta-analysis suggests that deletion size does not explain the incomplete penetrance of these 2 major manifestations, and that the critical region for the development of heart and palatal abnormalities is within LCR A-B, the smallest region of overlap among the three deletion sizes.

Highlights

Chromosome 22q11.2 microdeletion syndrome, a disorder caused by heterozygous loss of genetic material in chromosome region 22q11.2, has a broad range of clinical symptoms
Since all participants were selected from a cleft palate clinic, all of them had palate anomalies (PA), which would bias the analyses for this phenotypic component
Only congenital heart defects (CHD) data from this study was considered for the meta-analysis

Summary

Introduction

Chromosome 22q11.2 microdeletion syndrome, a disorder caused by heterozygous loss of genetic material in chromosome region 22q11.2, has a broad range of clinical symptoms. Major causative genes could be in the minimal region of overlap, while modifier genes could be in LCR B-C or LCR C-D and contribute to the diversity in observed phenotypes. This potential association could have prognostic implications and contribute to understanding the underlying disease mechanisms. Several studies have looked at the association between deletion size and phenotype, but none report statistical analysis [7, 8] Methodological limitations of these publications include dissimilar sample sizes, different clinical assessments and molecular studies used, differences in ascertainment sources and the fact that most individuals have the common 3 Mb deletion

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