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

Abstract

Background 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. 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. Results Eight 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 (OR AB 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 (OR AB v/s AC-AD : 1.731 [0.708–4.234]; OR AD v/s AB-AC : 0.628 [0.286–1.382]). Conclusions The 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. Electronic supplementary material The online version of this article (10.1186/s13023-019-1170-x) contains supplementary material, which is available to authorized users.

22q11.2 Microduplications: Two Clinical Reports Compared with Similar Cases from the Literature

“…24 For subjects with the common larger LCR22A-D duplication, there are more disease causing genes within the region and hence more similarities in structural and functional defects. 25 One protein coding gene of significance is SCARF2 that was involved in our subject 2 with a known association with the Van den Ende-Gupta syndrome, a very rare syndrome characterized by blepharophimosis, arachnodactyly, joint contractures, and characteristic dysmorphic features. 26 Except for craniofacial features in our proband, there were no other associated features.…”

The genetic workup for structural congenital heart disease

“…Further complicating CHD etiology is genetic heterogeneity. Using 22q11.2 deletion syndrome as an example again, the deletion ranges from ~0.7 megabases (Mb) to ~3 Mb, but a meta‐analysis failed to show an association between the deletion size and presence of CHD (Rozas, Benavides, León, & Repetto, ). Haploinsufficiency of the genes TBX1 and CRKL are thought to cause CHD in 22q11.2 deletion syndrome, linked to proximal deletions and distal deletions respectively (McDonald‐McGinn et al, ; Rozas et al, ).…”

“…CHD encompasses a wide spectrum of heterogenous malformations (Franklin et al, 2017), and Figure 1 shows the prevalence in graph form of the most common types of this spectrum (Liu et al, 2019). deletion size and presence of CHD (Rozas, Benavides, León, & Repetto, 2019). Haploinsufficiency of the genes TBX1 and CRKL are thought to cause CHD in 22q11.2 deletion syndrome, linked to proximal deletions and distal deletions respectively (McDonald-McGinn et al, 2015;Rozas et al, 2019).…”

“…deletion size and presence of CHD (Rozas, Benavides, León, & Repetto, 2019). Haploinsufficiency of the genes TBX1 and CRKL are thought to cause CHD in 22q11.2 deletion syndrome, linked to proximal deletions and distal deletions respectively (McDonald-McGinn et al, 2015;Rozas et al, 2019). Table 1 summarizes the common genetic syndromes causing congenital heart diseases.…”

Contribution of mitochondrial DNA heteroplasmy to the phenotypic variability in maternally transmitted 22q11.2 deletion syndrome

“…The syndrome is characterized by the variable expressivity of its phenotypes, illustrated by descriptions of phenotypic “extremes” that range from very ill newborns manifesting severe conotruncal heart disease, hypocalcemic seizures, cleft palate and immunodeficiency, to individuals with a history of learning disabilities and hypernasal speech due to a submucous cleft palate, or adolescents or adults with schizophrenia and no structural anomalies. Most individuals share a deletion of the same size, however deletion size does not appear to be associated with specific manifestations 2,4 . The cause of this variability is still unknown, and the causes may be genetic (inherited or acquired), epigenetic, environmental or stochastic.…”