Different Types of Deletions Created by Low-Copy Repeats Sequences Location in 22q11.2 Deletion Syndrome: Genotype–Phenotype Correlation

Abstract

The most frequent microdeletion, 22q11.2 deletion syndrome (22q11.2DS), has a wide and variable phenotype that causes difficulties in diagnosis. 22q11.2DS is a contiguous gene syndrome, but due to the existence of several low-copy-number repeat sequences (LCR) it displays a high variety of deletion types: typical deletions LCR A–D—the most common (~90%), proximal deletions LCR A–B, central deletions (LCR B, C–D) and distal deletions (LCR D–E, F). Methods: We conducted a retrospective study of 59 22q11.2SD cases, with the aim of highlighting phenotype–genotype correlations. All cases were tested using MLPA combined kits: SALSA MLPA KIT P245 and P250 (MRC Holland). Results: most cases (76%) presented classic deletion LCR A–D with various severity and phenotypic findings. A total of 14 atypical new deletions were identified: 2 proximal deletions LCR A–B, 1 CES (Cat Eye Syndrome region) to LCR B deletion, 4 nested deletions LCR B–D and 1 LCR C–D, 3 LCR A–E deletions, 1 LCR D–E, and 2 small single gene deletions: delDGCR8 and delTOP3B. Conclusions: This study emphasizes the wide phenotypic variety and incomplete penetrance of 22q11.2DS. Our findings contribute to the genotype–phenotype data regarding different types of 22q11.2 deletions and illustrate the usefulness of MLPA combined kits in 22q11.2DS diagnosis.

Homozygous 22q11.2 distal type II microdeletion is associated with syndromic neurodevelopmental delay

“…The four distal LCRs (E–H) are smaller and have a higher level of sequence variation, correlated with a lower frequency of NAHR‐mediated CNVs. Distal deletions are sub‐divided into three types: type I (LCR‐D to LCR‐E/F), type II (LCR‐E to LCR‐F), and type III (minimal region—LCR‐F to LCR‐G and encompassing SMARCB1 ; Gavril et al, 2022; Mikhail et al, 2014; Rauch et al, 2005; Shaikh et al, 2000).…”

“…Common features include growth restriction, developmental delay, intellectual disability, language delay, and minor craniofacial anomalies (Garcia-Miñaur et al, 2002;Kurahashi et al, 1996;Rauch et al, 2005). The four distal LCRs (E-H) are smaller and have a higher Gavril et al, 2022;Mikhail et al, 2014;Rauch et al, 2005;Shaikh et al, 2000).…”

Chromosome 22q11.2 Deletion Syndrome: A Comprehensive Review of Molecular Genetics in the Context of Multidisciplinary Clinical Approach

“…The deletion types and sizes in 22q11.2 DS show a high degree of variability due to several low-copy-number repeat sequences (LCR22A, LCR22B, LCR22C, LCR22D, LCR22E, and LCR22F) flanking the deleted region. Most patients (about 90%) show a 2.54 Mb heterozygous deletion comprising four repeats extending from LCR22A to LCR22D and involving approximately 40 genes [15]. The disease-causing genes mapping to the region spanned by LCR22A-LCR22D are, among others, TBX1, proline dehydrogenase PRODH, catechol-O-methyltransferase COMT, cell division cycle 45 CDC45, GP1BB, SNAP29, and Di-George critical regions DGCR2, DGCR6, DGCR6L, and DGCR8.…”

Chromosome 22q11.2 Deletion Syndrome: A Comprehensive Review of Molecular Genetics in the Context of Multidisciplinary Cinical Approach

“…The deletion types and sizes in 22q11.2 DS show a high degree of variability due to several low copy number repeat sequences (LCR22A, LCR22B, LCR22C, LCR22D, LCR22E, and LCR22F), flanking the deleted region. Most patients (about 90%) show a 2.54 Mb heterozygous deletion comprising four repeats extending from LCR22A to LCR22D and involving approximately 40 genes [15]. The diseasecausing genes mapping to the region spanned by LCR22A-LCR22D are, among others, TBX1, proline dehydrogenase PRODH, catechol-O-methyltransferase COMT, cell division cycle 45 CDC45, GP1BB, SNAP29, DiGeorge critical regions DGCR2, DGCR6, DGCR6L, DGCR8.…”

“…A proximal 1.25 Mb deletion, comprising LCR22A-LCR22B affects about 5% of individuals with 22q11.2 DS., whereas 2% of them show a deletion spanning the LCR22A-LCR22C region, and the next 5% have a smaller, atypical nested deletion extending from LCR22B or LCR22C to LCR22D. Distal deletions, flanked by LCR22D-E and LCR22D-F have been reported less frequently [15,16]. The complexity of 22q11.2 genetics is even more prominent due to the regulatory effect of deleted DGCR6, DGCR6L, and DGCR8 gene allele and mi-RNAs, such as miR-185, miR-4716, miR-3618, miR-1286, miR-1306, and miR-6816.…”