Genomic imbalances in craniofacial microsomia

Abstract

The aim of this study was to perform 22q11.2 deletion screening and chromosomal microarray analysis (CMA) in individuals clinically diagnosed with craniofacial microsomia (CFM) and review previously published cases of CFM with genomic imbalances. It included 54 individuals who were evaluated by a clinical geneticist. Copy number variants (CNVs) in the 22q11.2 region were investigated by multiplex ligation-dependent probe amplification (MLPA) for all individuals. The CMA was performed only for individuals with additional major features. MLPA revealed pathogenic CNVs at the 22q11 region in 3/54 (5.6%) individuals. CMA revealed pathogenic CNVs in 4/17 (23.5%) individuals, including the three CNVs at the 22q11 region also detected by MLPA, and CNVs classified as variants of unknown significance (VOUS) in 4/17 (23.5%) individuals. Pathogenic alterations were found at the 2p12, 5p15, 13q13, and 22q11 regions. VOUS were found at 3q29, 5q22.2, 5q22.1, and 9p22 regions. All individuals with pathogenic alterations presented additional major features, including congenital heart disease (CHD). The literature review revealed pathogenic CNVs in 17/193 (8.8%) individuals and most of them also presented additional major features, such as CHD, renal anomalies, or developmental delay. In conclusion, CNVs should be investigated in patients with CFM and additional major features.

Copy number variation analysis implicates novel pathways in patients with oculo‐auriculo‐vertebral‐spectrum and congenital heart defects

“…43 Moreover, an OAVS patient carrying a chromosome 9p22.1 duplication mapping close to the deletion of our patient has been recently described. 35 Hence, it is likely that the complex phenotype of our patient derives from co-occurring CNVs, where del (9p22), contributes to craniofacial features, and del (15q26.2q26.3) is causally associated with the other features (i.e., CHD, IUGR, and DD). The last OAVS subject with CNV and septal defect had a small duplication on chromosome 8q23.3 within CSMD3, a giant gene with unknown function, expressed mainly in brain and testis.…”

Oculo-auriculo-vertebral spectrum: new genes and literature review on a complex disease

“…Only few CNVs appeared to be recurrent. Interestingly, several studies reported 22q11.2 deletions or duplications in patients with OAVS phenotype 26–36. Some of these CNV have different boundaries compared with those found in DiGeorge syndrome and complex rearrangements were rarely described.…”

Genotypic and phenotypic variability of 22q11.2 microdeletions – an institutional experience

“…Goldenhar syndrome is characterized by facial asymmetry and pronounced facial defects, like microtia or anotia, benign ocular growths, and spinal abnormalities [ 37 , 38 ]. Goldenhar syndrome has been associated with 22q11.2 deletion syndrome [ 39 , 40 ]. It is interesting that our patient has a deletion in 22q11.2 LCR A whereas the reported cases harbor proximal, central, and distal deletions [ 39 , 40 ].…”

“…Goldenhar syndrome has been associated with 22q11.2 deletion syndrome [ 39 , 40 ]. It is interesting that our patient has a deletion in 22q11.2 LCR A whereas the reported cases harbor proximal, central, and distal deletions [ 39 , 40 ]. Goldenhar syndrome shows significant locus heterogeneity and has been associated with copy number variations (CNVs) at multiple chromosome regions including Xp22.33p22.31, 1p22.2p31.3, 2p11.2, 2p12, 2q11, 3q29, 4p16.3p15.33, 5p15, 5q22, 8q13.3, 9p22.1, 10q26.2q26.3, 12p13.33, 13q34, 14q23.1, 14q31.1q31.3, 15q24, 16p13.3, 17q11.2, 22q11.1, 22q11.1q11.21, and 22q11.2 [ 39 , 40 ].…”