Copy Number Variation Analysis in 98 Individuals with PHACE Syndrome

Abstract

PHACE syndrome is the association of large segmental facial hemangiomas and congenital anomalies, such as posterior fossa malformations, cerebral arterial anomalies, coarctation of the aorta, eye anomalies and sternal defects. To date, the reported cases of PHACE syndrome have been sporadic suggesting that PHACE may have a complex pathogenesis. We report here genomic copy number variation (CNV) analysis in 98 individuals with PHACE syndrome as a first step in deciphering a potential genetic basis of PHACE syndrome. A total of 3,772 CNVs (2,507 duplications and 1,265 deletions) were detected in 98 individuals with PHACE syndrome. CNVs were then eliminated if they failed to meet established criteria for quality, spanned centromeres or did not contain genes. CNVs were defined as “rare” if not documented in the Database of Genomic Variants. Ten rare CNVs were discovered (size range: 134–406 kb), located at 1q32.1, 1q43, 3q26.32-3q26.33, 3p11.1, 7q33, 10q24.32, 12q24.13, 17q11.2, 18p11.31, and Xq28. There were no rare CNV events that occurred in greater than one subject. Therefore, further study is needed to determine the significance of these CNVs in the pathogenesis of PHACE syndrome.

Evaluation of maternal history of miscarriage, infertility andin vitrofertilization as associated factors in PHACE

“…PHACE has a female predominance, although preliminary X‐inactivation studies have not demonstrated significant skewing in affected female patients or their mothers . Copy‐number variation studies have yet to identify a common pathogenic variant . We sought to determine whether there is an increased prevalence of miscarriage, infertility and/or use of in vitro fertilization (IVF) in the mothers of children with PHACE.…”

Atypical Presentation of PHACE Syndrome: Hidden Facial Hemangioma

“…Although the strong female predominance suggests an X-linked inheritance, skewed X-chromosome-inactivation has been identified in only a few cases, without statistical significance [14]. A series analyzing 98 individuals with PHACE syndrome discovered 10 rare genomic copy number variations, but none of these occurred in > 1 subject [15]. The deletions on 7q33 may also provide a genetic susceptibility to PHACE syndrome, but they are not the singular cause of phenotypic expression [12].…”

“…The deletions on 7q33 may also provide a genetic susceptibility to PHACE syndrome, but they are not the singular cause of phenotypic expression [12]. This suggests that PHACE syndrome may have a complex pathogenesis and likely genetic heterogenicity, while an X-linked gene mutation is possibly associated with a subset of occurrence [14,15].…”

Pathogenesis of infantile haemangioma

“…No specific mutation was identified for these syndromes; however, genomic copy number variation has been found in PHACE syndrome. 37 Vascular endothelial growth factor (VEGF) and VEGF receptors Several signalling pathways have been linked with IH pathogenesis, with the VEGF-A pathway being the key one. VEGF-A is a master regulator of angiogenesis and vasculogenesis.…”