Further evidence for a relationship between the 5p15 chromosome region and the oculoauriculovertebral anomaly

Abstract

The oculoauriculovertebral anomaly (OAV) or Goldenhar syndrome is a malformation complex that has been described in several chromosomal rearrangements. Among them a deletion of the terminal 5p has recurred in seven previous patients. We wish to report on an additional such patient in order to reinforce the significance of this genomic region in the cause of at least a subgroup of OAV cases. Future studies, particularly in the OAV patients with a lateral facial cleft, might define one genetic background of the disorder. Our patient had a complex translocation chromosome 45,XX, inv(2) (q32q37)mat, dic(5;21) (p15.3;q22.3)dn, resulting in a terminal 5p deletion, a terminal deletion of 21q demonstrated by FISH studies, and a duplication of 21q22.11-q22.12 documented by molecular karyotyping. In addition to OAV she developed myelodysplasia treated with bone marrow transplantation. We discuss her clinical findings with reference to her karyotype findings and review the patients with OAV and a terminal deletion of 5p.

Genome-Wide Scanning Reveals Complex Etiology of Oculo-Auriculo-Vertebral Spectrum

“…Based on the recently demonstrated role of structural variants in the etiology of complex diseases (Sebat et al 2007;Blauw et al 2008) and the presence of microdeletions in some sporadic cases with features of OAVS (Ala-Mello et al 2008;Xu et al 2008;Rooryck et al 2009;Huang et al 2010), we attempted to use high-density SNP-genotype data to determine the structural variation in this family, and found no significant differences of the CNV number and size between the affected and unaffected individuals. Although five CNVs (in 1q21.3, 9p11.2, 10q11.22, 11q11, and 13q31.1) were present in patients at higher ratios, they were also seen in unaffected family members.…”

“…Because of the elusive cause of OAVS and the substantial contribution of CNVs to genetic susceptibility of complex disorders, a genome-wide survey of genomic aberrations, including common and rare variants, might be used instead of a traditional genetic analysis. Recently, array studies indeed have confirmed the presence of microdeletions in some sporadic cases with features of OAVS (Ala-Mello et al 2008;Xu et al 2008;Rooryck et al 2009;Huang et al 2010). However, to our knowledge, a family-based association between CNVs and the OAVS phenotype has not been investigated.…”

“…Maternal use of medications (Jacobsson and Granstrom 1997;Johnston and Bronsky 1995) and maternal diabetes (Wang et al 2002) contribute to infants with OAVS, which suggests that nongenetic factors play a role in the development of OAVS. Nevertheless, chromosomal aberrations (Engiz et al 2007;Balci et al 2006;Choong et al 2003;Descartes 2006;Josifova et al 2004;Ala-Mello et al 2008;Xu et al 2008;Rooryck et al 2009) and the identification of several families with autosomal dominant (Tsai and Tsai 1993;Stoll et al 1998;Tasse et al 2007;Goodin et al 2009;Vendramini-Pittoli and Kokitsu-Nakata 2009) or recessive inheritance (Kaye et al 1992) indicate that OAVS has a hereditary basis.…”

“…In addition, a few patients showing clinical overlap with OAVS had mutations in sal-like 1 (SALL1) (Kohlhase et al 1999;Keegan et al 2001;Kosaki et al 2007) or Treacher Collins-Franceschetti syndrome 1 (TCOF1) (Su et al 2007), the genes responsible for most cases of Townes-Brocks syndrome [OMIM 107480] and Treacher Collins syndrome [OMIM 154500], respectively, which are also associated with first and second branchial arch anomalies. Even though cytogenetic alterations have been associated with many cases of OAVS, most of the chromosomal aberrations are patient-specific, except that chromosome 5p (Choong et al 2003;Descartes 2006;Josifova et al 2004;Ala-Mello et al 2008) and 22q (Balci et al 2006;Xu et al 2008;Derbent et al 2003;Digilio et al 2009) have been implicated in a number of cases.…”

Cranial Nerve Abnormalities in Oculo-Auriculo-Vertebral Spectrum

“…6 Familial history suggestive of both autosomal recessive and dominant inheritance has been reported, and genes on chromosomes 5, 12, 14, and 22 have been implicated. [7][8][9][10] However, most cases of OAVS are sporadic and without a known etiology. Abnormal embryonic vascular supply, 11 hematomas, and drug use during the early phases of gestation have been reported to cause the disruption of mesodermal migration, leading to defective formation of bone and soft-tissue structures.…”