Paternal deletion 6q24.3: A new congenital anomaly syndrome associated with intrauterine growth failure, early developmental delay and characteristic facial appearance

Abstract

Deletions of the long arm of chromosome 6 are relatively uncommon and to date minimal genotype-phenotype correlations have been observed. We report on three unrelated patients with de novo paternal interstitial deletions of 6q24.3. FISH mapping was used to delineate the minimal region of overlap between these three patients. Although all three patients had different size deletions and different breakpoints, two of the patients shared a 2.5 Mb region of overlap and strikingly similar facial features including a triangular face, frontal bossing with metopic prominence, short and upward-slanting palpebral fissures, asymmetry of upper eyelids, hooded eyelids, shallow orbits, prominent inferior orbital crease, wide mouth, and long and flat philtrum. They also had redundant skin, joint laxity, a small thorax, and early developmental delay. The smallest region of overlap between all three patients was a region of deletion less than 1 Mb; all had a history of IUGR and postnatal short stature without overt radiologic skeletal anomalies. The dysmorphic features, early developmental and growth delay may be due to the hemizygous state for one of the genes in the deleted region of two of the patients or to a long range effect of the deletion on expression of other genes. In addition, since imprinted genes have been reported in this region, paternal deletion of an imprinted gene in all three patients may contribute to the growth phenotype. We propose that this is a new congenital malformation syndrome associated with a paternal deletion of 6q24.3.

A de novo 0.63 Mb 6q25.1 deletion associated with growth failure, congenital heart defect, underdeveloped cerebellar vermis, abnormal cutaneous elasticity and joint laxity

“…Congenital anomalies of the heart or of the aortic arch have been classically reported in individuals with interstitial 6q deletions [Hopkin et al, 1997;Sukumar et al, 1999;Bisgaard et al, 2006;Caselli et al, 2007;Nowaczyk et al, 2008]. Interestingly, the TAB2 gene (OMIM # 605101), included within the deleted region of the present girl (see Fig.…”

“…Brain magnetic resonance imaging (MRI) showed underdevelopment of the inferior cerebellar vermis with a mildly prominent fourth ventricle (Fig. 3) Nowaczyk et al [2008] B: note the depressed nasal bridge, the palpebral fissures and the epicanthic folds, shared by both patients (the image shown in Figure 2B syndrome showed no evidence of expression of the fragile site on chromosome X. Conventional chromosome analysis revealed a normal karyotype.…”

“…In addition to that, the haplo insufficiency of the TAB2 gene at 6q25.1 (OMIM # 605101) has been recently demonstrated to be responsible for congenital heart defects [Thienpont et al, 2010]: cardiac malformations have been previously reported in many individuals with interstitial 6q deletions [Meng et al, 1992;Hopkin et al, 1997;Sukumar et al, 1999;Bisgaard et al, 2006;Caselli et al, 2007;Nowaczyk et al, 2008].…”

Alterations in sperm DNA methylation patterns at imprinted loci in two classes of infertility

“…At present, approximately 80 imprinted genes have been identified, many of which are implicated in tumorigenesis, fetal growth regulation, and embryonic development (5)(6)(7)(8). Pathological perturbation in the methylation imprints during gametogenesis or development can give rise to growth-related syndromes and is frequently observed in cancer (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

Evolution of Imprinting: Imprinted Gene Function in Human Disease

“…The situation is complicated by the fact that Zac1 knockout mice also exhibit reduced birth weights (Varrault et al, 2006), and paternally inherited deletions of 6q24 covering ZAC/PLAGL1 result in IUGR (Nowaczyk et al, 2008). These observations suggest deviations from an expression optimum, and it may be that IUGR in paternal 6q24 duplications and deletions has different developmental causes.…”