Dysmorphic features, simplified gyral pattern and 7q11.23 duplication reciprocal to the Williams-Beuren deletion

Abstract

We report a patient with mild pachygyria, ascertained during a screening of subjects with abnormal neuronal migration and/or epilepsy, having a 7q11.23 duplication reciprocal to the Williams-Beuren critical region (WBCR) deletion. He exhibited speech delay and mental retardation together to type II trigonocephaly and other abnormalities. The proband's mother carried the same imbalance, though her phenotype was milder and no abnormal conformation of the cranium was reported. She had suffered a few seizures in infancy, as already described in other duplicated subjects. This genomic imbalance, now described in 17 subjects, including one parent for each of the four probands, is associated with a variable phenotype. Speech impairment is present in most cases; no distinctive facial gestalt is recognizable; seizures have been reported in four subjects and brain magnetic resonance, performed in eight cases, resulted abnormal in six, while detected abnormal neuronal migration in two. Although the clinical description of additional cases is needed to delineate a definite phenotypic core for WBCR duplications, trigonocephaly, also reported in another dup(7)(q11.23) patient, is possibly a trait that, together with speech impairment, may call for clinically oriented specific screening. Abnormal development of the cerebral cortex, reported also in the Williams-Beuren deletion, suggests that at least one gene is present in the critical region whose deletion/duplication impairs neuronal migration.

The genomic basis of the Williams – Beuren syndrome

“…In a third of cases, the duplication is inherited from one parent; in a few of the reported families, the chromosome-transmitting parent displayed a mild pattern of WBS-duplication typical symptoms. This observation of only minor symptoms in the duplication-carrying parent could imply that, in addition to gene dosage effects, other mechanisms such as genetic and/or environmental interactions are important in determining the phenotypic outcome of patients with this genetic aberration [109,111,116,118]. Using FISH and quantitative real time PCR, the size of the duplication was calculated generally to be the same size as of the common deletion region in WBS (~1.5 Mb).…”

CNV and nervous system diseases – what’s new?

“…The most significant phenotypic component observed in almost all dup(7)(q11.23) patients is their moderate to severe language delay, paired with normal to only mildly impaired nonverbal and visuospatial skills (Somerville et al, 2005;Kriek et al, 2006;Berg et al, 2007;Depienne et al, 2007;Kirchhoff et al, 2007a;Torniero et al, 2007Torniero et al, , 2008Merritt and Lindor, 2008;Orellana et al, 2008). This pattern is the opposite of the typical WBS patients who display fluent expressive language alongside poor visuospatial skills (Mervis BCSTR1 BCSTR1 BBSTR1 BBSTR1 BBSTR1 BBSTR2 BBSTR2 BBSTR2 CR16T WS10 D7S1870 Cusco et al (2008).…”

“…Quite different from the sporadic nature of WBS, among the remaining 12 informative dup(7)(q11.23) cases, one inherited the duplication from his father (Kriek et al, 2006); three from their mothers (Berg et al, 2007;Torniero et al, 2008); 4/12 (33%) is astonishingly high compared to the familial WBS cases. This difference may be related to the milder phenotype of dup(7)(q11.23) compared to WBS (Berg et al, 2007).…”

“…1 ); these two duplications are thus the bona fide reciprocal duplications of the 1.55 Mb WBS common recurrent deletion. The breakpoints of the duplications described in Kriek et al (2006), Berg et al (2007), Depienne et al (2007), Kirchhoff et al (2007a), Merritt and Lindor (2008), Orellana et al (2008) and Torniero et al (2008) were not exactly mapped. They could be in any LCR or in the non-duplicated region between the LCRs Am and Bt; the duplications could thus be reciprocal to the common recurrent deletion, uncommon recurrent deletion (if the breakpoints are in Ac and Am), or perhaps some may represent nonrecurrent duplications.…”

“…WBS patients have a distinctive and characteristic facial phenotype, whereas the dup(7)(q11.23) patients, though having some mild dysmorphology, do not share a common gestalt (Somerville et al, 2005;Kriek et al, 2006;Berg et al, 2007;Depienne et al, 2007;Kirchhoff et al, 2007a;Torniero et al, 2007Torniero et al, , 2008Merritt and Lindor, 2008;Orellana et al, 2008). Most WBS patients display cardiovascular and connective tissue anomalies (the most common form being supravalcular aortic stenosis SVAS) resulting from haploinsufficiency of the ELN gene inside WBCR ( Fig.…”