An unusual combination of an atypical maternally inherited novel 0.3 Mb deletion in Williams-Beuren region and a de novo 22q11.21 microduplication in an infant with supravalvular aortic stenosis.

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by supravalvular aortic stenosis (SVAS), intellectual disability, overfriendliness and dysmorphic features. It is typically caused by 1.5-1.8 Mb deletions on 7q11.23. The 22q11.21 microduplication syndrome has a variable phenotype and is frequently associated with congenital heart disease. Here we present a unique patient, carrying aberrations within both of the above syndrome regions, referred for possible diagnosis of WBS because of SVAS. The patient was a boy who died suddenly 47 days after birth, possibly due to cardiac complications. Genetic testing was carried out, including array Comparative Genomic Hybridization (aCGH), Fluorescence In situ Hybridization (FISH) and Multiplex Ligation-Dependent Probe Amplification (MLPA) showing that the proband was heterozygous for a novel and atypical 0.3 Mb deletion in WBS region (7q11.23) encompassing the ELN gene. In addition, he was found heterozygous for a 22q11.21 microduplication. Parental studies revealed that the 7q11.23 deletion was inherited from the mother who also exhibited a cardiovascular phenotype, however very mild. The same maternally inherited deletion was detected in one of the proband's siblings, born two years later with a less severe SVAS. The 22q11.2 microduplication was de novo in origin. Detection and investigation of atypical deletions within known syndrome regions are crucial for better genotype-phenotype correlations and more accurate characterization of critical regions. The combined effect of two different genetic defects - one in a known syndrome region and one with variable clinical significance, is valuable for revealing gene interactions and enabling more accurate predictions, especially in prenatal diagnosis.

De novo mosaic MECP2 mutation in a female with Rett syndrome.

We describe a female with Rett syndrome carrying a rare de novo mosaic nonsense mutation on MECP2 gene, with random X-chromosome inactivation. Rett syndrome severity in females depends on mosaicism level and tissue specificity, X-chromosome inactivation, epigenetics and environment. Rett syndrome should be considered in both males and females.

Identification of a novel 15.5 kb SHOX deletion associated with marked intrafamilial phenotypic variability and analysis of its molecular origin.

Haploinsufficiency of the short stature homeobox contaning SHOX gene has been shown to result in a spectrum of phenotypes ranging from Leri-Weill dyschondrosteosis (LWD) at the more severe end to SHOX-related short stature at the milder end of the spectrum. Most alterations are whole gene deletions, point mutations within the coding region, or microdeletions in its flanking sequences. Here, we present the clinical and molecular data as well as the potential molecular mechanism underlying a novel microdeletion, causing a variable SHOX-related haploinsufficiency disorder in a three-generation family. The phenotype resembles that of LWD in females, in males, however, the phenotypic expression is milder. The 15523-bp SHOX intragenic deletion, encompassing exons 3-6, was initially detected by array-CGH, followed by MLPA analysis. Sequencing of the breakpoints indicated an Alu recombination-mediated deletion (ARMD) as the potential causative mechanism.

Deletion of SNURF/SNRPN U1B and U1B* upstream exons in a child with developmental delay and excessive weight.

Prader-Willi syndrome is a rare syndrome characterized by hypotonia, developmental delay and excessive appetite. This syndrome is caused by the loss of function of paternally-expressed genes located in an imprinting centre in 15q11-q13. Here, we report the case of a patient who was referred to us with Prader-Willi syndrome-like symptoms including obesity and developmental delay. Examination of this patient revealed that he was a carrier of a paternally inherited deletion that affected the U1B and U1B* upstream exons of the SNURF-SNRNP gene within the 15q11-q13 imprinted region. Mutations localized within this genomic region have not been previously reported in Prader-Willi syndrome patients. It is possible that disruption of upstream exons of SNURF-SNRNP could contribute to Prader-Willi phenotype by disrupting brain-specific alternative transcripts, although, case reports from further patients with a comparable phenotype are required.