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De novo balanced chromosomal aberrations (BCAs), such as reciprocal translocations and inversions, are genomic aberrations that, in approximately 25% of cases, affect the human phenotype. Delineation of the exact structure of BCAs may provide a precise diagnosis and/or point to new disease loci. We report on six patients with de novo balanced chromosomal translocations (BCTs) and one patient with a de novo inversion, in whom we mapped breakpoints to a resolution of 1 bp, using shallow whole-genome mate pair sequencing. In all seven cases, a disruption of at least one gene was found. In two patients, the phenotypic impact of the disrupted genes is well known (NFIA, ATP7A). In five patients, the aberration damaged genes: PARD3, EPHA6, KLF13, STK24, UBR3, MLLT10 and TLE3, whose influence on the human phenotype is poorly understood. In particular, our results suggest novel candidate genes for retinal degeneration with anophthalmia (EPHA6), developmental delay with speech impairment (KLF13), and developmental delay with brain dysembryoplastic neuroepithelial tumor (UBR3). In conclusion, identification of the exact structure of symptomatic BCTs using next generation sequencing is a viable method for both diagnosis and finding novel disease candidate genes in humans.

Background and Aim. Sotos syndrome 2 (MIM #614753), known also as Malan syndrome, is caused by heterozygous mutations/deletions of the NFIX gene located on chromosome 19p13.2. It manifests in developmental delay, intellectual impairment, macrocephaly, central nervous system anomalies, postnatal overgrowth, and craniofacial dysmorphism. Unusual behavior with/without autistic traits, ophthalmologic, gastrointestinal, musculo-skeletal, and hand/foot abnormalities are also frequent. Due to the limited number of such cases, no definitive conclusions about genotype-phenotype correlations have been possible. In the following paper, we discuss physical features consistent with Sotos syndrome 2 based on literature review and two new cases [a patient with de novo 19p13.2 deletion encompassing a part of the NFIX gene and a patient with de novo (not described so far) heterozygous missense mutation c.367C>T (p.Arg123Trp) in the NFIX gene]. Results: Apart from overgrowth and psychomotor developmental delay, the most consistent physical features of our two patients are dysmorphism including high forehead, downslanting palpebral fissures, pointed chin, and abnormalities of the pinna. Both show abnormal behavior and present with long, tapered fingers and toenail defect. No severe congenital malformations were noted. Conclusions: We hope these data will serve as a material for further studies and provide an opportunity to make more reliable genotype-phenotype correlations.

Background: Chromosomal duplications involving 17p13.3 have recently been defined as a new distinctive syndrome with several diagnosed patients. Some variation is known to occur in the breakpoints of the duplicated region and, consequently, in the phenotype as well. Aims: We report on a patient, the fifth to our knowledge, a 4-year-old girl with a pure de novo subtelomeric 17p13.2-pter duplication. She presents all of the facial features described so far for this duplication and in addition, a unilateral palmar transversal crease and oculocutaneous albinism which has not been reported previously. Methods: A detailed molecular description of the reported aberration and correlation with the observed phenotypical features based on a literature review. We discuss the possible molecular etiology of albinism in regard to the mode of inheritance. Conclusion: The new data provided here may be useful for further genotype correlations in syndromes with oculocutaneous albinism, especially of autosomal dominant inheritance.

Here we report a patient with 11p15.4p15.5 duplication and 13q34 deletion presenting with Beckwith-Wiedemann syndrome (BWS) and moderate deficiency of factor VII (FVII). The duplication was initially diagnosed on methylation-sensitive multiplex ligation-dependent probe amplification. Array comparative genome hybridization confirmed its presence and indicated a 13q34 distal deletion. The patient's clinical symptoms, including developmental delay and facial dysmorphism, were typical of BWS with paternal 11p15 trisomy. Partial 13q monosomy in this patient is associated with moderate deficiency of FVII and may also overlap with a few symptoms of paternal 11p15 trisomy such as developmental delay and some facial features. To our knowledge this is the first report of 11p15.4p15.5 duplication associated with deletion of 13q34 and FVII deficiency. Moreover, this report emphasizes the importance of detailed clinical as well as molecular examinations in patients with BWS features and developmental delay.

AIM OF THE STUDY Biochemical diagnosis of fetuses with multiple malformations--an attempt to determine the frequency of prenatal Smith-Lemli-Opitz syndrome. Discussion on trends in prenatal diagnosis of non-specific multiple malformations disorders. MATERIAL AND METHODS A total of 117 fetal samples were obtained. They were analyzed with gas chromatography/mass spectrometry (GC/MS) method to assess the concentration of 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC) in amniotic fluid samples and (or) to establish 7-dehydroestriol/estriol and 8-dehydropregnanetriol/pregnanetrio ratios in maternal urine. RESULTS In 4 cases Smith-Lemll-Opitz syndrome was confirmed. CONCLUSIONS Biochemical GC/MS sterol analyses of amniotic fluid or maternal urinary metabolites toward Smith- Lemli-Opitz syndrome, as cheap tests, should be performed in all pregnancies with suggestive ultrasound features (holoprosencephaly and(or) atrioventricular canal and(or) genital anomalies), especially when nuchal translucency is increased >3 mm, and after exclusion of chromosomal aberration in routine karyotyping or even arrayCGH.

We report on a patient with severe psychomotor disability, numerous dysmorphic features, and congenital malformations resulting from a complex genomic rearrangement on 16q24.1-q24.3 involving a de novo duplication-triplication pattern. To the best of our knowledge, this is the first reported patient presenting with this aberration within the distal chromosome 16q. We suggest that the clinical phenotype of our patient results from over-dosage of genes mapped to the region with duplication/triplication (five genes: FOXF1, FOXC2, ANKRD11, SPG7 and FANCA seem to play a peculiar role). Detailed molecular characterization and documentation of the complex genomic rearrangement observed in the proband and of the clinical presentation are important for accurate genotype-phenotype correlations in genetic counseling. Delineation of the gene map for the terminal region of chromosome 16q will provide insight into this chromosome 16q24.1-q24.3 contiguous gene duplication-triplication syndrome.