Kleefstra syndrome is a rare genetic disorder, with core phenotypic features encompassing developmental delay/intellectual disability, characteristic facial features – brachy(micro)cephaly, unusual shaped eyebrows, flat face with hypertelorism, short nose with anteverted nostrils, thickened lower lip, carpmouth with macroglossia - and childhood hypotonia. Some additional symptoms are observed in different percentage of the patients. Epilepsy is common symptom as well. The underlying cause of the syndrome is a submicroscopic deletion in the chromosomal region 9q34.3 or disruption of the euchromatin histone methyl transferase 1. We describe two Hungarian Kleefstra syndrome patients, one with the classic phenotype of the syndrome, the diagnosis was confirmed by subtelomeric FISH. Meanwhile in our second patient beside the classic phenotype a new symptom – abnormal antiepileptic drug metabolic response – could be observed. Subtelomere FISH confirmed the 9q34.3 terminal deletion. Because of the abnormal drug metabolism in our second patient, we performed array CGH analysis as well searching for other rearrangements. Array CGH analysis indicated a large – 1.211 Mb -, deletion only in the 9q subtelomeric region with breakpoints ch9:139,641,471-140,852,911. This is the first report on Kleefstra syndrome in patients describing a classical and a complex phenotype involving altered drug metabolism.

The 4q deletion syndrome shows a broad spectrum of clinical manifestations consisting of key features comprising growth failure, developmental delay, craniofacial dysmorphism, digital anomalies, and cardiac and skeletal defects. We have identified a de novo interstitial distal deletion in a 9 month-old girl with growth failure, developmental delay, ventricular septum defect in the subaortic region, patent foramen ovale and patent ductus arteriosus, vascular malformation of the lung, dysgenesis of the corpus callosum and craniofacial dysmorphism using array-comparative genomic hybridization. This de novo deletion is located at 4q28.3-31.23 (136,127,048 - 150,690,325), its size is 14.56 Mb, and contains 8 relevant genes (PCDH18, SETD7, ELMOD2, IL15, GAB1, HHIP, SMAD1, NR3C2) with possible contributions to the phenotype. Among other functions, a role in lung morphogenesis and tubulogenesis can be attributed to the deleted genes in our patient, which may explain the unique feature of vascular malformation of the lung leading to pulmonary hypertension. With the detailed molecular characterization of our case with 4q- syndrome we hope to contribute to the elucidation of the genetic spectrum of this disorder.

Interstitial deletions of 4q21 (MIM 613509) have already been reported in more than a dozen patients with deletions ranging from 2 to 15.1 Mb delineating a common phenotype including marked growth restriction, hypotonia, severe developmental delay with absent or delayed speech and distinctive facial features. A minimal critical region of 1.37 Mb accounting for the common features with 5 known genes (PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1) has been described so far. Here we report on a 5 year-old Hungarian girl presenting with severe developmental delay, good receptive language but absent spoken speech, short stature, dystrophy, hypotonia, distinctive facies including broad forehead, frontal bossing, downward slanting palpebral fissures, hypertelorism, hypoplastic ear-lobes, anteverted nostrils, short philtrum, small mouth, higharched palate, short, small hands and feet, distally narrowing fingers and clinodactyly. Cerebral MRI showed ventricular dilation and an increase in periventricular signal intensity. After extensive metabolic tests and exclusion of subtelomeric deletions array CGH analysis was performed using the Agilent Human Genome G3 SurePrint 8x60K Microarray (Agilent Technologies, USA), which detected a 4,85 Mb de novo interstitial deletion of 4q21.21-4q21.23. The clinical symptoms only partly overlap with reported 4q21 microdeletion cases. Among multiple annotated genes our patient is also haploinsufficient for the following genes: RASGEF1B being a strong candidate for the neurodevelopmental features and PRKG2 for severe growth delay. The first Hungarian case of 4q21 deletion adds to the phenotypic spectrum of this novel microdeletion syndrome and underlines the importance of array CGH to uncover the heterogeneous causes of intellectual disability.

We report a 14-month-old girl with submucous cleft palate, resolving mild hydrocephalus, severe hypotonia and joint contractures. The finding of extreme hydrocephalus, cleft palate and club feet in a fetus of the mother's previous pregnancy suggested an inherited defect. Chromosome analysis and FISH studies in the proband revealed an abnormal homolog 13 resulting in a duplication of distal chromosome 7q, 7q35-qter, and a very small associated deletion of distal chromosome 13q, 13q34-qter. The mother showed the balanced translocation. Similar clinical signs have been described with larger distal 7q duplications. Our findings suggest that 7q35-qter, and possibly the gene for sonic hedgehog (SHH) on 7q36, is the critical region for the typical facial features and the profound hypotonia observed in the 'trisomy of distal 7q' syndrome.

Among human supernumerary marker chromosomes, the occurrence of isodicentric form of 15 origin is relatively well known due to its high frequency, both in terms of gene content and associated clinical symptoms. The associated epilepsy and autism are typically more severe than in cases with interstitial 15q duplication, despite copy number gain of approximately the same genomic region. Other mechanisms besides segmental aneuploidy and epigenetic changes may also cause this difference. Among the factors influencing the expression of members of the GABA_A gene cluster, the imprinting effect and copy number differences has been debated. Limited numbers of studies investigate factors influencing the interaction of GABA_A cluster homologues. Five isodicentric (15) patients are reported with heterogeneous symptoms, and structural differences of their isodicentric chromosomes based on array comparative genomic hybridization results. Relations between the structure and the heterogeneous clinical picture are discussed, raising the possibility that the structure of the isodicentric (15), which has an asymmetric breakpoint and consequently a lower copy number segment, would be the basis of the imbalance of the GABA_A homologues. Studies of trans interaction and regulation of GABA_A cluster homologues are needed to resolve this issue, considering copy number differences within the isodicentric chromosome 15.

Large amounts of low copy number repeats in the 15q11.2q13.3 chromosomal region increase the possibility of misalignments and unequal crossover during meiosis in this region, leading to deletions, duplications, triplications and supernumerary chromosomes. Most of the reported cases with epilepsy, autism and Prader-Willi/Angelman syndrome are in association with rearrangements of the proximal long arm of chromosome 15. Here we report the first two unrelated Hungarian patients with the same epileptic and dysmorphic features, who were investigated by array comparative genomic hybridization (array CGH). By G-banded karyotype followed by FISH and array CGH we could detect partial tetrasomy of the 15q11.2q13.3 chromosomal region, supporting proximal 15q duplication syndrome. Findings of the array CGH gave fully explanation of the phenotypic features of these patients, including epileptic seizures, delayed development, hyperactivity and craniofacial dysmorphic signs. Besides the described features of isodicentric (15) (idic(15)) syndrome Patient 1. suffered from bigeminic extrasystoles and had postnatal growth retardation, which had been published only in a few articles. Dosage effect of some genes in the concerned genomic region is known, but several genes have no evidence to have dosage dependence. Our results expanded the previous literature data. We assume dosage dependence in the case of CHRNA7 and OTUD7A, which might be involved in growth regulation. On the other hand increased dosage of the KLF13 gene seems to have no direct causal relationship with heart morphology. The genomic environment of the affected genes may be responsible for the observed phenotype.