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Interstitial deletions involving 14q13.1q21.1 are rare. In the literature at least 10 cases involving this region have been described and all patients showed a phenotype within the holoprosencephaly (HPE) spectrum. Previous studies suggested the HPE8 region as a candidate locus for HPE at 14q13. We report an adolescent with a 14q13.1q21.1 deletion encompassing the HPE8 region associated with intellectual disability (ID), bilateral microphthalmia, and coloboma, without cerebral anomalies typical of HPE. Except for ocular defects (i.e., microphthalmia, coloboma) consistent with HPE-type anomalies, the minor facial dysmorphia was not suggestive for HPE and the absence of cerebral anomalies should rule out this diagnosis. The deletion of the potential HPE candidate genes NPAS3, EAPP, SNX6, and TULIP1, raises doubts about their pathologic role in determining HPE. It is likely that deletions of HPE genes are not sufficient to cause HPE, and that multiple genetic, chromosomal, and environmental factors interact to determine the variable clinical expression of HPE. This is the first case of a 14q deletion encompassing the HPE8 locus with the only features consistent with HPE-type anomalies affecting the ocular system (i.e., microphthalmia, coloboma), and without cerebral anomalies specific for HPE. The inclusion of potential HPE candidate genes in the deletion raises the question whether this patient is affected by a less severe form of HPE (HPE microform), or whether he has a new ID/MCA deletion syndrome.

Complex chromosomal rearrangements (CCRs) are structural aberrations involving more than two chromosomes with at least three breakpoints. CCRs can be divided into familial and de novo. Balanced CCR are extremely rare in humans and are at high risk of producing unbalanced gametes. Individuals with balanced CCR are usually phenotipically normal but report fertility problems, recurrent miscarriages or congenital anomalies in newborn offsprings as consequence of either meiotic failure or imbalanced chromosomes segregation.We describe the case of an unbalanced CCR involving chromosomes 1, 4 and 8 found in a girl with developmental delay, hexadactilia and microcephaly. The rearrangement, apparently balanced at a standard karyotype analysis and of maternal origin, was demonstrated to be unbalanced by array-CGH and FISH. In conclusion our study underlines the importance of the combined use of a quantitative technique, as array-CGH, to detect criptic segmental aneuploidies, and a qualitative tool, as FISH analysis, to physically map the localization of the chromosome segments involved, in order to realize the exact nature that underlies a chromosomal rearrangement.

We report two individuals with developmental delay and dysmorphic features, in whom array-based comparative genomic hybridization (array CGH) led to the identification of a 2p15p16.1 de novo deletion. In the first patient (Patient 1) a familial deletion of 6q12, inherited from her father, was also detected. In the second patient (Patient 2) in addition to the 2p15p16.1 microdeletion a de novo deletion in Xq28 was detected. Both individuals shared dysmorphic features and developmental delay with the six reported patients with a 2p15p16.1 microdeletion described in medical literature. Conclusion: in the first patient a 642 kb 2p16.1 deletion (from 60.604 to 61.246 Mb), and a 930 kb 6q12 familial deletion, was detected and in the second a 2.5 Mb 2p15p16.1 deletion (from 60.258 to 62.763 Mb), with a Xq28 deletion, was discovered. The common dysmorphic features and neurodevelopmental delay found in these patients are in agreement with the clinical phenotype of a microdeletion syndrome involving 2p15p16.1. Our data confirm the hypothesis suggesting that 2p15p16.1 deletion is a contiguous gene syndrome.

Chromosome 22, particularly the q11.2 sub-band, has long been recognized as responsible for multiple congenital anomaly disorders. In particular, its susceptibility to subtle microdeletions or, more rarely, microduplications has been attributed to the presence of several low-copy repeats spanning the region as mediators of nonallelic homologous recombination that result in 22q11.2 rearrangements. While recent data suggest that the frequency of 22q11.2 microduplications could be approximately half of all deletions, now only 50 unrelated cases have been reported thus far. However, it is reasonable to suppose that microduplications of 22q11.2 may be largely undetected as a result of a less-distinct, unpredictable, and/or milder phenotype ranging from normal to mild learning difficulties with/without other multiple defects. We report on the first case of myoclonic epilepsy in a 10-year-old boy carrying a de novo 22q11.2 microduplication. Emphasizing that this rare association could be one of the many unrecognized aspects underlying this new emerging syndrome and once again its clinical heterogeneity, we suggest further investigation of the function of the RAB36 gene and propose that in the screening of individuals with developmental delay, minor behavioral problems mild dysmorphology and seizures, investigation of 22q11.2 microduplications should be considered.

Interstitial deletions of the long arm of chromosome 14 are relatively rare. We report a 8.5-year-old girl with dysmorphic facial features and mental retardation associated with a de novo interstitial deletion of chromosome 14. The comparison between our patient and all published patients is reviewed. The genetic investigations have allowed us to define the critical chromosomal region and to start an accurate follow-up.

We report a modified method for the rapid detection of aneuploidies directly on human uncultured amniocytes that simplifies and shortens the entire experimental procedure, yielding signals which allow correct diagnosis of trisomy 21 in 97% of cases. The improvement is based on two points : 1) use of cosmid pockets specific for the Down's syndrome minimal region as FISH probes, and 2) a modified protocol for the fixation and preparation of amniocytes.

Summary: Purpose: Mental retardation, facial dysmorphisms, and neurologic and brain abnormalities are features of 6q terminal deletions. Epilepsy is frequently associated with this chromosome abnormality, but electroclinical findings are not well delineated. We report five unrelated patients with 6q terminal deletions and a peculiar clinical, EEG, and neuroradiologic picture of epilepsy, mental retardation, and colpocephaly. Methods: These three male and two female patients underwent general and neurologic examinations, repeated awake and sleep EEGs, and brain magnetic resonance imaging (MRI). A cytogenetic study and fluorescent in situ hybridization (FISH) with chromosome-specific subtelomeric probes were carried out in all cases. Results: All subjects had seizures characterized by vomiting, cyanosis, and head and eye version, with and without loss of consciousness. In four cases, EEGs showed posterior spike-andwave complexes, which were activated by sleep. No patient had status epilepticus or prolonged seizures. Brain MRI revealed colpocephaly and dysgenesis of the corpus callosum and brainstem in four patients; three of them also had hypertrophic massa intermedia. FISH analysis revealed a 6q terminal deletion in all patients, which ranged between 9 Mb (cases 2 and 3) and 16 Mb (case 4). Conclusions: We suggest that epilepsy associated with 6q terminal deletions is a new entity. Patients with dysmorphic features associated with focal occipital epilepsy, colpocephaly, and dysgenesis of the corpus callosum, thalami, and brainstem should be considered candidates for testing for 6q subtelomere deletions. Key Words: 6q Deletion—Epilepsy—EEG— Colpocephaly—Chromosome abnormalities.

We report a case of a 13-year-old girl with a 5.4 Mb de novo deletion, encompassing bands 2q23.3q24.1, identified by array-comparative genomic hybridization. She presented with minor facial and digital anomalies, mild developmental delay during infancy, and behavioral disorders. Few of the reported cases overlap this deletion and all only partially. We tried to compare the clinical features of the patient with the other cases, even though not all of them were molecularly characterized in detail. Considering the neuropsychiatric involvement of the proband and the clinical descriptions of other similar cases, we attempted to identify the genes more probably involved in neurological development and function in the deleted region, particularly GALNT13, KCNJ3 and NR4A2, which are expressed in neuronal cells.

Only a few reports on supernumerary r(1) chromosomes associated with a clinical phenotype have been published. We describe two unrelated patients with congenital malformations and developmental delay who were found to have a de novo supernumerary r(1) in 50% (Case 1) and 80% (Case 2) of the examined cells. Conventional cytogenetic techniques (QFQ, CBG, and DA-DAPI), complemented by fluorescence in situ hybridization studies using alpha satellite probes, showed that both small marker chromosomes (SMCs) primarily consisted of the centromere and heterochromatin of chromosome 1, a conclusion that was also supported by chromosome 1 painting. In an attempt to establish phenotype-genotype correlations, a further investigation was performed using YACs mapped to the chromosome 1 pericentromeric region. A fluorescent signal was evident after hybridization with Y934G9 (1q21) in Case 1 and Y959C4 (1p11.1-12) in Case 2. Partial trisomy of unique sequences flanking pericentromeric sequences is shown to underlie the clinical phenotype in both patients. This evidence should be taken into account when SMCs are ascertained, particularly in prenatal diagnosis.

The interstitial duplication of the long arm of chromosome 19 is a rare abnormality, characterized by developmental delay and dysmorphic features, also reported in association with cardiac, urinary, and CNS malformations. We describe a new case of de novo 19q12-q13.2 duplication characterized by fluorescent in situ hybridization (FISH) and array comparative genomic hybridization (CGH) and, by reviewing the data from previous articles, we report a tentative genotype/phenotype correlation. Four previously described cases showed the same or overlapping 19q duplications and shared with our patient common dysmorphisms, psychomotor retardation, and CNS malformations. The present description of a new case of 19q12-q13.2 duplication with a molecular cytogenetic and genomic characterization adds further elements to the understanding of the impact of the genomic segment on the phenotype.

Subtelomeric terminal 6p deletion has been recognized as a clinically identifiable syndrome including facial dysmorphism, malformation of the anterior eye chamber, hearing loss, heart defect and developmental delay. Genotype –phenotype correlations of previously published patients have been strongly suggested anterior eye segment anomalies as one of major malformation of the syndrome if the critical 6p25 region containing the FOXC 1 gene. In addition it has been hypothesized the presence in this region of one or more genes involved in hearing loss. We report on a case of terminal 6p deletion in a 47, XYY karyotype. Further characterization of the deletion with array comparative genome hybridization revealed also a cryptic microduplication on chromosome 19. The patient showed dysmorfic features, neuromotor retardation and profound language impairment, in absence of hearing loss and structural eye anomalies. As far as we know this is the first reported terminal 6p25.1 deletion case without eye dysgenesis precisely characterized by array-CGH. Our result could confirm that no genes in this region could be considered as an obvious candidate for hearing loss and demonstrate the need for further elucidation about function of the genes involved in eye developmental processes.

Vertebrate telomeres consist of tandem repeats of the TTAGGG sequence that cap the ends of chromosomes, protecting them from degradation and fusion. Extensive evidence has shown that telomere shortening and erosion lead lo chromo¬some end-to-end fusions and genomic instability, causing mental retardation and/or malformation syndromes. So far, over 19,000 patients with mental retardation have been tested and reported of whom -2.5% appeared to have a subtelomeric rearrange¬ment [Ravnan et al., 2006; Ballif et al., 2007; Ledbetter and Martin, 2007]. Since the identification of sub¬microscopic subtelomeric rearrangements as a major cause of mental retardation [Flint et al., 1995], testing for subtelomeric abnormalities among patients with mental retardation has become an important diag¬nostic tool. Although widespread screening among patients with mental retardation might be desirable, the current cost of testing is considered too expensive to allow unselected testing. Therefore clinical preselection is important. So far, selection for subtelomere testing has often been based on the checklist proposed by De Vries et al. [20011. (F, Family history of mental retardation; 2, prenatal onset growth retardation; 3, postnatal growth abnormal¬ities; 4, >2 facial dysmorphic features; 5, one or more non-facial dysmorphic features and/or congenital abnormality).Here we report on a patient with a 10 q26-10gter deletion. Our patient is a male, the first-born child of healthy non-consanguineous parents, with no family history of mental retardation or birth defects. He was born by caesarean delivery at 38 weeks of gestation.

Chromosomal abnormalities may cause autism by disrupting a gene or by providing a permissive genetic environment for mutations elsewhere in the genome to become expressed as autism. We report here on a patient with an apparently balanced de novo translocation of chromosomes 1q and 5q. He presented with minor dysmorphic features and renal malformations, mental retardation, and autism. Further characterization of the chromosomal rearrangement by FISH revealed a deletion in chromosome 1 from q23.3 to q24.2 corresponding to a region of rising interest in the research of autism susceptibility genes. The array-CGH technique gave better resolution of the breakpoints and the size of the deletion was calculated to be 4.97 Mb.

We describe a 3-year-old boy with complete agenesis of corpus callosum, developmental delay/mental retardation, anterior diaphragmatic hernia, Morgagni type, severe hypermetropia, and facial dysmorphism suggesting the diagnosis of Donnai–Barrow syndrome. Subtelomeric FISH analysis revealed a paternally-derived t(9;16) (q34.3;q24.3) translocation with partial 9q monosomy and partial 16q trisomy. As some facial features resemble the 9q emerging phenotype, we suggest the hypothesis that some patients with Donnai–Barrow syndrome might be abscribed to 9q terminal deletion. © 2006 Wiley-Liss, Inc.

The aim of this report is to provide an update on the natural history of the Cri du Chat Syndrome by means of the Italian Register (I.R.). Two hundred twenty patients were diagnosed by standard cytogenetic methods and 112 of these were also characterised by molecular-cytogenetic investigation (FISH). FISH analysis showed interstitial deletions, short terminal deletions and other rare rearrangements not previously correctly diagnosed by standard cytogenetics. The diagnosis was made in the first month of life in 42% and within first year in 82% of cases. The remaining 18% were diagnosed at an age ranging from 13 months to 47 years. At the last follow-up, patient age ranged from 8 months to 61 years. Mortality, already low, has decreased over time as it is lower between 1984-2002 compared to 1965-1983. Mortality was higher in patients with unbalanced translocations resulting in 5p deletions. Our data confirm that the cat-like cry and peculiar timbre of voice are the most typical signs of the syndrome, not only at birth but also later and these are the only signs which might suggest the diagnosis in patients with small deletions and mild clinical picture. A cytogenetic and clinical variability must be underlined. Cardiac, cerebral, renal and gastrointestinal malformations were more frequent in the patients with unbalanced translocations resulting in 5p deletions. Sucking and feeding difficulties and respiratory infections are frequent in the first months or years of life. Intubation difficulties linked to larynx anomalies must be considered. Psychomotor development is delayed in all patients but there is a variability related to deletion size and type as well as other genetic and environmental factors. However, the results showed an improvement in the acquisition of the development skills and progress in social introduction which should encourage caregivers and parents to work together in carrying out the rehabilitative and educational interventions.

PURPOSE: We evaluated the experiences of 19 Italian laboratories concerning 241 small supernumerary marker chromosomes (sSMCs) with the aim of answering questions arising from their origin from any chromosome, their variable size and genetic content, and their impact on the carrier's phenotype. METHODS: Conventional protocols were used to set up the cultures and chromosome preparations. Both commercial and homemade probes were used for the fluorescent in situ hybridization analyses. RESULTS: A total of 113 of the 241 sSMCs were detected antenatally, and 128 were detected postnatally. There were 52 inherited and 172 de novo cases. Abnormal phenotype was present in 137 cases (57%), 38 of which were antenatally diagnosed. A mosaic condition was observed in 87 cases (36%). In terms of morphology, monocentric and dicentric bisatellited marker chromosomes were the most common, followed by monocentric rings and short-arm isochromosomes. The chromosomes generating the sSMCs were acrocentric in 132 cases (69%) and non-acrocentric chromosomes in 60 cases (31%); a neocentromere was hypothesized in three cases involving chromosomes 6, 8, and 15. CONCLUSION: The presented and published data still do not allow any definite conclusions to be drawn concerning karyotype-phenotype correlations. Only concerted efforts to characterize molecularly the sSMCs associated or not with a clinical phenotype can yield results suitable for addressing karyotype-phenotype correlations in support of genetic counseling.

Summary: Purpose: Several studies attempted to clarify the genotype–phenotype correlations in patients with inverted duplication of chromosome 15 [inv dup(15)], which is usually characterized by severe mental retardation and epilepsy in individuals with large duplications including the Prader–Willi/Angelman region. We report two patients with inv dup(15) who, in spite of a large duplication, had a mild phenotype including adult-onset epilepsy. This report may help to define the milder spectrum of the syndrome. Methods: A 25-year-old girl with mild mental retardation had a 6-year history of absence seizures, with occasional head drop. Interictal EEG revealed diffuse spike–wave complexes. Epilepsy was well controlled by a combination of lamotrigine (LTG) and valproate (VPA). The other patient, a 27-year-old man with mild mental retardation, had a 5-year history of rare generalized tonic–clonic seizure during sleep, and frequent episodes of unresponsiveness, which appeared to be atypical absence seizures on video-EEG recordings. A combination of VPA and LTG led to a remarkable improvement, although no complete control. Results: Molecular analysis revealed a large inv dup15 in both patients. Conclusions: The discrepancy between the mild phenotype and the severe chromosomal abnormality detected in these two patients further supports the notion that the site of breakpoint might be contributory to the inv dup(15) phenotype. Inv dup(15) should be considered in atypical cases of generalized epilepsy of adult onset without clear-cut etiology.

The 18q- syndrome [MIM #601808] is a terminal deletion of the long arm of chromosome 18. The most common deletion extends from region q21 to qter. We report here a nine-year-old boy possessing a simple 18q- deletion who had abnormalities of the brain, skull, face, tooth, hair, bone, and skin, plus joint laxity, tongue palsy, subtle sensoneural deafness, mental and speech delay, attention deficit hyperactivity disorder (ADHD), tic, and restless legs syndromes. His karyotype was 46, XY, del (18)(q21.31-qter). The size of the deletion was approximately 45 cM. Most of these abnormalities were not explained by the 18q- deletion. The family pedigree suggested the presence of a subtle involvement of ectodermal and/or mesodermal structures. Karyotypes of the other family members were normal.