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Sindrome da microduplicazione 17p13.3, palatoschisi

SINDROME DI PALLISTER KILLIAN

Sindrome da duplicazione 1q21, riarrangimento genomico

gene NIPBL, Sindrome Cornelia de Lange

TUBEROUS SCLEROSIS, GENOMIC REARRANGEMENT

malformazioni cerebrali, anomalie setto pellucido

Ittiosi, disabilità intellettiva, riarrangiamenti genomici

delezione 17p11.2, Sindrome di Smith-Magenis, anomalie congenite multiple

Per una migliore comprensione patogenetica del ritardo mentale (RM) in combinazione o meno con le manifestazioni malformative, i tests di laboratorio sono di notevole importanza. La metodica CGH Array ha migliorato la sensibilità nella valutazione dei punti di rottura nelle delezioni cromosomiche. Qui presentiamo un caso di delezione 15q26.2-15qter in un bambina con medie note dismorfiche esterne (come la clinodattilia), interne (doppio distretto renale a destra) ed alcune alterazioni del linguaggio. L'analisi GCH Microarray è stata effettuata estraendo da linfociti di sangue periferico (Puregene DNA isolation kit, Gentra) e marcando (Cy5) il DNA del probando e realizzando l'Array CGH (Agilent human genome CGH Microarray Kit 4 x 44K, capacità risolutiva: 200Kb). La metodica FISH è stata realizzata mediante il multiprobe-T (Cytocell, UK) in accordo con le raccomandazioni della casa costruttrice. La comparazione genomica tra il DNA del probando ed il DNA di controllo (Human DNA, Promega), opportunamente marcato (Cy3), ha evidenziato la presenza di una monosomia parziale di circa 5,55 Mb del braccio lungo del cromosoma 15 (posizioni: da 94.783.205 a 100.338.915). La valutazione dei break points in tale monosomia ci consente di valutare i geni potenzialmente coinvolti nella patogenesi del RM. Particolare rilievo hanno i geni IGFR1, MEF2A e CHSY1 le cui alterazioni sembrano essere legate a più processi di sviluppo somatico e del SNC .

Autism Spectrum Disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders, characterized by qualitative impairment in social interaction and communication and restricted, repetitive and stereotyped patterns of behavior, interests and activities. They have a multifactorial etiology, but today different studies are showing the central role of genetics. Different genetic alterations were detected: chromosomal abnormalities, mutations, trinucleotide repeats and copy number variations (CNVs). Several studies identified many CNVs associated with ASDs and possible candidate genes, whose loss or gain could have a key role in the etiopathogenesis of these disorders. In particular, they seem to be involved in neurogenesis, neuronal migration, differentiation and degeneration. We want emphasize that the final phenotype is variable, related not only to the genetic background but also to environmental factors

Several studies have shown the importance of segmental deletions/duplications in the field of chromosome pathologies. Non allelic homologous recombination, NAHR, between chromosomes or sister chromatids, mediated by segmental duplications, is the foundation of frequent mechanisms for structural chromosome mutations such as micro-deletions, micro-duplications, translocations, inversions, and marker chromosomes. We analyzed three distinct genomic regions (22q11.2, 17p11.2, 16p11.2) and we discussed how the same chromosome region can be affected by deletion or by reciprocal duplication, respectively responsible for a syndrome or for a reciprocal counter-syndrome, with different phenotypic manifestations

INTELLECTUAL DISABILITY, EPILEPSY, MILD DYSMORPHISMS, 22q11.2 DISTAL DUPLICATION

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.

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.

Intellectual disability (ID) is a neurodevelopmental dis- order characterized by deficits in intellectual and adap- tive functioning that present before 18 years of age [1]. ID is heterogeneous in etiology and encompasses a broad spectrum of functioning, disability, needs and strengths. Originally formulated in strictly psychometric terms as performance greater than 2.5 SDs below the mean on intelligence testing, the conceptualisation of ID has been extended to include defects in adaptive beha- viours [2]. The term-global developmental delay-(GDD) is usually used to describe children younger than 5-years of age who fail to meet expected developmental milestones in multiple areas of intellectual functioning [1]. In both conditions the symptoms must be present in the early developmental period, but they may not become fully manifest until social demands exceed patients’ capacities. ID affects 1.5 to 2% of the population in Western countries and represents an important health burden [3]. During the past decade, advances in genetic research have enabled genomewide discovery of chromosomal copy-number and single-nucleotide changes in patients with ID and autism as well as in those with other neu- rodevelopmental disorders. These technological advances-which include array comparative genomic hybridization (CGH), single nucleotide polymorphism genotyping arrays and massively parallel sequencing- have transformed the approach to the identification of etiologic genes and genomic rearrangements in the research laboratory and are now being applied in the clinical diagnostic arena [4]. In this view, the American Academy of Pediatrics recently released a guidance for the clinician in rendering Pediatric Care [5]. The sug- gested clinical approach to the patient should be con- ducted closely with a geneticist and includes the child’s medical history, the family history, the physical and neu- rologic examinations (emphasizing the dysmorphology examination) and the examination for neurologic or behavioral signs that might suggest a specific recogniz- able syndrome or diagnosis. After this clinical evalua- tion, focused use of genetic laboratory tests, imaging and other consultations are critical in establishing the right diagnosis, its pattern of inheritance and the subse- quent follow-up. Finally, this guidance highlights a renewed emphasis on array CGH, that is now considered the first-line diagnostic test for children who present with GDD/ID of unknown cause, and on the identification of-treatable-causes of GDD/ID with the recommendation to consider screening for inborn errors of metabolism [5]. The future use of whole-genome or next generation sequencing offers pro- mises and challenges needing to be yet addressed before their regular implementation in the clinic.

Gastroschisis is an abdominal wall defect, typically located to the right of the umbilical cord, requiring an early surgical treatment shortly after birth. Affected patients can be identified during intrauterine life with US and should be delivered in referral hospitals where a multisciplinary approach can be provided, involving neonatologists, clinical geneticists, surgeons and other specialists. These patients require a complex management in Neonatal Intensive Care Unit (NICU) and a long term follow-up after discharge. Exceed the acute neonatal condition, gastroschisis has a good prognosis, if there are no overlapping complications, and it should be differentiated from omphalocele, burdened with worse prognosis, and other conditions in the wide spectrum of abdominal wall defects.

Background: VATER association was first described in 1972 by Quan and Smith as an acronym which identifies a non-random co-occurrence of Vertebral anomalies, Anal atresia, Tracheoesophageal fistula and/or Esophageal atresia, Radial dysplasia. It is even possible to find out Cardiovascular, Renal and Limb anomalies and the acronym VACTERL was adopted, also, embodying Vascular, as single umbilical artery, and external genitalia anomalies. Methods: Data on patients with esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) admitted in the Neonatal Intensive Care Unit (NICU) between January 2003 and January 2013 were evaluated for the contingent occurrence of typical VACTERL anomalies (VACTERL-type) and non tipical VACTERL anomalies (non-VACTERL-type). The inclusion criterion was the presence of EA with or without TEF plus two or more of the following additional malformations: vertebral defects, anal atresia, cardiovascular defects, renal anomalies and lower limb deformities, like radial dysplasia. Results: Among 52 patients with EA/TEF, 20 (38,4%) had isolated EA and 7 (21,8%) had a recognized etiology such a syndrome and therefore were excluded. Among 32 infants with EA and associated malformations, 15 (46,8%) had VACTERL association. The most common anomalies were congenital heart defects (73,3%), followed by vertebral anomalies (66,6%). Many patients also had additional non-VACTERL-type defects. Single umbilical artery was the most common one followed by nervous system abnormalities and anomalies of toes. Between the groups of infants with VACTERL type and non-VACTERL-type anomalies, there are several overlapping data regarding both the tipically described spectrum and the most frequently reported non-VACTERL-type malformations. Thus, it is possible to differentiate infants with a full phenotype (VACTERL full phenotype) and patients that do not meet all the criteria mentioned above, but with some homologies with the first group (VACTERL partial phenotype). Conclusion: The high frequency of non-VACTERL-type anomalies encountered in full and partial phenotype patients would suggest the need for an extension of the clinical criteria for the diagnosis of VACTERL association and also for pre- and post-operative management and follow-up in the short and long term.

When normal development and growth of the calvarial sutures is disrupted, craniosynostosis (premature calvarial suture fusion) may result. Classical craniosynostosis syndromes are autosomal dominant traits and include Apert, Pfeiffer, Crouzon, Jackson-Weiss, and Saethre-Chotzen syndromes. In these conditions, there is premature fusion of skull bones leading to an abnormal head shape, ocular hypertelorism with proptosis, and midface hypoplasia. It is known that mutations in the fibroblast growth factor receptors 1, 2, and 3 cause craniosynostosis. We report on a child with a clinically diagnosed Pfeiffer syndrome that shows the missense point mutation Q289P in exon 8 of the FGFR2 gene. This is a mutation not previously described in the Pfeiffer syndrome but reported in the Crouzon, Jackson-Weiss, and Saethre-Chotzen syndromes. In this paper, we propose the concept that these disorders may represent one genetic condition with phenotypic variability.

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.

Epilepsy is one of the most common neurological disorders in humans with a prevalence of 1% and a lifetime incidence of 3%. Idiopathic epilepsies occur in the absence of identifiable causal factors, but recent evidences show the role of genetic factors in the developing of these disorders. In particular, several studies focused their attention on the role of copy number variations (CNVs) in the etiology of epilepsy. In recent years, many CNVs have been identified, like 15q11.2, 15q13.3 and 16p13.11 microdeletions, 22q11.2 microduplication and many others. Possible candidate genes included in these regions were also studied and they seem to be involved in neuronal transmission and ion transport. The possibility to identify new rare CNVs allow a greater understanding of the mechanisms of epilepsy and other neurodevelopmental disorders.