E. Salzano

Array‐CGH and clinical characterization in a patient with subtelomeric 6p deletion without ocular dysgenesis

Subtelomeric terminal 6p deletion has been recognized as a clinically identifiable syndrome including facial dysmorphism, malformation of the anterior eye chamber, hearing loss, heart defects, and developmental delay. Genotype–phenotype correlations of previously published patients have strongly suggested anterior eye segment anomalies as one of the major malformations of the syndrome if the critical 6p25 region contains the FOXC 1 gene. In addition, the presence in this region of one or more genes involved in hearing loss has been hypothesized. We report a patient with a 47,XYY karyotype and submicroscopic terminal 6p deletion. Further characterization of the deletion with array comparative genome hybridization also revealed a cryptic microduplication on chromosome 19. The patient showed dysmorphic 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 suggests that the genes in this region may not be obvious candidates for hearing loss and demonstrate the need for further elucidation of the function of the genes involved in eye developmental processes.

Paternal uniparental disomy chromosome 14-like syndrome due a maternal de novo 160 kb deletion at the 14q32.2 region not encompassing the IG- and the MEG3-DMRs: Patient report and genotype-phenotype correlation.

The human chromosome 14q32 carries a cluster of imprinted genes which include the paternally expressed genes (PEGs) DLK1 and RTL1, as well as the maternally expressed genes (MEGs) MEG3, RTL1as, and MEG8. PEGs and MEGs expression at the 14q32.2‐imprinted region are regulated by two differentially methylated regions (DMRs): the IG‐DMR and the MEG3‐DMR, which are respectively methylated on the paternal and unmethylated on the maternal chromosome 14 in most cells. Genetic and epigenetic abnormalities affecting these imprinted gene clusters result in two different phenotypes currently known as maternal upd(14) syndrome and paternal upd(14) syndrome. However, only few patients carrying a maternal deletion at the 14q32.2‐imprinted critical region have been reported so far. Here we report on the first patient with a maternal de novo deletion of 160 kb at the 14q32.2 chromosome that does not involves the IG‐DMR or the MEG3‐DMR but elicits a full upd(14)pat syndromes phenotype encompassing the three mentioned MEGs. By the analysis of this unique genotype–phenotype correlation, we further widen the spectrum of the congenital anomalies associated to this rare disorder and we propose that the paternally expressed imprinted RTL1 gene, as well as its maternally expressed RTL1as antisense transcript, may play a prominent causative role.

Delineating a new critical region for juvenile myoclonic epilepsy at the 22q11.2 chromosome.

We read with great interest the article entitled “The unexpected role of copy number variations in juvenile myoclonic epilepsy” by Helbig I. et al. [1] published in the supplemental special issue “Juvenile myoclonic epilepsy: What is it really?” [July 2013] of this journal. We thought that it would be appropriate to report the 22q11.2 chromosome as an additional proposed critical region for juvenile myoclonic epilepsy (JME) in order to raise awareness that 22q11.2 distal rearrangements may not be so uncommon in populations with epilepsy and to suggest the need to further study individuals with both microdeletions and duplications at 22q11.2. In fact, epileptic seizures are frequent in chromosomal disorders, but only a few of these disorders are associated with specific seizure and EEG patterns [2–4]. Thus, it is assumed that causative chromosomal aberrations offer the opportunity to identify genes which may be involved in idiopathic epilepsies [3]. In patients with JME, several autosomal genes have been reported to show heterozygous (CACNB4, CLCN2, GABRA1, EFHC1) [5–8] and, in a single case, homozygous mutations (GABRD) [9]. Further loci have been linked to chromosomes 5q, 6p, and 15q [10–12]. However, most forms of JME seem to follow polyor oligogenic inheritance. The 22q11.2 chromosome has long been implicated in several genomic disorders with neurological impairment including DiGeorge/velocardiofacial syndrome (DGS/VCFS), der(22) syndrome, and cat-eye syndrome (CES), which are associated with either decreased or increased gene dosage [13–16]. Recent evidence presumes that these different congenital anomaly disorders share a physical region of overlap containing chromosome 22-specific lowcopy repeats (LCRs) composed of a complex modular structure with a high degree of sequence homology (N95%) over large stretches within the repeats. Low-copy repeats predispose to homologous recombination events andmediatemeiotic nonallelic homologous recombinations (NAHR) resulting in genomic rearrangements of the 22q11.2 chromosome, including microdeletion and duplication [16–18]. While the cat-eye and der(22) syndromes are rare disorders characterized by duplications (tetrasomy and trisomy, respectively) of part of 22q11.2; on the contrary, 22q11.2 microdeletions, associated with DGS/VCFS, occur more often in the general population with an estimated frequency of 1/4000–6000 live births [19]. Even though recent data suggest that the frequency of 22q11.2 microduplications could be approximately half that of the deletions, relatively few duplications have been detected among human genomic disorders. Up to now, about 100 patients have been reported, and a high frequency of familial duplications has been detected [20]. This discrepancy may be due, in part, to the remarkable phenotypic variability of the duplications [21,22], which may complicate the clinical recognition of the corresponding syndromes. So far, several studies focused on the potential connection between certain epilepsy phenotypes and the 22q11.2 locus. Kao et al. [23]

Denys-Drash syndrome (DDS)

Deletion or chromosomal rearrangements of 11p13 critical region are rarely reported: only 1 DDS case was found carrier of 11p13-p12 deletion and none with Frasier Syndrome (Jadresic et al.1991). However cytogenetic deletion involving 11p11 and 11p13 are described in sporadic Wilms Tumor and in Wilms tumor in association to WAGR (Wilms tumor, aniridia, genitourinary anomalies and mental retardation) Syndrome (OMIM #194072).

INTELLECTUAL DISABILITY, EPILEPSY AND MILD DYSMORPHISMS DUE 22q11.2 DISTAL DUPLICATION: CLINICAL AND MOLECULAR CHARACTERIZATION OF A 0.5 Mb MINIMAL CRITICAL REGION

Developmental problems in extremely preterm children with borderline intellectual functioning and free from neurosensory disabilities at 6.5 years in Sweden (the EXPRESS study)THE EXPRESS/CHARM STUDY : 6.5 YEAR OLD CHILDREN BORN EXTREMELY PRETERM ARE LESS PHYSICALLY ACTIVE THAN TERM PEERSEarly-life hyperglycemia in extremely preterm infants affects neurodevelopment at 6 years of age

Intellectual disabilitiy in developmental age

Intellectual disability (ID) is a neurodevelopmental disorder characterized by deficits in intellectual and adaptive 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 behaviours [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 neurodevelopmental 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 suggested clinical approach to the patient should be conducted closely with a geneticist and includes the childs medical history, the family history, the physical and neurologic examinations (emphasizing the dysmorphology examination) and the examination for neurologic or behavioral signs that might suggest a specific recognizable syndrome or diagnosis. After this clinical evaluation, focused use of genetic laboratory tests, imaging and other consultations are critical in establishing the right diagnosis, its pattern of inheritance and the subsequent 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 promises and challenges needing to be yet addressed before their regular implementation in the clinic.