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Chromosome 9p deletion represents a clinically and genetically heterogeneous condition characterized by a wide spectrum of phenotypic manifestations and a variable size of the deleted region. The deletion breakpoint occurs from 9p22 to 9p24 bands, and the large majority of cases have either terminal deletions or translocations involving another chromosome. Here we report on two patients with similar inherited interstitial 9p24.3 deletion involving only DOCK8 and KANK1 genes. Interestingly, the two patients showed non-overlapping phenotypic traits ranging from a complex phenotype in one to only trigonocephaly with minor dysmorphic features and hand anomalies in the other one. The factors underlying the phenotypic variation associated with seemingly identical genomic alterations are not entirely clear, even if smaller variants, single-nucleotide changes, and epigenetic or stochastic factors altering the expression of genes within functionally relevant pathways have been recently shown to contribute to phenotypic variation. We discuss the role of the two genes and propose possible explanations for the clinical heterogeneity of the phenotype of the two patients., (Copyright © 2015. Published by Elsevier Masson SAS.)

Background: Rare copy number variations (CNVs) are today recognized as an important cause of various neurodevelopmental disorders, including mental retardation and epilepsy. In some cases, a second CNV may contribute to a more severe clinical presentation., Results: Here we describe a patient with epilepsy, mental retardation, developmental disorders, and dysmorphic features, who inherited a deletion of 16p13.11 and a triplication of 19p13.3 from his father and mother, respectively. The mother presented mild mental retardation and language delay too., Conclusions: We discuss the phenotypic consequences of the two CNVs and suggest that their synergistic effect is likely responsible for the complicated clinical features observed in our patient.

CHL1 gene maps at 3p26.3 and encodes a cell adhesion molecule of the immunoglobulin superfamily highly expressed in the brain. CHL1 regulates neuronal migration and neurite overgrowth in the developing brain, while in mature neurons it accumulates in the axonal membrane and regulates synapse function via the clathrin-dependent pathways. To our knowledge, to date only three familial cases presenting heterozygous deletion of chromosome 3 at band p26.3, including only the CHL1 gene, have been reported. All the patients presented cognitive impairment characterized by learning and language difficulties. Here, we describe a six-year-old boy in which array-CGH analysis disclosed a terminal 3p26.3 deletion. The deletion was transmitted from his normal mother and included only the CHL1 gene. Our patient presented microcephaly, short stature, mild mental retardation, learning and language delay, and strabismus. In our study we compare the phenotypic and molecular cytogenetic features of CHL1 gene deletion cases. Verbal function developmental delay seems to be a common key finding. The concomitance of the genetic and phenotypic alterations could be a good evidence of a new emerging syndrome associated with the deletion of CHL1 gene alone, although the identification of new cases is required., (2014 Elsevier Masson SAS. All rights reserved.)

Background: Since the introduction of the array-CGH technique in the diagnostic workup of mental retardation, new recurrent copy number variations and novel microdeletion/microduplication syndromes were identified. These findings suggest that some genomic disorders have high penetrance but a wide range of phenotypic severity., Results: We present the clinical and molecular description of four unrelated patients affected by neurodevelopmental disorders and overlapping 7q31.1 microdeletion/microduplication, identified by array-CGH and involving only part of the IMMP2L gene., Conclusion: IMMP2L encodes an inner mitochondrial membrane protease-like protein, which is required for processing of cytochromes inside mitochondria. Numerous studies reported that this gene is implicated in behavioural disorders such as autistic spectrum disorders, attention-deficit hyperactivity disorders, and Gilles de la Tourette syndrome. We discuss the functions of the gene suggesting that IMMP2L may act as risk factor for neurological disease.

Copy number variants represent an important cause of neurodevelopmental disorders including epilepsy, which is genetically determined in 40% of cases. Epilepsy is caused by chromosomal imbalances or mutations in genes encoding subunits of neuronal voltage- or ligand-gated ion channels or proteins related to neuronal maturation and migration during embryonic development. Here, we report on a girl with mild intellectual disability and idiopathic partial epilepsy. Array-CGH analysis showed a 1.040 Mb de novo interstitial deletion at 9q21.13 band encompassing only four genes, namely RORB, TRPM6, NMRK1, OSTF1, two open reading frames (C9orf40, C9orf41), and a microRNA (MIR548H3). RORB encodes a nuclear receptor highly expressed in the retina, cortex, and thalamus. We hypothesize its role in producing the phenotype of our patient and compare this case with other ones previously reported in the literature to better identify a genotype-phenotype correlation., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Mutations in neuronal voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A may play an important role in the etiology of neurological diseases and psychiatric disorders, besides various types of epilepsy. Here we describe a 3-year-old boy with autistic features, language delay, microcephaly and no history of seizures. Array-CGH analysis revealed an interstitial deletion of ~291.9kB at band 2q24.3 disrupting the entire SCN2A gene and part of SCN3A. We discuss the effects of haploinsufficiency of SCN2A and SCN3A on the genetic basis of neurodevelopmental and neurobehavioral disorders and we propose that this haploinsufficiency may be associated not only with epilepsy, but also with autistic features., (© 2013 Elsevier B.V. All rights reserved.)

Microarray-based comparative genomic hybridization (array-CGH) led to the discovery of genetic abnormalities among patients with complex phenotype and normal karyotype. Also several apparently normal individuals have been found to be carriers of cryptic imbalances, hence the importance to perform parental investigations after the identification of a deletion/duplication in a proband. Here, we report the molecular cytogenetic characterization of two individuals in which the microdeletions/duplications present in their parents could have predisposed and facilitated the formation of de novo pathogenic different copy number variations (CNVs). In family 1, a 4-year-old girl had a de novo pathogenic 10.5 Mb duplication at 15q21.2q22.2, while her mother showed a 2.262 Mb deletion at 15q13.2q13.3; in family 2, a 9-year-old boy had a de novo 1.417 Mb deletion at 22q11.21 and a second paternal deletion of 247 Kb at 22q11.23 on the same chromosome 22. Chromosome 22 at band q11.2 and chromosome 15 at band q11q13 are considered unstable regions. We could hypothesize that 15q13.2q13.3 and 22q11.21 deletions in the two respective parents might have increased the risk of rearrangements in their children. This study highlights the difficulty to make genetic counseling and predict the phenotypic consequences in these situations.

Background: terminal deletions of the distal portion of the short arm of chromosome 3 cause a rare contiguous gene disorder characterized by growth retardation, developmental delay, mental retardation, dysmorphisms, microcephaly and ptosis. The phenotype of individuals with deletions varies from normal to severe. It was suggested that a 1,5 Mb minimal terminal deletion including the two genes CRBN and CNTN4 is sufficient to cause the syndrome. In addition the CHL1 gene, mapping at 3p26.3 distally to CRBN and CNTN4, was proposed as candidate gene for a non specific mental retardation because of its high level of expression in the brain., Methods and Results: we describe two affected siblings in which array-CGH analysis disclosed an identical discontinuous terminal 3p26.3 deletion spanning less than 1 Mb. The deletion was transmitted from their normal father and included only the CHL1 gene. The two brothers present microcephaly, light mental retardation, learning and language difficulties but not the typical phenotype manifestations described in 3p- syndrome., Conclusion: a terminal 3p26.3 deletion including only the CHL1 gene is a very rare finding previously reported only in one family. The phenotype of the affected individuals in the two families is very similar and the deletion has been inherited from an apparently normal parent. As already described for others recurrent syndromes with variable phenotype, these findings are challenging in genetic counselling because of an evident variable penetrance.

Unbalanced translocations, that involve the proximal chromosome 15 long arm and the telomeric region of a partner chromosome, result in a karyotype of 45 chromosomes with monosomy of the proximal 15q imprinted region. Here, we present our analysis of eight such unbalanced translocations that, depending on the parental origin of the rearranged chromosome, were associated with either Prader-Willi or Angelman syndrome. First, using FISH with specific BAC clones, we characterized the chromosome 15 breakpoint of each translocation and demonstrate that four of them are clustered in a small 460 kb interval located in the proximal 15q14 band. Second, analyzing the sequence of this region, we demonstrate the proximity of a low-copy repeat 15 (LCR15)-duplicon element that is known to facilitate recombination events at meiosis and to promote rearrangements. The presence, in this region, of both a cluster of translocation breakpoints and a LCR15-duplicon element defines a new breakpoint cluster (BP6), which, to our knowledge, is the most distal breakpoint cluster described in proximal 15q. Third, we demonstrate that the breakpoints for other rearrangements including large inv dup (15) chromosomes do not map to BP6, suggesting that it is specific to translocations. Finally, the translocation breakpoints located within BP6 result in very large proximal 15q deletions providing new informative genotype-phenotype correlations.

A second case of fetal XXXXY-syndrome detected by prenatal chromosome analysis is presented. The pathological findings include a facial aspect featuring fetal Down's syndrome, hypogenitalism and hypogonadism with excessive reduction of germ cells and also skeletal abnormalities that may be interpreted as early changes, preceding phalangeal shortening V and radioulnar synostosis.

A 2-year-old girl had a de novo duplication in the long arm of one chromosome 7 and an increased level of the enzyme beta-glucuronidase in cultured fibroblasts. The phenotype of the girl partly overlaps those of two presumptive syndromes due to secondary partial trisomies 7q. The ratio of the enzyme activity was 1.43 to the controls, and 1.37 to her parent's values. We could not define the abnormality but suggest two alternatives: either the patient is trisomic for region q112 to q22 or for the region q22 to q34. If the second alternative is correct the locus for beta-glucuronidase is possibly assigned to band 7q22.

Instability of the centromeric region of chromosome 1 and multibranched configurations formed by different numbers and combinations of arms of chromosomes 1, 9, and 16 were found in cultured lymphocytes of a 12-year-old male with combined IgA and IgE deficiency. No chromosome abnormalities were found in fibroblast cultures from the patient or in blood cultures from his parents. A possible effect on the frequency of the abnormalities of the almost continuous antibiotic treatment received by the patient was found both in vivo and in vitro, but no abnormalities were found in blood cultures from control subjects who received similar treatment. Interphase association of chromosomes 1, 9, and 16 and a high frequency of interchanges among the centromeric regions of these chromosomes due to the presence of a fragile site is assumed to be the cause of the abnormalities.

Cytogenetic investigations for diagnostic purposes were performed on 1000 first trimester samples of chorionic villi (CVS) in two laboratories using similar techniques. Fetal karyotyping was the primary indication for CVS in 912 and maternal age was the major indication in 758 of them. The risk category "previous child/fetus with chromosome abnormality" included 74 diagnoses, while the category "chromosome abnormality in one of the parents" included 38 diagnoses. Sex determination was the primary indication for CVS in 53 pregnancies. The overall incidence of chromosomal abnormalities was 70, of which 47 were balanced and 23 unbalanced. The results are detailed for each of the risk categories and the incidence of abnormal karyotypes is given for each year of maternal age. In the maternal age of 35-37 years the incidence of unbalanced karyotypes was 2.9% and in the years 38 onwards it was 6.6%. The incidence of unbalanced karyotypes was about 4% when the sampling was made in the weeks 9 to 12 but six abnormal karyotypes were found among 39 CVS performed at the eight week of gestation. The 11 trisomies of the type not found at birth were clustered between the 8th and the 10th week of pregnancy. The technical problems encountered in this experience and the preliminary estimates of fetal loss are discussed.