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Cat Eye Syndrome (CES) is a rare genetic disease caused by the presence of a small supernumerary marker chromosome derived from chromosome 22, which results in a partial tetrasomy of 22p‐22q11.21. CES is classically defined by association of iris coloboma, anal atresia, and preauricular tags or pits, with high clinical and genetic heterogeneity. We conducted an international retrospective study of patients carrying genomic gain in the 22q11.21 chromosomal region upstream from LCR22‐A identified using FISH, MLPA, and/or array‐CGH. We report a cohort of 43 CES cases. We highlight that the clinical triad represents no more than 50% of cases. However, only 16% of CES patients presented with the three signs of the triad and 9% not present any of these three signs. We also highlight the importance of other impairments: cardiac anomalies are one of the major signs of CES (51% of cases), and high frequency of intellectual disability (47%). Ocular motility defects (45%), abdominal malformations (44%), ophthalmologic malformations (35%), and genitourinary tract defects (32%) are other frequent clinical features. We observed that sSMC is the most frequent chromosomal anomaly (91%) and we highlight the high prevalence of mosaic cases (40%) and the unexpectedly high prevalence of parental transmission of sSMC (23%). Most often, the transmitting parent has mild or absent features and carries the mosaic marker at a very low rate (<10%). These data allow us to better delineate the clinical phenotype associated with CES, which must be taken into account in the cytogenetic testing for this syndrome. These findings draw attention to the need for genetic counseling and the risk of recurrence. [ABSTRACT FROM AUTHOR]

Objective: To define the residual risk of morbidity‐related outcome in fetuses with nuchal translucency (NT) of 3.5 mm or more after normal genetic testing and mid‐trimester anomaly scan. Methods: A total of 114 fetuses with isolated NT of 3.5 mm or more, normal karyotype, and array‐based comparative genomic hybridization (array‐CGH) were included and divided in three groups: NT 3.5–4.5 mm, NT 4.5–6 mm, and NT greater than 6 mm. RASopathy testing and ultrasound follow up were performed in all fetuses. We evaluated: (1) incidence of genetic disorders; (2) incidence of structural abnormalities; (3) pregnancy outcome; (4) long‐term pediatric outcome before (point 1) and after (point 2) a normal RASopathy testing and mid‐trimester anomaly scan. Results: After normal karyotype and array‐CGH the residual risk of morbidity‐related outcome was 24.64% for NT 3.5–4.5 mm, 25% for NT 4.5–6 mm and 76.47% for NT more than 6 mm. After a normal RASopathy testing and mid‐trimester anomaly scan the residual risks decreased to 7.14%, 8.69%, and 33.3% in the three groups, respectively. Conclusion: In fetuses with an NT of 3.5 mm or more and both normal karyotype and array‐CGH, the rate of morbidity‐related outcome depends on NT size. A normal RASopathy testing and mid‐trimester ultrasound are reassuring but the residual risk of morbidity‐related outcome is increased compared with the general population, particularly if NT is greater than 6 mm. Synopsis: Fetuses with nuchal translucency ≥3.5 mm have increased risk of morbidity‐related postnatal outcome, even when karyotype, Array‐CGH, RASopathy testing, and anomaly scan are normal. [ABSTRACT FROM AUTHOR]

Background: The 3q29 microduplication syndrome is a rare genomic disorder characterized by an extremely variable neurodevelopmental phenotype usually involving a genomic region ranging from 1.6 to 1.76 Mb. A small microduplication of 448.8 Kb containing only two genes was recently described in a patient with a 3q29 microduplication that was proposed as the minimal critical region of overlap of this syndrome. Methods: Molecular karyotyping (array‐CGH) was performed on DNA extracted from peripheral blood samples using Agilent‐California USA Human Genome CGH Microarray 4 × 180 K. The proband and his younger brother were further tested with a next generation sequencing (NGS) panel including genes implicated in autism spectrum disorder and in neurodevelopmental disorders. Quantitative real‐time PCR was applied to verify the abnormal array‐CGH findings. Results: Here, we report on a family with two males with neurodevelopmental disorders and an unaffected sibling with a small 3q29 microduplication (432.8 Kb) inherited from an unaffected mother that involves only two genes: DGL1 and BDH1. The proband had an additional intragenic duplication inherited from the unaffected father. Further testing was negative for Fragile X syndrome and for genes implicated in autism spectrum disorder and in neurodevelopmental disorders. Conclusion: To the best of our knowledge, one of the family members here analyzed is the second reported case of a patient carrying a small 3q29 microduplication including only DGL1 and BDH1 genes and without any additional genetic aberration. The recognition of the clinical spectrum in patients with the critical region of overlap associated with the 3q29 duplication syndrome should prove valuable for predicting outcomes and providing more informed genetic counseling to patients with duplications in this region. [ABSTRACT FROM AUTHOR]

It has been estimated that Copy Number Variants (CNVs) account for 10%–20% of patients affected by Developmental Disorder (DD)/Intellectual Disability (ID). Although array comparative genomic hybridization (array‐CGH) represents the gold‐standard for the detection of genomic imbalances, common Agilent array‐CGH 4 × 180 kb arrays fail to detect CNVs smaller than 30 kb. Whole Exome sequencing (WES) is becoming the reference application for the detection of gene variants and makes it possible also to infer genomic imbalances at single exon resolution. However, the contribution of small CNVs in DD/ID is still underinvestigated. We made use of the eXome Hidden Markov Model (XHMM) software, a tool utilized by the ExAC consortium, to detect CNVs from whole exome sequencing data, in a cohort of 200 unsolved DD/DI patients after array‐CGH and WES‐based single nucleotide/indel variant analyses. In five out of 200 patients (2.5%), we identified pathogenic CNV(s) smaller than 30 kb, ranging from one to six exons. They included two heterozygous deletions in TCF4 and STXBP1 and three homozygous deletions in PPT1, CLCN2, and PIGN. After reverse phenotyping, all variants were reported as causative. This study shows the interest in applying sequencing‐based CNV detection, from available WES data, to reduce the diagnostic odyssey of additional patients unsolved DD/DI patients and compare the CNV‐detection yield of Agilent array‐CGH 4 × 180kb versus whole exome sequencing. [ABSTRACT FROM AUTHOR]

Congenital contractural arachnodactyly (CCA) is caused by pathogenic FBN2 variants; however, the contributions of copy number variations (CNVs) to CCA are still unknown. Here, we report on a familial case of CCA, in which a novel multiexon deletion of exons 35–39 in FBN2 was identified after simple CNV prediction. [ABSTRACT FROM AUTHOR]

Background: Terminal deletions of the long arm of chromosome 7 are well known and frequently associated with syndromic holoprosencephaly due to the involvement of the SHH (aliases HHG1, SMMCI, TPT, TPTPS, and MCOPCB5) gene region. However, interstitial deletions including CNTNAP2 (aliases Caspr2, KIAA0868, and NRXN4) and excluding the SHH region are less common. Methods: We report the clinical and molecular characterization associated with pure 7q35 and 7q35q36.1 deletion in two unrelated patients as detected by oligonucleotide‐based array‐CGH analysis. Results: The common clinical features were abnormal maternal serum screening during first‐trimester pregnancy, low occipitofrontal circumference at birth, hypotonia, abnormal feet, developmental delay, impaired language development, generalized seizures, hyperactive behavior, friendly personality, and cranio‐facial dysmorphism. Both deletions occurred de novo and sequencing of CNTNAP2, a candidate gene for epilepsy and autism showed absence of mutation on the contralateral allele. Conclusion: Combined haploinsufficiency of GALNTL5 (alias GalNAc‐T5L), CUL1, SSPO (aliases SCO‐spondin, KIAA0543, and FLJ36112), AOC1(alias DAO), RHEB, and especially KMT2C (alias KIAA1506 and HALR) with monoallelic disruption of CNTNAP2 may explain neurologic abnormalities, hypotonia, and exostoses. Haploinsufficiency of PRKAG2 (aliases AAKG, AAKG2, H91620p, WPWS, and CMH6) and KCNH2 (aliases Kv11.1, HERG, and erg1) genes may be responsible of long QT syndrome observed for one patient. [ABSTRACT FROM AUTHOR]

Background: The recent introduction of microarrays for genetic analyses has allowed higher etiological diagnostic rates in patient with intellectual disability (ID), autism spectrum disorders (ASD), epilepsy and multiple congenital anomalies (MCA), because of its resolution. This approach still results of high complexity and some limitations have been reported. In fact, it discloses several variants of unknown significance (VOUS) or incidental findings. In all cases, a massive amount of data is generated, because of this, the analysis and the interpretation is very difficult and often without a definitive conclusion. Method: We analysed an Italian cohort of 343 patients with ID, MCA and ASD by array‐comparative genomic hybridization. The purpose of this work was to consider the proportion of the chromosomal abnormalities in such cohort and to assess the distribution of the different type of the chromosomal abnormalities concerning their pathogenic significance, their origin and their correlation to these clinical phenotypes. Results: Array‐comparative genomic hybridization analysis revealed 76 positive results. Abnormalities were detected in 27.8% of patients with ID, 11.1% with ASD, 10.7% with epilepsy and 19.4% with multiple congenital anomalies. The anomalies were classified in three major groups: group 1 (27 patients) with pathogenic alterations (P group); group 2 (34 patients) with VOUS potentially pathogenic (PP group); and group 3 (13 patients) with VOUS potentially benign (PB group). As expected, comparing the diagnostic groups, we observed a greater number of deletions in the P group and that all the abnormalities of the PB group were inherited. Conclusions: Our retrospective study resulted in confirming the high detection rate of microarrays. CNV classification remains a complex procedure. The difficulty in CNV classification points out the importance of the patient selection, helping the interpretation of the molecular cytogenetic results. [ABSTRACT FROM AUTHOR]

46,XX testicular disorder of sex development (46,XX TDSD) is a relatively rare condition characterised by the presence of testicular tissue with 46,XX karyotype. The present study aims to reveal the phenotype to genotype correlation in a series of sex‐determining region Y (SRY)‐positive 46,XX TDSD cases. We present the clinical findings, hormone profiles and genetic test results of six patients with SRY‐positive 46,XX TDSD and give the details and follow‐up findings of our three of previously published patients. All patients presented common characteristics such as azoospermia, hypergonadotropic hypogonadism and an SRY gene translocated on the terminal part of the short arm of one of the X chromosomes. Mean ± standard deviation (SD) height of the patients was 164.78 ± 8.0 cm. Five patients had decreased secondary sexual characteristics, and three patients had gynaecomastia with varying degrees. Five of the seven patients revealed a translocation between protein kinase X (PRKX) and inverted protein kinase Y (PRKY) genes, and the remaining two patients showed a translocation between the pseudoautosomal region 1 (PAR1) of X chromosome and the differential region of Y chromosome. X chromosome inactivation (XCI) analysis results demonstrated random and skewed XCI in 5 cases and 1 case, respectively. In brief, we delineate the phenotypic spectrum of patients with SRY‐positive 46,XX TDSD and the underlying mechanisms of Xp;Yp translocations. [ABSTRACT FROM AUTHOR]

Background: Corpus callosum agenesis (ACC) is one of the most frequent Central Nervous System (CNS) malformations. However, genetics underlying isolated forms is still poorly recognized. Here, we report on two female familial cases with partial ACC. The proband shows isolated partial ACC and a mild neurodevelopmental phenotype. A fetus from a previous interrupted pregnancy exhibited a complex phenotype including partial ACC and the occurrence of a de novo 17q12 microduplication, which was interpreted as probably disease‐causing. Methods: A trio‐based clinical exome sequencing (CES) was performed. Results: Clinical exome sequencing data analysis led to identifying a heterozygous nonsense variant (NM_139058.3:c.922G>T; NP_620689.1:p.Glu308Ter) in the aristaless related homeobox gene (ARX) in the proband, with a putative de novo occurrence, producing a hypothetical protein lacking two essential domains. Sanger analysis confirmed the wild‐type status of both parents in different tissues, and disclosed the occurrence of the nonsense variant in the fetus of the interrupted pregnancy, suggesting a formerly unrecognized contribution of the ARX mutation to the fetus' phenotype and gonadal or gonadosomatic mosaicism in one of the parents. Conclusion: This study describes the phenotype associated with a heterozygous loss of function variant in ARX. Moreover, it highlights the importance of investigating both chromosomal and genetic contributions in cases of complex syndromic phenotypes involving CNS. [ABSTRACT FROM AUTHOR]

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorder with a worldwide prevalence of about 5%. The disorder is characterized by inattentive, hyperactive and impulsive behavior and is often comorbid with other neuropsychiatric conditions. Array comparative genomic hybridization (array‐CGH) testing has been proved to be useful to detect chromosomal aberrations in several neuropsychiatric conditions including autism spectrum disorders (ASD) and intellectual disability (ID). The usefulness of array‐CGH in the ADHD clinics is still debated and no conclusive evidence has been reached to date. We performed array‐CGH in 98 children and adolescents divided in two similarly sized groups according to the clinical diagnosis: (a) one group diagnosed with ADHD as primary diagnosis; (b) the other group in which ADHD was co‐morbid with ASD and/or ID. We detected pathogenetic and likely pathogenetic copy number variants (CNVs) in 12% subjects in which ADHD was co‐morbid with autism and/or intellectual disability and in 8.5% subjects diagnosed with ADHD as primary diagnosis. Detection of CNVs of unknown clinical significance was similar in the two groups being 27% and 32%, respectively. Benign and likely benign CNVs accounted for 61% and 59.5% in the first and second group, respectively. Differences in the diagnostic yield were not statistically significant between the two groups (P >.05). Our data strongly suggest that array‐CGH (a) is a valuable diagnostic tool to detect clinically significant CNVs in individuals with ADHD even in the absence of comorbidity with ASD and/or ID and (b) should be implemented routinely in the ADHD clinics. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) affects approximately 15 million Americans. Approximately 2 million of these are classified as being refractory to treatment (TR‐MDD). Because of the lack of available therapies for TR‐MDD, and the high risk of suicide, there is interest in identifying new treatment modalities and diagnostic methods. Understanding of the impact of genomic copy number variation in the etiology of a variety of neuropsychiatric phenotypes is increasing. Low copy repeat elements at 15q13.3 facilitate non‐allelic homologous recombination, resulting in recurrent copy number variants (CNVs). Numerous reports have described association between microdeletions in this region and a variety of neuropsychiatric phenotypes, with CHRNA7 implicated as a candidate gene. However, the pathogenicity of 15q13.3 duplications is less clear. As part of an ongoing study, in which we have identified a number of metabolomic anomalies in spinal fluid from TR‐MDD patients, we also evaluated genomic copy number variation in patients (n = 125) and controls (n = 26) via array‐based copy number genomic hybridization (CGH); the case frequency was compared with frequencies reported in a prior study as well as a larger population‐sized cohort. We identified five TR‐MDD patients with microduplications involving CHRNA7. CHRNA7 duplications are the most common CNVs identified by clinical CGH in this cohort. Therefore, this study provides insight into the potential involvement of CHRNA7 duplications in the etiology of TR‐MDD and informs those involved with care of affected individuals. [ABSTRACT FROM AUTHOR]

MECP2 duplication syndrome (MDS; OMIM 300260) is an X‐linked neurodevelopmental disorder caused by nonrecurrent duplications of the Xq28 region involving the gene methyl‐CpG‐binding protein 2 (MECP2; OMIM 300005). The core phenotype of affected individuals includes infantile hypotonia, severe intellectual disability, very poor‐to‐absent speech, progressive spasticity, seizures, and recurrent infections. The condition is 100% penetrant in males, with observed variability in phenotypic expression within and between families. Features of MDS in individuals of African descent are not well known. Here, we describe a male patient from Cameroon, with MDS caused by an inherited 610 kb microduplication of Xq28 encompassing the genes MECP2, IRAK1, L1CAM, and SLC6A8. This report supplements the public data on MDS and contributes by highlighting the phenotype of this condition in affected individuals of African descent. [ABSTRACT FROM AUTHOR]

The AMME syndrome defined as the combination of Alport syndrome, intellectual disability, midface hypoplasia, and elliptocytosis (AMME) is known to be a contiguous gene syndrome associated with microdeletions in the region Xq22.3q23. Recently, using exome sequencing, missense pathogenic variants in AMMECR1 have been associated with intellectual disability, midface hypoplasia, and elliptocytosis. In these cases, AMMECR1 gene appears to be responsible for most of the clinical features of the AMME syndrome except for Alport syndrome. In this article, we present two unrelated male patients with short stature, mild intellectual disability or neurodevelopmental delay, sensorineural hearing loss, and elliptocytosis harboring small microdeletions identified by array‐CGH involving TMEM164 and AMMECR1 genes and SNORD96B small nucleolar RNA for one patient, inherited from their mothers. These original cases further confirm that most specific AMME features are ascribed to AMMECR1 haploinsufficiency. These cases reporting the smallest microdeletions encompassing AMMECR1 gene provide new evidence for involvement of AMMECR1 in the AMME phenotype and permit to discuss a phenotype related to AMMECR1 haploinsufficiency: developmental delay/intellectual deficiency, midface hypoplasia, midline defect, deafness, and short stature. [ABSTRACT FROM AUTHOR]

Fusion anomalies of the Müllerian ducts are associated with an increased risk for miscarriage and premature labor. In most cases polygenic‐multifactorial inheritance can be assumed but autosomal‐dominant inheritance with reduced penetrance and variable manifestation should be considered. We performed array‐comparative genomic hybridization (CGH) analysis in a cohort of 103 patients with Müllerian fusion anomalies. In 8 patients we detected microdeletions and microduplications in chromosomal regions 17q12, 22q11.21, 9q33.1, 3q26.11 and 7q31.1. The rearrangement in 17q12 including LHX1 and HNF1β as well as in 22q11.21 have already been observed in MRKHS (Mayer‐Rokitansky‐Küster‐Hauser syndrome). In summary, we (1) detected causative micro‐rearrangements in patients with Müllerian fusion anomalies, (2) show that Müllerian fusion anomalies and MRKHS may have a common etiology, and (3) identified new candidate genes for Müllerian fusion anomalies. [ABSTRACT FROM AUTHOR]

Background Array-comparative genomic hybridization (array- CGH) is a widely used technique to detect copy number variants ( CNVs) associated with developmental delay/intellectual disability ( DD/ ID). Aims Identification of genomic disorders in DD/ ID. Materials and methods We performed a comprehensive array- CGH investigation of 1,015 consecutive cases with DD/ ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs. Results We identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries probably affecting the regulatory landscape. Discussion and conclusion We show how phenotypic and genetic analyses of array- CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects. [ABSTRACT FROM AUTHOR]

We report on a girl diagnosed prenatally with agenesis of the corpus callosum (ACC) on fetal ultrasound and MRI. On postnatal follow-up she was noted to have developmental delay, facial dysmorphism, autism spectrum disorder, and posterior polymorphous corneal dystrophy (PPD). Array-comparative genomic hybridization analysis (Array-CGH) showed a 2.05 Mb de novo interstitial deletion at 10p11.23p11.22. The deleted region overlaps 1 OMIM Morbid Map gene, ZEB1 (the zinc finger E-box binding homeobox transcription factor 1), previously associated with posterior polymorphous corneal dystrophy type 3 (PPCD3). To our best knowledge this is the first reported case with a deletion of the ZEB1 gene in an individual with ACC and PPD, showing that the haploinsufficiency of the ZEB1 is likely the cause of our patient's phenotype. [ABSTRACT FROM AUTHOR]

Background GNE myopathy is a rare genetic disease characterized by progressive muscle atrophy and weakness. It is caused by biallelic mutations in the GNE gene that encodes for the bifunctional enzyme, uridine diphosphate ( UDP)-N-acetylglucosamine (Glc NAc) 2-epimerase/N-acetylmannosamine (Man NAc) kinase. Typical characteristics of GNE myopathy include progressive myopathy, first involving anterior tibialis muscle and sparing the quadriceps, and rimmed vacuoles on muscle biopsy. Identifying biallelic mutations by sequencing of the GNE gene confirms the diagnosis of GNE myopathy. In a subset of patients, diagnostic confirmation is challenged by the identification of mutations in only one allele, suggesting mutations in deep intronic regions or regulatory regions. Methods We performed targeted sequencing and copy number variant ( CNV) analysis of GNE in two siblings who clinically presented with GNE myopathy. Further molecular and biochemical studies were done to characterize the effect of a previously uncharacterized GNE mutation. Results We report two siblings of Indian descent with characteristic features of GNE myopathy, including progressive skeletal muscle weakness initially involving the anterior tibialis, and rimmed vacuoles on muscle biopsy, in which a heterozygous mutation, p.Val727Met, was identified in both affected siblings, but no other deleterious variants in either coding region or exon-intron boundaries of the gene. Subsequent insertion/deletion analysis identified a novel 11.3-kb deletion (Chr9 [ GRCh37]: g.36257583_36268910del) encompassing the GNE promoter region, with breakpoints residing in Alu repeats. Gene expression analysis revealed reduced GNE mRNA and protein levels, confirming decreased expression of the deleted allele harboring the deletion. Conclusions We have identified GNE as one of the genes susceptible to Alu-mediated recombination. Our findings suggest that the deletion may encompass the promoter or another region necessary for GNE expression. In patients with typical manifestations of GNE myopathy and a single GNE variant identified, copy number variant ( CNV) analysis may be useful in arriving at the diagnosis. [ABSTRACT FROM AUTHOR]

Chromosome 22q11.2 deletion is the most common chromosomal alteration associated with DiGeorge syndrome (DGS), even though this is not the only underlying cause of DGS. In rare patients, mutations in a single gene, TBX1, have been described resulting in a DGS phenotype. Recently, it has been reported that at least part of the TBX1 mutant phenotype is due to excessive bone morphogenetic proteins (BMP) signaling. Evidence suggests that miRNA may modulate the expression of critical T-box transcriptional regulators during midface development and Bmp-signaling. We report on a 7-year-old Caucasian male born to a mother affected with gestational diabetes (GDM) who had a 371Kb-interstitial deletion of 3p12.3 identified by array CGH, involving the ZNF717, MIR1243, and 4273 genes. The child presented with a DiGeorge anomaly (DGA) associated with unilateral renal agenesis and language delay. The immunological evaluation revealed a severe reduction and impairment of T lymphocytes. FISH analysis and TBX1 sequencing were negative. Among the miRNA-4273 predicted target genes, we found BMP3, which is involved in several steps of embryogenesis including kidney and lung organogenesis and in insulin gene expression. Since, DGA is not commonly found in newborns of diabetic mothers, we hypothesize that the pathogenesis of DGA associated with GDM is multifactorial, involving both genetic and/or epigenetic cofactors. [ABSTRACT FROM AUTHOR]

The femoral facial syndrome (FFS) is a rare congenital anomaly syndrome characterized by bilateral femoral hypoplasia and facial dysmorphism. The etiology of FFS is currently unknown but maternal/gestational diabetes has been proposed as a strong risk factor for syndromic femoral hypoplasia. In affected children born to non-diabetic mothers, a genetic contribution to FFS is suspected; however, no chromosomal anomalies or gene mutations have been identified so far. Here, we report on a girl with FFS and a de novo complex chromosome rearrangement of terminal chromosome 2q37.2. Radiographs of the pelvis and lower limbs showed bilateral shortening and bowing of the femur and radiographs of hands and feet revealed a brachydactyly type E (BDE). Using high resolution array-CGH, qPCR, and FISH, we detected a ∼1.9 Mb duplication in the chromosomal region 2q37.2 and a ∼5.4 Mb deletion on chromosome 2q37.3 that were absent in the parents. The duplication contains six genes and the deletion encompasses 68 genes; the latter has previously been shown to cause BDE (through haploinsufficiency for HDAC4) but not femoral hypoplasia. Therefore, we propose that the duplication 2q37.2 could be causative for the femur phenotype. To the best of our knowledge, our report is the first to propose a genetic cause in a case of FFS. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The 5q14.3 duplication is a rare condition comprising speech and developmental delay, microcephaly, and mild ventriculomegaly. The region 5q14.3 contains several genes but the predominant role for the onset of the neurodevelopmental phenotype has been attributed to MEF2C. We describe the prenatal identification of 5q14.3 duplication, including MEF2C, in a monochorionic twin pregnancy with corpus callosum anomalies, confirmed by autopsy. To the best of our knowledge, this cerebral finding has been observed for the first time in 5q14.3 duplication patients, possibly widening the neurological picture of this scarcely known syndrome. A pathogenetic role of MEF2C overexpression in brain development may be assumed, but further studies are needed. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Partial monosomy of the long arm of chromosome 7 has been characterized by wide phenotypic manifestations, but holoprosencephaly (HPE) and sacral agenesis have frequently been associated with this chromosomal deletion. A clear relationship between genotype and phenotype remains to be defined in the 7q deletion syndrome. Three patients (1, 2, and 3) were investigated with 7q terminal deletion and compared with similar deletion cases in the literature in order to stratify the phenotypes associated with 7q35 and 7q36 terminal deletion patients. Patients 1, 2, and 3 were carrying a de novo terminal deletion at bands 7q36.2, 7q35, and 7q36.1, respectively. In patient 3, a small Xq28 duplication was also identified by array-CGH. Our patients presented with heterogeneous phenotypic manifestations, which could imply the possible role of environmental factors (multifactorial inheritance), structural variations in the non-coding regions, penetrance, and/or polymorphism. The varying length of deletion was also taken into account. Growth retardation was the most frequent symptom found in both 7q35 and 7q36 patients we reviewed. The occurrence of HPE and sacral malformation together was seen in less than 10% of the reviewed cases in both kinds of deletion. HPE was associated mainly in cases with an unbalanced translocation. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The use of array-comparative genomic hybridization (array-CGH) in routine clinical work has allowed the identification of many new copy number variations (CNV). The 16p13.11 duplication has been implicated in various congenital anomalies and neurodevelopmental disorders, but it has also been identified in healthy individuals. We report a clinical observation of two brothers from related parents each carrying a homozygous 16p13.11 duplication. The propositus had mild intellectual disability and posterior urethral valves with chronic renal disease. His brother was considered a healthy child with only learning disabilities and poor academic performances. However, a routine medical examination at 25-years-old revealed a mild chronic renal disease and ureteropelvic junction obstruction. Furthermore, the father presented with a unilateral renal agenesis, thus it seemed that a 'congenital anomalies of kidney and urinary tract' (CAKUT) phenotype segregated in this family. This may be related to the duplication, but we cannot exclude the involvement of additional genetic or non-genetic factors in the urological phenotype. Several cohort studies showed association between this chromosomal imbalance and different clinical manifestations, but rarely with CAKUT. The duplication reported here was similar to the larger one of 3.4 Mb previously described versus the more common of 1.6 Mb. It encompassed at least 11 known genes, including the five ohnologs previously identified. Our observation, in addition to expanding the clinical spectrum of the duplication provides further support to understanding the underlying pathogenic mechanism. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In recent years, characterization of cancer and its environment has become necessary. However, studies of the cancer microenvironment remain insufficient. Copy number variations (CNVs) occur in 40% of cancer-related genes, but few studies have reported the correlation between CNVs in morphologically normal tissues adjacent to cancer and cancer progression. In this study, we evaluated cancer cell migration and invasion according to the genetic differences between cancer tissues and their surrounding normal tissues. To study the field cancerization effect, we screened 89 systemic metastasis-related CNVs from morphologically normal tissues adjacent to colon cancers. Among these CNVs, LIM and senescent cell antigen-like domain 2 ( PINCH-2) showed copy number amplification and upregulation of mRNA in the nonrelapsed group compared to the systemic relapse group. PINCH-2 expression in colon cancer cells was lower than that in normal epithelial colon cells at both the protein and mRNA levels. Suppression of PINCH-2 resulted in decreased formation of the PINCH-2-IPP (PINCH-2, integrin-linked kinase and α-parvin) complex and reciprocally increased formation of the PINCH-1-IPP complex. Although PINCH-2 expression of survival pathway-related proteins (Akt and phospho-Akt) did not change upon suppression of PINCH-2 expression, cell migration-related proteins [matrix-metalloproteinase (MMP)−9 and −11] were upregulated through autocrine and paracrine activation. Thus, PINCH-2 participates in decreased systemic recurrence by competitively regulating IPP complex formation with PINCH-1, thereby suppressing autocrine and paracrine effects on motility in colon cancer. This genetic change in morphologically normal tissue suggests a field cancerization effect of the tumor microenvironment in cancer progression. [ABSTRACT FROM AUTHOR]

Deletions or intragenic mutations involving the MEF2C gene on chromosome 5q14.3 have generally been associated with a relatively uniform phenotype characterized by severe developmental delay, absent speech, stereotypies, absent or limited gait abilities, lack of a typical facial gestalt and scarcity of major malformations. We report on a patient of Cypriot descent with a de novo, approximately 147 kb in size, partial MEF2C deletion removing exons 1 to 3. He had a history of severe intellectual disability with absent speech, poor eye contact, hand stereotypies and a wide-based gait. A broad-based, shallow jugular pit with an overlying vascular malformation was also present. Partial MEF2C deletions have only been reported in a very small number of patients and have on occasion been associated with relatively milder phenotypes. We present a patient of Cypriot descent with such a deletion and review previously published literature on partial MEF2C gene deletions postulating a key role of the first few exons in the pathogenesis of the disease. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We report on the molecular characterization of a microdeletion of approximately 2.5 Mb at 2p11.2 in a female baby with left congenital aural atresia, microtia, and ipsilateral internal carotid artery agenesis. The deletion was characterized by fluorescence in situ hybridization, array comparative genomic hybridization, and whole genome re-sequencing. Among the genes present in the deleted region, we focused our attention on the FOXI3 gene. Foxi3 is a member of the Foxi class of Forkhead transcription factors. In mouse, chicken and zebrafish Foxi3 homologues are expressed in the ectoderm and endoderm giving rise to elements of the jaw as well as external, middle and inner ear. Homozygous Foxi3-/- mice have recently been generated and show a complete absence of the inner, middle, and external ears as well as severe defects in the jaw and palate. Recently, a 7-bp duplication within exon 1 of FOXI3 that produces a frameshift and a premature stop codon was found in hairless dogs. Mild malformations of the outer auditory canal (closed ear canal) and ear lobe have also been noted in a fraction of FOXI3 heterozygote Peruvian hairless dogs. Based on the phenotypes of Foxi3 mutant animals, we propose that FOXI3 may be responsible for the phenotypic features of our patient. Further characterization of the genomic region and the analysis of similar patients may help to demonstrate this point. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Brain malformations are a major cause of therapy-refractory epilepsy as well as neurological and developmental disabilities in children. This study examined the frequency and the nature of copy number variations among children with structural brain malformations and refractory epilepsy. The medical records of all children born between 1990 and 2009 in the epilepsy registry at the Astrid Lindgren's Children's Hospital were reviewed and 86 patients with refractory epilepsy and various brain malformations were identified. Array-CGH analysis was performed in 76 of the patients. Pathogenic copy number variations were detected in seven children (9.2%). In addition, rearrangements of unclear significance, but possibly pathogenic, were detected in 11 (14.5%) individuals. In 37 (48.7%) patients likely benign, but previously unreported, copy number variants were detected. Thus, a large proportion of our patients had at least one rare copy number variant. Our results suggest that array-CGH should be considered as a first line genetic test for children with cerebral malformations and refractory epilepsy unless there is a strong evidence for a specific monogenic syndrome. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Distal limb contractures (DLC) represent a heterogeneous clinical and genetic condition. Overall, 20-25% of the DLC are caused by mutations in genes encoding the muscle contractile apparatus. Large interstitial deletions of the 3p have already been diagnosed by standard chromosomal analysis, but not associated with a specific phenotype. We report on four patients with syndromic DLC presenting with a de novo 3p14.1p13 microdeletion. The clinical features associated multiple contractures, feeding problems, developmental delay, and intellectual disability. Facial dysmorphism was constant with low-set posteriorly rotated ears and blepharophimosis. Review of previously reported cases with a precise mapping of the deletions, documented a 250 kb smallest region of overlap (SRO) necessary for DLC. This region contained one gene, EIF4E3, the first three exons of the FOXP1 gene, and an intronic enhancer of FOXP1 named hs1149. Sanger sequencing and locus quantification of hs1149, EIF4E3, and FOXP1 in a cohort of 11 French patients affected by DLC appeared normal. In conclusion, we delineate a new microdeletion syndrome involving the 3p14.1p13 locus and associated with DLC and severe developmental delay. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Mutations of the CDKL5 gene cause early epileptic encephalopathy. Patients manifest refractory epilepsy, beginning before the age of 3 months, which is associated with severe psychomotor delay and features that overlap with Rett syndrome. We report here a patient with mosaicism for CDKL5 exonic deletion, with the presence of two mutant alleles. The affected 4-year-old girl presented with infantile spasms, beginning at the age of 9 months, but subsequent progression of the disease was consistent with the classical CDKL5-related phenotype. A deletion of exons 17 and 18 was suspected on the basis of Multiplex Ligation Probe Amplification analysis, but unexpected results for cDNA analysis, which showed the presence of an abnormal transcript with the deletion of exon 18 only, led us to suspect that two distinct events might have occurred. We used custom array-CGH to determine the size and breakpoints of these deletions. Exon 18 was deleted from one of the abnormal alleles, and exon 17 was deleted from the other. A Fork Stalling and Template Switching (FoSTeS) mechanism was proposed to explain the two events, given the presence of regions of microhomology at the breakpoints. We propose here an original involvement of the FoSTeS mechanism to explain the co-occurrence of these two events in the CDKL5 gene in a single patient. This patient highlights the difficulties involved in the detection of such abnormalities, particularly when they occur in a mosaic state and involve two distinct mutational events in a single gene. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray-based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6). © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Typical Xq25 duplications are large and associated with heterogeneous phenotypes. Recently, small duplications involving this genomic region and encompassing the GRIA3 and STAG2 genes have been reported. These Xq25 microduplications are associated with a recognizable syndrome including intellectual disability and distinctive facial appearance. We report on Xq25 microduplications in two unrelated families identified by array comparative genomic hybridization. In both families, the genomic imbalances segregated with the disease in male individuals, while the phenotypes of the heterozygous females appeared to be modulated by their X-inactivation pattern. These rearrangements of about 600 kb involved only three genes: THOC2, XIAP, and STAG2. Further characterization by FISH analyses showed tandem duplication in the Xq25 locus of these genes. These data refine the Xq25 candidate region, identifying a minimal duplicated region of about 270 kb encompassing the XIAP and STAG2 genes. We discuss the function of the genes in the rearrangements and their involvement in the pathogenesis of this disorder. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

NSD1 point mutations, submicroscopic deletions and intragenic deletions are the major cause of Sotos syndrome, characterized by pre-postnatal generalized overgrowth with advanced bone age, learning disability, seizures, distinctive facial phenotype. Reverse clinical phenotype due to 5q35 microduplication encompassing NSD1 gene has been reported so far in 27 cases presenting with delayed bone age, microcephaly, failure to thrive and seizures in some cases, further supporting a gene dosage effect of NSD1 on growth regulation and neurological functions. Here we depict the clinical presentation of three new cases with 5q35 microduplication outlining a novel syndrome characterized by microcephaly, short stature, developmental delay and in some cases delayed bone maturation, without any typical facial or osseous anomalies. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Interstitial 2q36 deletion is a rare event. Only two previously published cases of 2q36 deletions were characterized using array-CGH. This is the first case diagnosed prenatally. Methods We report on the prenatal diagnosis of a 2q36.1q36.3 interstitial deletion in a fetus with facial dysmorphism, spina bifida, and cleft palate. Results Array-CGH analysis revealed a 5.6 Mb interstitial deletion of the long arm of chromosome 2q36.1q36.3, including the PAX3 and EPHA4 genes. Conclusion The present study reinforces the hypothesis that PAX3 haploinsufficiency may be associated with neural tube defects in humans and suggests that the EPHA4 gene might be implicated during palate development. This report also illustrates the added value of array-CGH to detect cryptic chromosomal imbalances in malformed fetuses and to improve genetic counseling prenatally. Birth Defects Research (Part A) 100:507-511, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We report on a young child with intellectual disability and unilateral coronal craniosynostosis leading to craniofacial malformations. Standard karyotype showed an apparently balanced translocation between chromosomes 2 and 15 [t(2;15)(q21;q21.3)], inherited from his mother. Interestingly, array-CGH 180K showed a 3.64 Mb de novo deletion on chromosome 15 in the region 15q21.3q22.2, close to the chromosome 15 translocation breakpoints. This deletion leads to haploinsufficiency of TCF12 gene that can explain the coronal craniosynostosis described in the patient. Additional FISH analyses showed a complex balanced maternal chromosomal rearrangement combining the reciprocal translocation t(2;15)(q21;q21.3), and an insertion of the 15q22.1 segment into the telomeric region of the translocated 15q fragment. The genomic imbalance in the patient is likely caused by a crossing-over that occurs in the recombination loop formed during the maternal meiosis resulting in the deletion of the inserted fragment. This original case of a genomic microdeletion of TCF12 exemplifies the importance of array-CGH in the clinical investigation of apparently balanced rearrangements but also the importance of FISH analysis to identify the chromosomal mechanism causing the genomic imbalance. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We describe a 6-month-old female with developmental delay, hypotonia, supernumerary nipples, and distinct craniofacial features. Postnatal chromosome analysis revealed an unbalanced karyotype involving a der (5) and array-CGH defined two unbalanced regions with partial 2.3 Mb deletion of 5q35.3 in combination with a large 19.5 Mb duplication of chromosome 10 from q25.3 to q26.3. Parental karyotyping analysis showed that the father was carrier of a balanced t(5;10)(q35;q25). Two cousins of the proband with similar facial features had the same unbalanced karyotype with presence of the der (5) inherited from the malsegregation of the familial translocation. Additionally, three siblings (two deceased and one abortion) manifested a more severe phenotype including congenital heart defect, cleft palate, and agenesis of the corpus callosum and were diagnosed with unbalanced karyotypes inherited from the familial balanced translocation. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Small supernumerary marker chromosomes ( sSMCs) are structurally abnormal chromosomes that cannot be characterized by karyotype. In many prenatal cases of de novo sSMC, the outcome of pregnancy is difficult to predict because the euchromatin content is unclear. This study aimed to determine the presence or absence of euchromatin material of 39 de novo prenatally ascertained sSMC by array-comparative genomic hybridization (array- CGH) or single nucleotide polymorphism ( SNP) array. Cases were prospectively ascertained from the study of 65,000 prenatal samples [0.060%; 95% confidence interval ( CI), 0.042-0.082]. Array- CGH showed that 22 markers were derived from non-acrocentric markers (56.4%) and 7 from acrocentic markers (18%). The 10 additional cases remained unidentified (25.6%), but 7 of 10 could be further identified using fluorescence in situ hybridization; 69% of de novo sSMC contained euchromatin material, 95.4% of which for non-acrocentric markers. Some sSMC containing euchromatin had a normal phenotype (31% for non-acrocentric and 75% for acrocentric markers). Statistical differences between normal and abnormal phenotypes were shown for the size of the euchromatin material (more or less than 1 Mb, p = 0.0006) and number of genes (more or less than 10, p = 0.0009). This study is the largest to date and shows the utility of array- CGH or SNP array in the detection and characterization of de novo sSMC in a prenatal context. [ABSTRACT FROM AUTHOR]

Objectives Rolandic epilepsies (REs) represent the most frequent epilepsy in childhood. Patients may experience cognitive, speech, language, reading, and behavioral issues. The genetic origin of REs has long been debated. The participation of rare copy number variations (CNVs) in the pathophysiology of various human epilepsies has been increasingly recognized. However, no systematic search for microdeletions or microduplications has been reported in RE so far. Methods Array comparative genomic hybridization (aCGH) and quantitative polymerase chain reaction (qPCR) were used to analyze the genomic status of a series of 47 unrelated RE patients who displayed various types of electroclinical manifestations. Results Thirty rare CNVs were detected in 21 RE patients. Two CNVs were de novo, 12 were inherited, and 16 were of unknown inheritance. Each CNV was unique to one given patient, except for a 16p11.2 duplication found in two patients. The CNVs of highest interest comprised or disrupted strong candidate or confirmed genes for epileptic and other neurodevelopmental disorders, including BRWD3, GRIN2A, KCNC3, PRKCE, PRRT2, SHANK1, and TSPAN7. Significance Patients with REs showed rare microdeletions and microduplications with high frequency and heterogeneity. Whereas only a subset of all genomic alterations found here may actually participate in the phenotype, the novel de novo events as well as several inherited CNVs contain or disrupt genes, some of which are likely to influence the emergence, the presentation, or the comorbidity of RE. The future screening of cohorts of larger size will help in detecting more de novo or recurrent events and in appreciating the possible enrichment of specific CNVs in patients with RE. [ABSTRACT FROM AUTHOR]

Genetic analyses were performed in a male patient with suspected Prader-Willi syndrome who presented with hypogonadism, excessive eating, central obesity, small hands and feet and cognition within the low normal range. However, he had no neonatal hypotonia or feeding problems during infancy. Chromosome analysis showed a normal male karyotype. Further analysis with array-CGH identified a mosaic 847 kb deletion in 15q11-q13, including SNURF-SNRPN, the snoRNA gene clusters SNORD116 (HBII-85), SNORD115, (HBII-52), SNORD109 A and B (HBII-438A and B), SNORD64 (HBII-13), and NPAP1 ( C15ORF2). MLPA confirmed the deletion and the results were compatible with a paternal origin. Metaphase-FISH verified the mosaicism with the deletion present in 58% of leukocytes analyzed. Three smaller deletions in this region have previously been reported in patients with Prader-Willi syndrome phenotype. All three deletions included SNORD116, but only two encompassed parts of SNURF-SNRPN, implicating SNORD116 as the major contributor to the Prader-Willi phenotype. Our case adds further information about genotype-phenotype correlation and supports the hypothesis that SNORD116 plays a major role in the pathogenesis of Prader-Willi syndrome. Furthermore, it examplifies diagnostic difficulties in atypical cases and illustrates the need for additional testing methods when Prader-Willi syndrome is suspected. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Array comparative genomic hybridization is now a powerful tool to investigate patients with multiple congenital abnormalities and intellectual/motor impairment, and genomic imbalances are identified in a growing number of children with intellectual disability. Deletions in the 17p13.1 region have been reported in patients with dysmorphic features and developmental delay but a consistent phenotype has yet to emerge. Here, we report on the diagnosis of a 17p13.1 microdeletion of 829 kb in an 8-year-old girl presenting with profound cognitive disability, psychomotor delay, facial dysmorphisms, and refractory epilepsy. This deletion comprises 44 genes, including 8 OMIM morbid genes. We discuss genetic, clinical, and epileptic features comparing our patient with those previously reported in the literature. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aneuploidy or alteration in chromosome numbers is a characteristic feature in cancer that is generally a consequence of defective chromosome segregation during cell division. Molecular cytogenetic analyses have conferred substantial evidence with regards to the chromosomal architectures in cancer. Most importantly, the fluorescence in situ hybridization (FISH) technique that plays a leading role in diagnostic pathology for its single-cell analysis has provided crucial information regarding genomic variations in malignant cells. Further development of molecular cytogenetic methodologies such as chromosome specific FISH karyotyping and comparative genomic hybridization have also helped in the detection of cryptic genetic changes in cancer. But, the recent advancement of high throughput sequencing technologies have provided a more comprehensive genomic analyses resulting in novel chromosome rearrangements, somatic mutations as well as identification of fusion genes leading to new therapeutic targets. This review highlights the application of early molecular cytogenetics and the recent high throughput genomic approaches in characterizing various cancers and their invaluable support in cancer therapeutics. [ABSTRACT FROM AUTHOR]

ABSTRACT West syndrome is a well-recognized form of epilepsy, defined by a triad of infantile spasms, hypsarrhythmia and developmental arrest. West syndrome is heterogenous, caused by mutations of genes ARX, STXBP1, KCNT1 among others; 16p13.11 and 17q21.31 microdeletions are less frequent, usually associated with intellectual disability and facial dysmorphism. So-called 'idiopathic' West syndrome is of better prognostic, without prior intellectual deficiency and usually responsive to anti-epileptic treatment. We report on a boy falling within the scope of idiopathic West syndrome, with no dysmorphic features and normal development before the beginning of West syndrome, with a good resolution after treatment, bearing a de novo 15q13.3 microdeletion. Six genes are located in the deleted region, including CHRNA7, which encodes a subunit of a nicotinic acetylcholine receptor, and is frequently associated with epilepsy. Exploration of the 15q13.3 region should be proposed in idiopathic West syndrome. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We develop a mathematical theory needed for moment estimation of the parameters in a general shifting level process (SLP) treating, in particular, the finite state space case geometric finite normal (GFN) SLP. For the SLP, we give expressions for the moment estimators together with asymptotic (co)variances, following, completing, and correcting Cline ( Journal of Applied Probability 20, 1983, 322-337); formulae are then made more explicit for the GFN-SLP. To illustrate the potential uses, we then apply the moment estimation method to a GFN-SLP model of array comparative genomic hybridization data. We obtain encouraging results in the sense that a segmentation based on the estimated parameters turns out to be faster than with other currently available methods, while being comparable in terms of sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Interstitial deletions of the long arm of the chromosome 17 are relatively rare. Up to 17 cases involving the q22-q23.3 band have been reported so far. A common phenotype has not yet been delineated and epilepsy has been reported in only 2 out of 17 cases. We describe a clinical phenotype of epilepsy characterized by myoclonic atonic and absence seizures in a 6-year-old boy carrying a de novo 17q22q23 deletion detected by oligonucleotide array comparative genomic hybridization (aCGH). © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

An insertional translocation (IT) can result in pure segmental aneusomy for the inserted genomic segment allowing to define a more accurate clinical phenotype. Here, we report on two siblings sharing an unbalanced IT inherited from the mother with a history of learning difficulty. An 8-year-old girl with developmental delay, speech disability, and attention-deficit hyperactivity disorder (ADHD), showed by GTG banding analysis a subtle interstitial alteration in 21q21. Oligonucleotide array comparative genomic hybridization (array-CGH) analysis showed a 4q13.1-q13.3 duplication spanning 8.6 Mb. Fluorescence in situ hybridization (FISH) with bacterial artificial chromosome (BAC) clones confirmed the rearrangement, a der(21)ins(21;4)(q21;q13.1q13.3). The duplication described involves 50 RefSeq genes including the EPHA5 gene that encodes for the EphA5 receptor involved in embryonic development of the brain and also in synaptic remodeling and plasticity thought to underlie learning and memory. The same rearrangement was observed in a younger brother with behavioral problems and also exhibiting ADHD. ADHD is among the most heritable of neuropsychiatric disorders. There are few reports of patients with duplications involving the proximal region of 4q and a mild phenotype. To the best of our knowledge this is the first report of a duplication restricted to band 4q13. This abnormality could be easily missed in children who have nonspecific cognitive impairment. The presence of this behavioral disorder in the two siblings reinforces the hypothesis that the region involved could include genes involved in ADHD. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Several patients with partial trisomy 6p resulting from parental balanced translocations or from a de novo duplication or insertion have already been described. Here, we report on the first case of familial pure trisomy 6p as a result of interstitial tandem duplication. The patient, an 11-year-old female, presented with mild dysmorphic features, moderate intellectual disability with behavioral disturbances, immunodeficiency, and epilepsy. Conventional cytogenetic analysis showed a duplication of the 6p region in the patient and in her mother presenting with a partially overlapping phenotype. The rearrangement was confirmed and defined by molecular cytogenetic analysis, including FISH and array CGH analysis showing a gain of ∼13.8 Mb from 6p12.3 to 6p21.31. The phenotype of a pure partial trisomy 6p is extremely heterogeneous depending on the gene contents of the duplicated region. The clinical features of our patients have been compared with overlapping cases from the literature. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We report on three males with de novo overlapping 7.5, 9.8, and 10 Mb duplication of chromosome 20q11.2. Together with another patient previously published in the literature with overlapping 20q11 microduplication, we show that such patients display common clinical features including metopic ridging/trigonocephaly, developmental delay, epicanthal folds, and short hands. The duplication comprised the ASXL1 gene, in which de novo heterozygous nonsense or truncating mutations have recently been reported in patients with Borhing-Opitz syndrome. Because of craniofacial features in common with Borhing-Opitz syndrome, in particular metopic ridging/trigonocephaly, we suggest that duplication of ASXL1 contributes to the phenotype. These observations suggest a novel microduplication syndrome, and reporting of additional patients with molecular characterization will allow more detailed genotype-phenotype correlations. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We report on an 8-year-old female patient with multiple malformations including bilateral cleft lip and palate, coloboma, and craniosynostosis. She presented with severe intellectual disability, seizures, and gastrointestinal dysfunction. Mitochondrial investigations in a muscle biopsy revealed reduced activity in complex I of the mitochondrial respiratory chain. Chromosome analysis and fluorescent in situ hybridization (FISH) studies showed an isodicentric marker chromosome 14 that was identified in all cells analyzed in peripheral blood lymphocytes and cultured fibroblasts. Parental chromosome studies were normal. To further characterize the marker chromosome and determine its origin, we performed array-based comparative genomic hybridization (CGH) and polymorphic marker analysis with quantitative fluorescent PCR (QF-PCR). The combined results from cytogenetic and array-CGH analyses showed tetrasomy 14p13q13.1 and results from the QF-PCR point to formation of the marker chromosome in the maternal meiosis. Isodicentric chromosomes involving partial 14q have previously been reported in four cases; however, this is the first patient with tetrasomy 14p13q13.1 in non-mosaic form surviving beyond infancy. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We report on a child with Jacobsen syndrome (JBS, OMIM 147791) and abnormalities consistent with Beckwith-Wiedemann syndrome (BWS, OMIM 130650). The constitutional karyotype was apparently normal, but FISH analysis with probes specific for the short and long arms of chromosome 11 found 11qter deletion with 11pter trisomy in 80% of the cells studied. Array-CGH identified breakpoints in the 11p15.3 and 11q24.1 regions consistent with Jacobsen and Beckwith-Wiedemann syndromes. We suggest that this chromosome imbalance results from a pericentric inversion of chromosome 11 inherited from the father, with mosaicism resulting from meiotic recombination of a paternal inversion followed by mitotic recombination during the first embryonic divisions. This hypothesis is supported by the results of microsatellite marker analysis. Three previous cases of pericentric inversion and recombination of chromosome 11 have been reported. Our case is unusual in that it combines the Jacobsen and Beckwith-Wiedemann syndromes with mosaicism. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Anterior pituitary aplasia (APA) is a very rare cause of congenital-onset multiple pituitary hormone deficiency (CO-MPHD). We report on molecular analysis and clinical follow-up of three previously reported cases of APA [Scommegna et al., 2004], who share a characteristic physical and neuropsychological profile. Mutation analysis of genes encoding transcription factors involved in pituitary development ( PROP1, POUF1, HESX1, LHX3, and LHX4) did not demonstrate a any mutation. In order to identify the genetic cause underlying the phenotypes we performed an array-based comparative genomic hybridization (array-CGH), which showed a cryptic interstitial deletion of 9p (200 kb), including the TEK and MOBKL2B, in one patient. Although an apparently identical deletion was carried by the clinically normal father, we assumed that the patient's phenotype might be due to a recessive mutation in the other allele. However, sequence analysis of exons and splice junctions of these genes did not detect pathogenic or predisposing variants in the three patients. We suggest that the constellation of clinical signs in these patients constitutes a previously undescribed syndrome, whose genetic cause has yet to be identified. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Complex chromosome rearrangements (CCRs) are rare genomic structural aberrations involving three or more breakpoints on two or more chromosomes. About one-third of all CCRs are familial. Transmittance of such a CCR results either in genomic imbalance due to abnormal segregation at meiosis I or is stably passed on to the next generation. Here we present a phenotypically normal mother with a CCR involving chromosomes 1, 3, and 5 that gave birth to a phenotypically abnormal son. The boy presented with hypotonia, mild facial dysmorphisms, and severe intellectual disability. Conventional karyotyping revealed the same apparently balanced CCR as in the mother. However, by use of array-comparative genome hybridization (array-CGH) and fluorescence in situ hybridization (FISH) we discovered that one of the derivative chromosomes in the patient contained a de novo rearrangement. It appears that during transmission of the CCR, an additional de novo deletion and duplication had arisen in one of the derivative chromosomes. We speculate that this was the result of the inverted duplication with a distal deletion mechanism. We also demonstrate the importance of high-resolution breakpoint analysis in CCRs and stress that genetic counseling of a familial CCR is not straightforward. To our knowledge, this would be the first description of this mechanism operating on a structurally abnormal chromosome. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]