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Objectives: Myotonia is a clinical sign typical of a group of skeletal muscle channelopathies, the non‐dystrophic myotonias. These disorders are electrophysiologically characterized by altered membrane excitability, due to specific genetic variants in known causative genes (CLCN1 and SCN4A). Juvenile Myoclonic Epilepsy (JME) is an epileptic syndrome identified as idiopathic generalized epilepsy, its genetics is complex and still unclarified. The co‐occurrence of these two phenotypes is rare and the causes likely have a genetic background. In this study, we have genetically investigated an Italian family in which co‐segregates myotonia, JME, or abnormal EEG without seizures was observed. Methods: All six individuals of the family, 4 affected and 2 unaffected, were clinically evaluated; EMG and EEG examinations were performed. For genetic testing, Exome Sequencing was performed for the six family members and Sanger sequencing was used to confirm the candidate variant. Results: Four family members, the mother and three siblings, were affected by myotonia. Moreover, EEG recordings revealed interictal generalized sharp‐wave discharges in all affected individuals, and two siblings were affected by JME. All four affected members share the same identified variant, c.644 T > C, p.Ile215Thr, in SCN4A gene. Variants that could account for the epileptic phenotype alone, separately from the myotonic one, were not identified. Significance: These results provide supporting evidence that both myotonic and epileptic phenotypes could share a common genetic background, due to variants in SCN4A gene. SCN4A pathogenic variants, already known to be causative of myotonia, likely increase the susceptibility to epilepsy in our family. Plain Language Summary: This study analyzed all members of an Italian family, in which the mother and three siblings had myotonia and epilepsy. Genetic analysis allowed to identify a variant in the SCN4A gene, which appears to be the cause of both clinical signs in this family. [ABSTRACT FROM AUTHOR]

Objective: N‐methyl‐d‐aspartate (NMDA) receptors are expressed at synaptic sites, where they mediate fast excitatory neurotransmission. NMDA receptors are critical to brain development and cognitive function. Natural variants to the GRIN1 gene, which encodes the obligatory GluN1 subunit of the NMDA receptor, are associated with severe neurological disorders that include epilepsy, intellectual disability, and developmental delay. Here, we investigated the pathogenicity of three missense variants to the GRIN1 gene, p. Ile148Val (GluN1‐3b[I481V]), p.Ala666Ser (GluN1‐3b[A666S]), and p.Tyr668His (GluN1‐3b[Y668H]). Methods: Wild‐type and variant‐containing NMDA receptors were expressed in HEK293 cells and primary hippocampal neurons. Patch‐clamp electrophysiology and pharmacology were used to profile the functional properties of the receptors. Receptor surface expression was evaluated using fluorescently tagged receptors and microscopy. Results: Our data demonstrate that the GluN1(I481V) variant is inhibited by the open pore blockers ketamine and memantine with reduce potency but otherwise has little effect on receptor function. By contrast, the other two variants exhibit gain‐of‐function molecular phenotypes. Glycine sensitivity was enhanced in receptors containing the GluN1(A666S) variant and the potency of pore block by memantine and ketamine was reduced, whereas that for MK‐801 was increased. The most pronounced functional deficits, however, were found in receptors containing the GluN1(Y668H) variant. GluN1(Y668H)/2A receptors showed impaired surface expression, were more sensitive to glycine and glutamate by an order of magnitude, and exhibited impaired block by extracellular magnesium ions, memantine, ketamine, and MK‐801. These variant receptors were also activated by either glutamate or glycine alone. Single‐receptor recordings revealed that this receptor variant opened to several conductance levels and activated more frequently than wild‐type GluN1/2A receptors. Significance: Our study reveals a critical functional locus of the receptor (GluN1[Y668]) that couples receptor gating to ion channel conductance, which when mutated may be associated with neurological disorder. [ABSTRACT FROM AUTHOR]

Key points: What's already known about this topic? Six individuals between 5‐ and 19‐year‐old were reported with pathogenic variants in RAC3 responsible for brain malformations involving midline. What does this study add? RAC3‐fetopathy is associated with fetal akinesia deformation sequence, and complex brain malformations including corpus callosum agenesis, diencephalosynapsis, kinked brainstem, and vermian hypoplasia.The differential diagnoses with prenatal kinked brainstem include fetopathies related to KIAA1109, L1CAM, Walker‐Warburg syndrome and tubulinopathies. The present report adds the RAC3 related condition to this list. [ABSTRACT FROM AUTHOR]

Introduction: Depending on the location of insertion of the gained region, F8 duplications can have variable clinical impacts from benign impact to severe haemophilia A phenotype. Aim: To characterize two large Xq28 duplications involving F8 incidentally detected by chromosome microarray analysis (CMA) in two patients presenting severe intellectual disability but no history of bleeding disorder. Methods: Whole genome sequencing (WGS) was performed in order to characterize the two large Xq28 duplications at nucleotide level. Results: In patient 1, a 60–73 kb gained region encompassing the exons 23–26 of F8 and SMIM9 was inserted at the int22h‐2 locus following a non‐homologous recombination between int22h‐1 and int22h‐2. We hypothesized that two independent events, micro‐homology‐mediated break‐induced replication (MMBIR) and break‐induced replication (BIR), could be involved in this rearrangement. In patient 2, the CMA found duplication from 101 to 116‐kb long encompassing the exons 16–26 of F8 and SMIM9. The WGS analysis identified a more complex rearrangement with the presence of three genomic junctions. Due to the multiple micro‐homologies observed at breakpoints, a replication‐based mechanism such as fork stalling and template switching (FoSTeS) was greatly suspected. In both cases, these complex rearrangements preserved an intact copy of the F8. Conclusion: This study highlights the value of WGS to characterize the genomic junction at the nucleotide level and ultimately better describe the molecular mechanisms involved in Xq28 structural variations. It also emphasizes the importance of specifying the structure of the genomic gain in order to improve genotype‐phenotype correlation and genetic counselling. [ABSTRACT FROM AUTHOR]

Exome sequencing was performed in 2 unrelated families with progressive myoclonus epilepsy. Affected individuals from both families shared a rare, homozygous c.191A > G variant affecting a splice site in SLC7A6OS. Analysis of cDNA from lymphoblastoid cells demonstrated partial splice site abolition and the creation of an abnormal isoform. Quantitative reverse transcriptase polymerase chain reaction and Western blot showed a marked reduction of protein expression. Haplotype analysis identified a ~0.85cM shared genomic region on chromosome 16q encompassing the c.191A > G variant, consistent with a distant ancestor common to both families. Our results suggest that biallelic loss‐of‐function variants in SLC7A6OS are a novel genetic cause of progressive myoclonus epilepsy. ANN NEUROL 2021;89:402–407 [ABSTRACT FROM AUTHOR]

Key Clinical Message: Chromosomal microarray (CMA) can detect pathogenic copy number variations in 15–20% of individuals with intellectual disability and in 10% of patients with autism spectrum disorders. The diagnostic rate in specific learning disorders (SLD) is unknown. Our study emphasizes the usefulness of CMA in the diagnostic workout assessment of familial SLD. [ABSTRACT FROM AUTHOR]

Objective: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE).Methods: The de novo p.Glu590Lys variant was identified by whole-exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients.Results: The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5-21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike-wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox-Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development.Interpretation: Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. Ann Neurol 2018;83:926-934. [ABSTRACT FROM AUTHOR]

We report the clinical and molecular cytogenetic characterization of four unrelated patients from France and Spain, carrying 2p14 microdeletions and presenting with intellectual disability and dysmorphisms. 2p14 microdeletions are very rare. Seven patients have been reported so far harboring deletions including 2p14p15 and encompassing OTX1, whose haploinsufficiency is frequently associated with genitourinary defects. To date, only one patient has been reported carrying a more proximal 2p14 microdeletion which does not include OTX1. Here, we report three further patients carrying proximal 2p14 microdeletions not including OTX1 and one patient carrying a more distal 2p14p15 microdeletion including this gene, providing new insights into the associated phenotypic spectrum. First, our study and a review of the literature showed that 3/4 patients carrying proximal 2p14 microdeletions had sensorineural hearing loss, suggesting the presence of a previously unreported deafness-causing gene in this chromosomal region. Second, one patient developed a progressive cardiomyopathy, suggesting that a cardiac follow-up should be systematically warranted even in the absence of congenital heart disease. We speculate that ACTR2 and MEIS1 might respectively play a role in the pathogenesis of the observed deafness and cardiomyopathy. Third, we observed other previously unreported features such as glaucoma, retinopathy, and mild midline abnormalities including short corpus callosum, hypospadias and anteriorly placed anus. Finally, the patient carrying a 2p14p15 deletion including OTX1 had normal kidneys and genitalia, thus confirming that OTX1 haploinsufficiency is not invariably associated with genitourinary defects. In conclusion, our study contributes significantly to delineate the phenotypic spectrum of 2p14 microdeletions. [ABSTRACT FROM AUTHOR]

We report a novel syndromic disorder of sex development observed in three male siblings, presenting with the association of micropenis without hypospadias, cryptorchidism, very low level of antimüllerian hormone in the neonatal period, and no persistent müllerian duct structures, suggesting a progressive regression of testicular function. The patients described here showed a striking neurological involvement including bilateral periventricular cysts observed in the anterior part of the frontal horns prenatally and increasing in size and number over time, associated with infra and supratentorial parenchymal atrophy, dilated ventricular system, corpus callosum hypoplasia, severe intellectual disability, and epilepsy. Associated features included a distinctive facies, joint contractures, retinopathy, and hearing loss. Pathological examination was consistent with testicular dysgenesis and leukoencephalopathy with spongiosis and microcalcifications. To the best of our knowledge, this disease, characterized by a recognizable pattern of malformations, has not been previously reported. An exhaustive genetic and metabolic evaluation was normal. Autosomal recessive inheritance was considered to be likely, on the basis of SNP studies. We hope that the detailed description provided here of the clinical, radiological, and pathological findings observed in this family will help to identify further unrelated patients, and ultimately, to clarify the genetic basis of this condition. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We report here on an 8-year-old girl and her mother, both displaying similar facial dysmorphism, speech delay, and mild to moderate intellectual disability. Array-CGH studies revealed the same interstitial 3q26.32 microdeletion encompassing a single coding gene, TBL1XR1, in both patients. The TBL1XR1 protein, which has four WD40 repeats, has been shown to bind the nuclear corepressor (NCOR) and histone deacetylase-3 complexes (HDAC3). TBL1XR1 mutations have recently been implicated in autism spectrum disorders, but our patients displayed no autistic behavior. Our findings suggest that TBL1XR1 haploinsufficiency can cause intellectual disability with a recognizable dysmorphism, without necessarily causing autistic behavior. © 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]

A girl patient born to healthy nonconsanguineous parents was referred at age 3 years and 2 months to our genetics department for testing due to developmental delay and postnatal microcephaly. Initial clinical evaluation revealed an overall developmental delay, mildly dysmorphic features, thin, sparse fair hair, and fair skin. Postnatal microcephaly and progressive ataxia and spasticity appeared later. Array CGH karyotyping showed a 333 kb de novo microdeletion on 3p22 covering the entire genomic sequence of a single gene, CTNNB1, which codes for β-catenin. β-catenin is a sub-unit of a multiprotein complex, which is part of the Wnt signaling pathway. In mice, a conditional homozygous β-catenin knockout displays loss of neurons, impaired craniofacial development, and hair follicle defects, which is similar to the phenotype presented by the patient described in this clinical report. Thus, CTNNB1 haploinsufficiency causes neuronal loss, craniofacial anomalies and hair follicle defects in both humans and mice. Point mutations in CTNNB1 in human have recently been reported but this is the first observation of a new recognizable multiple congenital anomaly/mental retardation syndrome caused by CTNNB1 haploinsufficiency. This clinical report should prompt a search for point mutations in CTNNB1 in patients presenting developmental delay, mild hair, skin and facial anomalies, and neurodegeneration characterized by postnatal microcephaly, and progressive ataxia and spasticity. © 2014 Wiley Periodicals, Inc. [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]

FG syndrome, Lujan syndrome, and Ohdo syndrome, the Maat-Kievit-Brunner type, have been described as distinct syndromes with overlapping non-specific features and different missense mutations of the MED12 gene have been reported in all of them. We report a family including 10 males and 1 female affected with profound non-specific intellectual disability (ID) which was linked to a 30-cM region extending from Xp11.21 (ALAS2) to Xq22.3 (COL4A5). Parallel sequencing of all X-chromosome exons identified a frameshift mutation (c.5898dupC) of MED12. Mutated mRNA was not affected by non-sense mediated RNA decay and induced an additional abnormal isoform due to activation of cryptic splice-sites in exon 41. Dysmorphic features common to most affected males were long narrow face, high forehead, flat malar area, high nasal bridge, and short philtrum. Language was absent or very limited. Most patients had a friendly personality. Cognitive impairment, varying from borderline to profound ID was similarly observed in seven heterozygous females. There was no correlation between cognitive function and X-chromosome inactivation profiles in blood cells. The severe degree of ID in male patients, as well as variable cognitive impairment in heterozygous females suggests that the duplication observed in the present family may have a more severe effect on MED12 function than missense mutations. In a cognitively impaired male from this family, who also presented with tall stature and dysmorphism and did not have the MED12 mutation, a 600-kb duplication at 17p13.3 including the YWHAE gene, was found in a mosaic state. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We report on three patients presenting moderate intellectual disability, delayed language acquisition, and mild facial dysmorphia. Array-CGH studies revealed overlapping interstitial 12p13.1 microdeletions encompassing all or part of GRIN2B. GRIN2B encodes the NR2B subunit of the N-methyl- D-aspartate (NMDA) receptor. This receptor is a heteromeric glutamate-activated ion channel, present throughout the central nervous system. It plays a critical role in corticogenesis, neuronal migration, and synaptogenesis during brain development. GRIN2B alterations, including mutation and gene disruption by apparently balanced chromosomal rearrangements, have been described in patients with intellectual disability and autism spectrum disorder. We report here on the first cases of GRIN2B deletion, enlarging the spectrum of GRIN2B abnormalities. Our findings confirm the involvement of this gene in neurodevelopmental disorders. © 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]

Pitt-Hopkins syndrome (PTHS) is characterized by distinctive facial dysmorphism, profound intellectual disability, and the possible occurrence of epilepsy and breathing anomalies. It is caused by haploinsufficiency of the TCF4 gene. No significant difference in clinical severity has been reported to date between PTHS patients carrying 18q21 deletions including the TCF4 gene, and those harboring TCF4 point mutations, suggesting a lack of genotype/phenotype correlation. Moreover, the size of 18q21 deletions including the TCF4 gene does not appear to have a significant effect on the phenotypic severity, suggesting that TCF4 haploinsufficiency is the most important prognostic factor in 18q deletions. We describe two unrelated patients presenting with clinical features reminiscent of PTHS and carrying mosaic interstitial 18q21 deletions characterized by array comparative genomic hybridization. One of the patients presented the lowest level of mosaic 18q21 deletion reported to date (5-10%). Our report and a review of the literature show that the mosaic status does not appear to have a significant effect on the clinical severity of 18q21 deletions, which are associated with a poor neurological outcome, whereas a mosaic TCF4 point mutation can result in a significantly milder phenotype. Malformations of internal organs are currently considered to be rare in PTHS. The patients described here had visceral anomalies, suggesting that a full morphological assessment, including heart and abdominal ultrasound scans, should be performed systematically in PTHS patients. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose: The continuous spike and waves during slow-wave sleep syndrome (CSWSS) and the Landau-Kleffner (LKS) syndrome are two rare epileptic encephalopathies sharing common clinical features including seizures and regression. Both CSWSS and LKS can be associated with the electroencephalography pattern of electrical status epilepticus during slow-wave sleep and are part of a clinical continuum that at its benign end also includes rolandic epilepsy (RE) with centrotemporal spikes. The CSWSS and LKS patients can also have behavioral manifestations that overlap the spectrum of autism disorders (ASD). An impairment of brain development and/or maturation with complex interplay between genetic predisposition and nongenetic factors has been suspected. A role for autoimmunity has been proposed but the pathophysiology of CSWSS and of LKS remains uncharacterized. Methods: In recent years, the participation of rare genomic alterations in the susceptibility to epileptic and autistic disorders has been demonstrated. The involvement of copy number variations (CNVs) in 61 CSWSS and LKS patients was questioned using comparative genomic hybridization assays coupled with validation by quantitative polymerase chain reaction (PCR). Key Findings: Whereas the patients showed highly heterogeneous in genomic architecture, several potentially pathogenic alterations were detected. A large number of these corresponded to genomic regions or genes ( ATP13A4, CDH9, CDH13, CNTNAP2, CTNNA3, DIAPH3, GRIN2A, MDGA2, SHANK3) that have been either associated with ASD for most of them, or involved in speech or language impairment, or in RE. Particularly, CNVs encoding cell adhesion proteins (cadherins, protocadherins, contactins, catenins) were detected with high frequency (≈20% of the patients) and significant enrichment (cell adhesion: p = 0.027; cell adhesion molecule binding: p = 9.27 × 10−7). Significance: Overall our data bring the first insights into the possible molecular pathophysiology of CSWSS and LKS. The overrepresentation of cell adhesion genes and the strong overlap with the genetic, genomic and molecular ASD networks, provide an exciting and unifying view on the clinical links among CSWSS, LKS, and ASD. [ABSTRACT FROM AUTHOR]

We report on clinical and cytogenetic studies in a 7-year-old child with moderate intellectual disability, short stature, mild dysmorphism, and hearing loss. R-chromosome banding showed a de novo autosomal marker originating from the 17p chromosome segment in all cells analyzed. Array comparative genome hybridization (aCGH) was used to determine the gene content and proximal and distal breakpoints of the small supernumerary marker chromosome (SMC). These breakpoints mapped to the centromere of chromosome 17 and the 17p11.2 region, respectively. Unexpectedly, aCGH analysis also revealed a de novo deletion of 800 kb encompassing six genes in the 17q23.2 region, including MED13 (also known as THRAP1). We compared our patient with other reported cases of SMC(17), to determine the respective contributions of the duplication and the deletion to the phenotype. We cannot entirely exclude a minor role for the SMC(17), but we suggest that MED13 haploinsufficiency was responsible for the phenotype of the patient particularly the cataract, hearing loss and semicircular canal dysplasia. Moreover, this report highlights the usefulness of aCGH for the specification of gene content in cases of abnormality, facilitating the establishment of accurate phenotype-genotype correlations and the detection of other, complex rearrangements. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Partial trisomy 9p is one of the most common detected autosomal structural anomalies, so the phenotype-genotype correlation of this rearrangement has been well described. Despite variation in size of the 9p duplications, trisomy 9p syndrome is characterized by typical dysmorphic features and a variable but constant psychomotor and mental retardation. Previously reported phenotype genotype correlation studies proposed that the critical region for phenotype is located in 9p22. We report here on a new patient with partial trisomy 9p13.3→9pter in an 8-year-old boy with typical trisomy 9p dysmorphic features but a normal mental development. Cytogenetics investigations showed that our patient karyotype was 47,XY,+ der(22)t(9;22)(p13.q11) inherited by a 3:1 disjunction of a maternal reciprocal translocation t(9;22)(p13.q11). FISH and array CGH analysis were used to better characterize duplicated chromosomal regions and showed a large duplication of chromosome 9p13.3→9pter associated to microduplication in 22q11.1. The size of the duplications in chromosomes 9p and 22q were estimated about 33.9 and 2.67 Mb, respectively. The comparison between this case and those reported in the literature allows us to support that all syndromes show variability and that not all partial trisomies 9p are associated with intellectual disability. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

We report on a novel Xq11.11 microdeletion in a patient presenting with severe mental retardation (MR), focal epilepsy, tall stature, macrocephaly, and dysmorphism. This 1.3 Mb deletion, identified using array CGH, includes a single gene with known function- ARHGEF9-plus 1 gene with unknown function and three putative genes. ARHGEF9 encodes collybistin (Cb) that plays an important role in the localization of gephyrin which is the key protein of the scaffolding system of inhibitory synapses and is essential for postsynaptic clustering of both GABAA and glycine receptors. Cb-deficient male mice show reduced exploratory behavior, impaired spatial learning, increased anxiety scores, and reduction of gephyrin-dependent GABA receptor clusters in amygdala and hippocampus. Mutations or disruption of ARHGEF9 due to chromosomal rearrangements have been found in three patients with various clinical presentations: nevertheless, all 3 presented with MR and 2 with epilepsy. The case we report on provides further evidence for the role of ARHGEF9 in cognitive development. The other phenotypic features in our patient, including macrosomia and dysmorphism, may also be related to the loss of this gene. Alternatively, they may be consequences of the loss of one or more of the other genes located within the deletion or of the disruption of sequences regulating neighboring genes. Additional case reports with identical or overlapping deletions would help in defining the phenotype associated with ARHGEF9 haploinsufficiency. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: Pallister–Killian syndrome (PKS) is a rare sporadic disorder caused by tetrasomy of the short arm of chromosome 12. The main clinical manifestations are global developmental delay, intellectual disability, epilepsy, dysmorphic features, hypopigmented and/or hyperpigmented lesions, and multiple congenital anomalies. PKS is associated with tissue mosaicism, which is difficult to diagnose through peripheral blood sample by conventional cytogenetic methods and fluorescence in situ hybridization. Methods: Here, we report five patients with PKS. We delineate their clinical phenotypes and we compare them with previously published cases. We used array Comparative Genomic Hybridization (aCGH) with DNA extracted from peripheral blood samples. The five patients have also been tested by conventional cytogenetics techniques. Results: Four out of five patients showed tetrasomy 12p by aCGH. Three of the four patients have typical i(12p) and one of the four demonstrated atypical tetrasomy 12p. The percentage of mosaicism was as low as 20%. Our cohort exhibited the typical PKS phenotypes. Conclusion: Our results demonstrate the efficacy of aCGH for the diagnosis of PKS from DNA extracted from lymphocytes. Thus, for patients suspected of PKS, we recommend performing aCGH on lymphocytes at an early age before  proceeding to skin biopsy. aCGH on peripheral blood samples is sensitive in detecting low level of mosaicism and it is less invasive method than skin biopsy. We reviewed also the literature concerning the previously published PKS patients diagnosed by aCGH. [ABSTRACT FROM AUTHOR]

Partial trisomy 9p is one of the most common detected autosomal structural anomalies, so the phenotype-genotype correlation of this rearrangement has been well described. Despite variation in size of the 9p duplications, trisomy 9p syndrome is characterized by typical dysmorphic features and a variable but constant psychomotor and mental retardation. Previously reported phenotype genotype correlation studies proposed that the critical region for phenotype is located in 9p22. We report here on a new patient with partial trisomy 9p13.3→9pter in an 8-year-old boy with typical trisomy 9p dysmorphic features but a normal mental development. Cytogenetics investigations showed that our patient karyotype was 47,XY,+ der(22)t(9;22)(p13.q11) inherited by a 3:1 disjunction of a maternal reciprocal translocation t(9;22)(p13.q11). FISH and array CGH analysis were used to better characterize duplicated chromosomal regions and showed a large duplication of chromosome 9p13.3→9pter associated to microduplication in 22q11.1. The size of the duplications in chromosomes 9p and 22q were estimated about 33.9 and 2.67 Mb, respectively. The comparison between this case and those reported in the literature allows us to support that all syndromes show variability and that not all partial trisomies 9p are associated with intellectual disability., (Copyright © 2011 Wiley-Liss, Inc.)

We report on the diagnosis of a 17p13.1 deletion in a 10-year-old boy. The patient presented with mild developmental delay, facial dysmorphism, joint hyperlaxity, pes planus, hypermetropia, hearing loss, and achromic patches following the Blaschko's lines on the right part of the thorax. Chromosome R-banding was normal. Array CGH using a 244 K oligonucleotide array showed a homogeneous de novo 17p13.1 microdeletion of 400 kb involving TP53 and 25 other genes, including genes involved in brain function (EFNB3, FXR2). To our knowledge, six patients presenting with a constitutional 17p13.1 microdeletion involving the TP53 gene have been reported. We discuss the phenotype of this microdeletion and the genetic counseling issues, especially regarding the risk of cancer associated with the deletion of the TP53 gene., (Copyright 2010 Wiley-Liss, Inc.)