Looks Can Be Deceiving: Diagnostic Power of Exome Sequencing in Debunking 15q11.2 Copy Number Variations.

: The pathogenetic role of 15q11.2 Copy Number Variations (CNVs) remains contentious in the scientific community, as microdeletions and microduplications in this region are linked to neurodevelopmental disorders with variable expressivity. This study aims to explore the diagnostic utility of Exome Sequencing (ES) in a cohort of pediatric patients with 15q11.

Generation of iPSCs from identical twin, one affected by LHON and one unaffected, both carrying a combination of two mitochondrial variants: m.14484 T>C and m.10680G>A.

Leber hereditary optic neuropathy (LHON) is one of the most common mitochondrial illness, causing retinal ganglion cell degeneration and central vision loss. It stems from point mutations in mitochondrial DNA (mtDNA), with key mutations being m.3460G > A, m.

Case report: A novel pathogenic FRMD7 variant in a Turner syndrome patient with familial idiopathic infantile nystagmus.

Infantile idiopathic nystagmus (IIN) is an oculomotor disorder characterized by involuntary bilateral, periodic ocular oscillations, predominantly on the horizontal axis. X-linked IIN (XLIIN) is the most common form of congenital nystagmus, and the FERM domain-containing gene () is the most common cause of pathogenesis, followed by mutations in . To date, more than 60 pathogenic variants have been identified, and the physiopathological pathways leading to the disease are not yet completely understood.

Neurologic, Neuropsychologic, and Neuroradiologic Features of -Related Syndrome.

Background And Objectives: Heterozygous mutations or deletions of the gene are known to cause a syndrome characterized by intellectual disability, neurodevelopmental disorders, facial dysmorphisms, hypotonia, and ataxia; the latter is quite common despite in most patients brain MRI is reported to be normal. Despite the predominant neurologic involvement of -related syndrome, a systematic definition of neurologic, cognitive/behavioral, and neuroradiologic features is lacking.

Methods: We report on 6 patients (2 females and 4 males, age range 2-12 years), of whom 4 carrying a heterozygous point mutation of the gene and 2 with 10q26 deletion encompassing the gene, diagnosed at Carlo Besta Neurologic Institute of Milan, Italy.

Rhythmic cortical myoclonus in patients with 6Q22.1 deletion.

DNA deletions involving 6q22.1 region result in developmental encephalopathy (DE), often associated with movement disorders and epilepsy. The phenotype is attributed to the loss of the NUS1 gene included in the deleted region.

The relevance of mitochondrial DNA variants fluctuation during reprogramming and neuronal differentiation of human iPSCs.

The generation of inducible pluripotent stem cells (iPSCs) is a revolutionary technique allowing production of pluripotent patient-specific cell lines used for disease modeling, drug screening, and cell therapy. Integrity of nuclear DNA (nDNA) is mandatory to allow iPSCs utilization, while quality control of mitochondrial DNA (mtDNA) is rarely included in the iPSCs validation process. In this study, we performed mtDNA deep sequencing during the transition from parental fibroblasts to reprogrammed iPSC and to differentiated neuronal precursor cells (NPCs) obtained from controls and patients affected by mitochondrial disorders.

Generation of two human iPSC lines, FINCBi002-A and FINCBi003-A, carrying heteroplasmic macrodeletion of mitochondrial DNA causing Pearson's syndrome.

Pearson marrow pancreas syndrome (PMPS) is a sporadic mitochondrial disease, resulting from the clonal expansion of a mutated mitochondrial DNA (mtDNA) molecule bearing a macro-deletion, and therefore missing essential genetic information. PMPS is characterized by the presence of deleted (Δ) mtDNA that co-exist with the presence of a variable amount of wild-type mtDNA, a condition termed heteroplasmy. All tissues of the affected individual, including the haemopoietic system and the post-mitotic, highly specialized tissues (brain, skeletal muscle, and heart) contain the large-scale mtDNA deletion in variable amount.

CGH Findings in Children with Complex and Essential Autistic Spectrum Disorder.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a strong genetic basis. We accurately assessed 209 ASD subjects, categorized in complex (47) and essential (162), and performed array comparative genomic hybridization to identify pathogenic and recurrent Copy Number Variants (CNVs). We found 117 CNVs in 75 patients, 11 classified as pathogenic.

Cerebrospinal fluid glutamate changes in functional movement disorders.

The aim of this study was to assess cerebrospinal fluid (CSF) concentrations of specific amino acids using a high-performance liquid chromatography system in a sample of patients with functional movement disorders (FMDs) and in a sample of controls. CSF levels of glutamate were significantly lower in patients with FMD than in controls. This finding argues in favor of glutamatergic dysfunction in the pathophysiology of FMD.

Neurological phenotype of Potocki-Lupski syndrome.

Potocki-Lupski syndrome is a condition mainly characterized by infantile hypotonia, developmental delay/intellectual disability (DD/ID), and congenital anomalies, caused by duplications of the 17p11.2 region, encompassing RAI1 gene. Its clinical presentation is extremely variable, especially for what concerns the cognitive level and the behavioral phenotype.

Generation of a human iPSC line, FINCBi001-A, carrying a homoplasmic m.G3460A mutation in MT-ND1 associated with Leber's Hereditary optic Neuropathy (LHON).

Leber's Hereditary Optic Neuropathy (LHON) is a maternally inherited disorder caused by homoplasmic mutations of mitochondrial DNA (mtDNA). LHON is characterized by the selective degeneration of the retinal ganglion cells (RGC). Almost all LHON maternal lineages are homoplasmic mutant (100% mtDNA copies are mutant) for one of three frequent mtDNA mutations now found in over 90% of patients worldwide (m.

Severe Phenotype in a Patient With Homozygous 15q21.2 Microdeletion Involving , , and Genes, Resembling Infantile Developmental Disorder With Cardiac Arrhythmias (IDDCA).

Homozygous and compound heterozygous mutations in gene have been associated with a wide spectrum of clinical presentations, ranging from neurodevelopmental issues with or without cardiac arrhythmia (LADCI) to severe developmental delay with epileptic encephalopathy, retinal dystrophy, and heart rhythm abnormalities (IDDCA). While missense or missense/non-sense mutations usually lead to milder form, the biallelic loss of function of 5 gene causes the severe multisystemic IDDCA phenotype. So far, only 27 patients have been described with -associated disease.

Chromosomal Microarray Analysis Has a Poor Diagnostic Yield in Children with Developmental Delay/Intellectual Disability When Concurrent Cerebellar Anomalies Are Present.

Chromosomal microarray analysis is commonly used as screening test for children with neurodevelopmental issues, also in case of complex neurological phenotypes. Developmental delay/intellectual disability is a common presentation sign in pediatric ataxias, diseases with high clinical and genetic heterogeneity. In order to determine the diagnostic yield of Array-CGH in such conditions, all the tests performed in the last 10-year activity of a single referral center in children who present, besides the neurodevelopmental impairment, cerebellar abnormalities have been systematically gathered.

Correction: Sciacca, F. L., et al. Microduplication of 15q13.3 and Microdeletion of 18q21.32 in a Patient with Moyamoya Syndrome. Int. J. Mol. Sci. 2018, 19, 3675.

The authors wish to make the corrections to this paper [...

The noncoding RNA AK127244 in 2p16.3 locus: A new susceptibility region for neuropsychiatric disorders.

The presence of redundant copy number variants (CNVs) in groups of patients with neurological diseases suggests that these variants could have pathogenic effect. We have collected array comparative genomic hybridization (CGH) data of about 2,500 patients affected by neurocognitive disorders and we observed that CNVs in 2p16.3 locus were as frequent as those in 15q11.

Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.

Genetic studies of intellectual disability and identification of monogenic causes of obesity in humans have made immense contribution toward the understanding of the brain and control of body mass. The leptin > melanocortin > SIM1 pathway is dysregulated in multiple monogenic human obesity syndromes but its downstream targets are still unknown. In ten individuals from six families, with overlapping 6q16.

The Diagnostic Yield of Array Comparative Genomic Hybridization Is High Regardless of Severity of Intellectual Disability/Developmental Delay in Children.

Microarray-based comparative genomic hybridization is a method of molecular analysis that identifies chromosomal anomalies (or copy number variants) that correlate with clinical phenotypes. The aim of the present study was to apply a clinical score previously designated by de Vries to 329 patients with intellectual disability/developmental disorder (intellectual disability/developmental delay) referred to our tertiary center and to see whether the clinical factors are associated with a positive outcome of aCGH analyses. Another goal was to test the association between a positive microarray-based comparative genomic hybridization result and the severity of intellectual disability/developmental delay.

Frequency of NFKBIA deletions is low in glioblastomas and skewed in glioblastoma neurospheres.

The NF-kB family of transcription factors is up-regulated in inflammation and different cancers. Recent data described heterozygous deletions of the NF-kB Inhibitor alpha gene (NFKBIA) in about 20% of glioblastomas (GBM): deletions were mutually exclusive with epidermal growth factor receptor (EGFR) amplification, a frequent event in GBM. We assessed the status of NFKBIA and EGFR in 69 primary GBMs and in corresponding neurospheres (NS).

An autoinflammatory neurological disease due to interleukin 6 hypersecretion.

Autoinflammatory diseases are rare illnesses characterized by apparently unprovoked inflammation without high-titer auto-antibodies or antigen-specific T cells. They may cause neurological manifestations, such as meningitis and hearing loss, but they are also characterized by non-neurological manifestations. In this work we studied a 30-year-old man who had a chronic disease characterized by meningitis, progressive hearing loss, persistently raised inflammatory markers and diffuse leukoencephalopathy on brain MRI.

MEF2C deletions and mutations versus duplications: a clinical comparison.

5q14.3 deletions including the MEF2C gene have been identified to date using genomic arrays in patients with severe developmental delay or intellectual disability, stereotypic behavior, epilepsy, cerebral malformations and a facial gestalt not really distinctive though characterized by broad and/or high, bulging forehead, upslanting palpebral fissures, flat nasal root and bridge, small, upturned nose, hypotonic small mouth resulting in cupid bow/tented upper lip. MEF2C mutations have been also identified in patients with overlapping phenotype so that it is considered the gene responsible for the 5q14.

5p13 microduplication syndrome: a new case and better clinical definition of the syndrome.

Chromosome 5p13 duplication syndrome (OMIM #613174), a contiguous gene syndrome involving duplication of several genes on chromosome 5p13 including NIPBL (OMIM 608667), has been described in rare patients with developmental delay and learning disability, behavioral problems and peculiar facial dysmorphisms. 5p13 duplications described so far present with variable sizes, from 0.25 to 13.

Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome.

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17-74 kb in 9% of the patients.