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CNVs: pathogenic mechanisms

AFFECTING GENES AND OTHER SEQUENCES CNVs may be clinically neutral or pathogenic. Because they typically lead to imbalances of large genomic tracts, which often include more than one gene or regulatory region, when CNVs are pathogenic they usually cause severe or very severe diseases. Gene deletions, duplications or multiplications as caused by CNVs may be pathogenic through one of the following mechanisms (CNVs: pathogenic mechanisms): Direct

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CNVs: non-homologous recombination

During DNA synthesis To further deepen the topic of CNVs formation: beyond evolution, we’ll now go into non-homologous recombination. Non-homologous recombination is a DNA repair mechanism which is not based on homology principles. There are two types of non-homologous recombination: replicative and non-replicative. Non-homologous recombination is the basis of non-recurrent CNVs. Most pathogenic microduplications and microdeletions are rare non-recurrent CNVs. Non-recurrent CNVs are: preferentially located in microhomology sites (2-15 bp). Microhomology sites are too small

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CNVs: NAHR (Non Allelic Homologous Recombination)

ON DIFFERENT ALLELES Expanding the topic about CNVs formation: beyond evolution, it is necessary to talk about NAHR: NAHR (Non Allelic Homologous Recombination) Homologous recombination (HR) guides the exchange of genomic material during the meiosis contributing to human inter individual variation. HR takes place between two allelic homologous regions (e.g. between two regions located at the same locus on two homologous chromosome, e.g. between a certain

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CNVs formation: beyond evolution

BEYOND EVOLUTION LCRs/DSs cause CNVs Mechanisms of DNA replication and repair are the basis for the formation of CNVs. CNVs formation is also strictly dependent from the action of some particular genomic regions called low copy repeats (LCRs) or segmental duplications (SDs). LCRs/SDs are tracts of duplicated DNA which are comprised between 1 and 400 Kb in size and of which sequence identity is not

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CNVs: detection methods

WHOLE & NOT Molecular diagnostics at present can be subdivided in “whole” approach (Whole Exome or Whole Genome) and “targeted” approach (single gene or single panel testing). Methods for the detection of CNVs vary significantly on the desired type of approach. Here below a guide to the right choice (and the techniques we have chosen). “WHOLE” APPROACHES Microarray technology (array-CGH and SNP-array) The microarray technology is

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CNVs databases

STORING IMBALANCES Due to the amount and complexity of information relating to Copy Number Variations (CNVs), the scientific community felt the need to organize all available data, and future submissions, into open-source online repositories. Luckily, some of these resources are reciprocally synchronized, so that conflicting information is reduced to the minimum. The most important CNVs databases are: dbVar  This database is managed by the NCBI

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Multi-allelic CNVs (mCNVs)

mCNVs: YET TO BE DISCOVERED Several hundreds of human genomic traits (and maybe even more) show CNVs (Copy Number Variations) within a very large range of alleles. Such CNVs are also called multi-allelic CNVs (mCNVs). Non-Allelic Homologous Recombination (NAHR) mCNVs can evolve with mechanism of non-allelic homologous recombination (NAHR) at a much higher mutational rate than SNPs (Single Nucletoide Polymorphisms). Because of NAHR events, mCNVs may show

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CNVs: a universe of variations

Defning CNVs Genetic variants of the human genome can differ very much in size. From the smallest ones (variants affecting on single nucleotide: Single Nucleotide Variations – SNVs) to the largest ones (variants affecting the shape and number of an entire chromosome), everything can stay in the middle. Variants comprised between 1,000 bp (1Kb) and 1,000,000 bp (1Mb) are usually referred to as Structural Variations

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ClinVar or HGMD?

Which one is the best database? Genetic testing remains the most complex and difficult among all laboratory tests, both from the technical and the medical point of view. Since an excellent bioinformatic pipeline is fundamental to produce good data for the geneticist and because several bioinformatic tools are available today, it is necessary to choose well when establishing standard operating protocols for variant filtering and annotation. During the bioinformatic and

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MLPA: 10 questions and answers

MLPA: Q&A MLPA is acronym for Multiplex Ligation Probe Amplification, which is a special molecular technique based on PCR. It is used to scan large deletions/duplications/multiplications which are not detectable by standard sequencing (either NGS or Sanger). The alternative to this technique is the qPCR (quantitative PCR). Is it necessary to always perform MLPA? No, it isn’t always indicated. Multiplex Ligation Probe Amplification is usually indicated whenever large deletions/duplications have

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Tuberous sclerosis: catching mosaicism and intronic mutations

Recommended testing at Breda Genetics for this condition (also to test for mosaicism): Tuberous sclerosis (TSC1, TSC2) If negative: MLPA analysis (TSC1, TSC2 gene). If negative: Exonic ultra-deep sequencing (600x) and SNaPshot analysis Summary Tuberous Sclerosis Complex (TSC), also called Bourneville syndrome, is a multisystem disorder with variable expressivity characterized by hamartomas in multiple organ systems. It mainly affects the brain and the skin, with

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How to interpret the results of a genetic test: general flow-chart and common pitfalls

Unlike most other analytics in medicine, where automation is king even in the interpretation of the results, genetic testing still remains complex under all aspects. In particular for what concerns the interpretation of the results, despite the solid efforts made in developing artificial intelligence, the human factor is still pivotal and a good final outcome still operator-dependent. We can divide the process of validating the

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p.Gly2019Ser: the common LRRK2 mutation

LRRK2 p.Gly2019Ser Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of inherited Parkinson’s disease (PD), and also a risk factor for idiopathic PD. The LRRK2 missense mutation p.Gly2019Ser, which causes the substitution of a glycine with a serine at codon 2019 of the amino acidic chain, is the most common LRRK2 mutation. The penetrance of this mutation is incomplete and is age-dependent. Therefore, it has been speculated that

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Newly identified genes in Rett-like patients

Rett and Rett-like disorders Breda Genetics panel recommended for this conditions: Rett and Rett-like syndrome disorders (MECP2, FOXG1, CDKL5, MEF2C, TCF4, GABRD, WDR45, SMC1A) Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting the central nervous system. Being most frequently transmitted as an X-linked dominant disorder caused by MECP2 mutations (90% of cases), RTT primarily affects females, making it one of the most common genetic causes

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MMP21 mutations causing autosomal recessively inherited heterotaxy

Causing a developmental disorder By whole-exome and whole-genome sequencing evidence has been found that MMP21 gene mutations may cause an autosomal recessively inherited form of heterotaxy. Heterotaxy (or heterotaxia) is an abnormal positioning of the thoracic and/or abdominal organs reversing left/right with respect to normal. The incidence is approximately 1/15,000. Mutations in several other genes and all kinds of inheritance (autosomal dominant, recessive, X-linked) have been so far reported. Matrix metalloproteinases,

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Mental Retardation 5 (MRD5 – SYNGAP1 gene mutations)

Recommended testing for this condition at Breda Genetics: Single gene testing based on exome sequencing (SYNGAP1 gene). If negative: upgrade to full exome data analysis. Summary SYNGAP1 gene mutations have been associated with autism or autism spectrum disorders, nonsyndromic intellectual disability, delay of psychomotor development, acquired microcephaly, and several forms of idiopathic generalized epilepsy. The condition caused by SYNGAP1 gene mutations is called MRD5 (Mental Retardation, autosomal

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Incidental findings: current opinions of professionals and patients

What are incidental findings? The more exome and genome sequencing spread, the more the ascertainment and return of incidental findings becomes of crucial importance and ethical relevance. Incidental findings which are sometimes referred to as “secondary” findings or more common among researchers “incidentalome”, are defined as the counterpoint to the primarily sought after diagnostic results or as additional findings unrelated to the primary test indication. In

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Familial dyskinesia with facial myokymia (ADCY5 gene)

A hyperkinetic disorder Familial dyskinesia with facial myokymia (also known as ADCY5-related dyskinesia) is an autosomal dominant mixed hyperkinetic disorder characterized by paroxysmal choreiform, myoclonic, and/or dystonic movements of the limbs and neck with frequent facial involvement. Onset is typically from infancy to late adolescence. The severity is variable, sometimes resulting in difficulty walking and talking. The disorder has been intially reported by Bird and

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Polyphen/Polyphen-2

A tool to predict the effect of missense variants Polyphen, now available in its version Polyphen-2, predicts the impact of a missense variant (also referred to as nsSNP: non synonymous single nucleotide polymorphism) based on (1) protein sequence (2) phylogenetic information and (3) structural information. So Polyphen is able to do the so called functional annotation of missense variants. The software actually looks if the mutation is falling within

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