First-Tier Array CGH in Clinically Variable Entity Diagnosis: 22q13.3 Deletion Syndrome

Phelan-McDermid (PMS) or 22q13 deletion syndrome (OMIM 606232) is a rare genetic disorder with highly variable clinical presentation. The phenotype includes generalized neonatal hypotonia, developmental delay with intellectual disability and delayed speech, mild dysmorphic features, and autistic behavior. The genetic defects of PMS consist of 22q13.3 deletions or chromosomal structural rearrangements involving SHANK3 gene; the loss of function mutations of SHANK3 gene was reported in a minority of cases. The 22q13.3 deletions vary in size, from 0.2 to over 9 Mb, and, although larger deletions are generally associated with more severe phenotypes, the genotype-phenotype correlations are not clear-cut for all patients. SHANK3 is considered the main candidate gene for the neurologic features of PMS. PMS is a rare disorder, often underdiagnosed. There are no established clinical diagnostic criteria for PMS. The genetic tests typically used are chromosomal microarray and multiplex ligation-dependent probe amplification (MLPA) or fluorescent in situ hybridization (FISH) for copy number analysis of SHANK3 gene; next-generation sequencing (NGS) or Sanger sequencing is used for pathogenic mutation screening of SHANK3. In this chapter, we report three cases with PMS and summarize the clinical and genetic diagnostic approaches of this condition, highlighting the role of chromosomal microarray technology in the identification of rare, but significantly impacting patient’s life, DNA copy number abnormalities

Novel clinical finding in duplication syndrome

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The influence of brush cutter's vibrations on human body

Abstract. In recent years there have been many cases of HAVS being reported for people who work in agriculture, horticulture, landscape gardening and forestry. The work described in this paper assesses the transmitted vibration to the human body from a hand guided power tool, means a brushcutter. As it is known the brushcutters induce a high level of vibrations on human operators. Depending by brushcutter's type, exposure time and human subjectivity, we can discuss about the vibration influence on human body. Long exposure to hand-arm vibration, whole body vibration and mechanical overloading is considered a potential cause of professional diseases

Genetic testing in myelodysplastic syndromes contribution in diagnosis, prognostic and clinical management

Myelodysplastic syndromes (MDS) represent a group of clonal hematological malignancies characterized by ineffective hematopoiesis. Other hematological disorders associating dysplastic features are grouped under the myelodysplastic/ myeloproliferative neoplasms (MDS/MPN) category. The great diversity of the acquired chromosomal abnormalities described in MDS highlights the molecular heterogeneity of these diseases. We report on 12 MDS and 3 MDS/MPN patients investigated by cytogenetic and molecular techniques (FISH). The most frequent chromosomal anomalies were 5q deletion and trisomy 8. Other trisomies, deletions and new translocations were also detected. MDS and MDS/MPN stand as challenging entities in hemato-oncology due to their heterogeneity. Thus, genetic testing provides important means for diagnosis confirmation and offers further insight into the prognosis and management of these patients

Microarray-based comparative genomic hybridization (aCGH) between basic research and clinical diagnostic

In the vast spectrum of human pathology, a significant proportion is represented by genetic disorders. To elucidate the mechanisms leading to disease, various approaches have been used: G-banded karyotyping and FISH allow the survey of the entire genome for large aberrations or analysis of pre-defined segments, while sequencing detects nucleotide alterations with the prior requirement of knowing which DNA segment to address. The last two decades have seen the rise of another generation of investigative methods, such as aCGH, which inquire the condition of the whole genome at sequence level; starting as a research instrument, aCGH is increasingly regarded as a powerful diagnostic tool for clinical use. As an example of its utility in the diagnostic of mental retardation, we present three cases where aCGH contributed to the identification and refinement of the precise genetic aberrations

Autistic Behavior as Novel Clinical Finding in OFD1 Syndrome

Orofaciodigital syndrome I (OFD1–MIM #311200) is a rare ciliopathy characterized by facial dysmorphism, oral cavity, digit, and brain malformations, and cognitive deficits. OFD1 syndrome is an X-linked dominant disorder reported mostly in females. The gene responsible for this condition, OFD1 centriole and centriolar satellite protein (OFD1), is involved in primary cilia formation and several cilia-independent biological processes. The functional and structural integrity of the cilia impacts critical brain development processes, explaining the broad range of neurodevelopmental anomalies in ciliopathy patients. As several psychiatric conditions, such as autism spectrum disorders (ASD) and schizophrenia, are neurodevelopmental in nature, their connections with cilia roles are worth exploring. Moreover, several cilia genes have been associated with behavioral disorders, such as autism. We report on a three-year-old girl with a complex phenotype that includes oral malformations, severe speech delay, dysmorphic features, developmental delay, autism, and bilateral periventricular nodular heterotopia, presenting a de novo pathogenic variant in the OFD1 gene. Furthermore, to the best of our knowledge, this is the first report of autistic behavior in a female patient with OFD1 syndrome. We propose that autistic behavior should be considered a potential feature of this syndrome and that active screening for early signs of autism might prove beneficial for OFD1 syndrome patients

FLT3-ITD DNA allelic burden, but not mRNA levels, influences the biological characteristics of AML patients

FMS-like tyrosine kinase 3 gene internal tandem (FLT3-ITD) mutations represent one of the most frequent genetic lesions in acute myeloid leukemia (AML) and imparts a negative prognostic. For an optimal patient management, current clinical guidelines recommend the evaluation of the allelic ratio (AR), expressed as the DNA FLT3-ITD/WT mutational burden. We sought to evaluate the differences between the AR and FLT3-ITD/WT mRNA ratio (RR) and their respective impact on the biological characteristics of AML patients. A total of 32 DNA and mRNA samples from AML patients with FLT3-ITD were evaluated. There was a good correlation between the AR and RR (Spearman’s rho= 0.652, P <0.001). None of the biological characteristics were influenced by the RR values, whereas patients with high AR values (≥0.5) had higher WBC counts (Mann-Whitney, P= 0.01), LDH levels (Mann-Whitney, P= 0.037), and circulating blasts levels (Mann-Whitney, P= 0.023) than patients with low AR values (<0.5). Also, there was a good correlation between AR values and WBC count (Spearman’s correlation, P= 0.001), and LDH levels (Spearman’s correlation, P= 0.007). In our study population the AR, but not the RR, influenced the biological characteristic of patients suggesting a dose-independent effect of FLT3-ITD mutations

Treatment of Epilepsy Associated with Common Chromosomal Developmental Diseases

Chromosomal diseases are heterogeneous conditions with complex phenotypes, which include also epileptic seizures. Each chromosomal syndrome has a range of specific characteristics regarding the type of seizures, EEG findings and specific response to antiepileptic drugs, significant in the context of the respective genetic etiology. Therefore, it is very important to know these particularities, in order to avoid an exacerbation of seizures or some side effects. In this paper we will present a review of the epileptic seizures and antiepileptic treatment in some of the most common chromosomal syndromes

Rare hematologic neoplasms an acute megakaryocytic leukemia case report

Acute megakaryoblastic leukemia (AMKL) is a rare disorder in adults, particularly challenging due to difficulties in diagnosis, its complex genetic abnormalities and severe prognostic. A high percentage of AMKL cases bear cytogenetic abnormalities and, among them, 70-80% show complex karyotypes. We report on a 46 year-old male patient diagnosed with AMKL, after an initial evolution as acute lymphoblastic leukemia Burkitt-like. Highly complex chromosomal abnormalities were revealed by cytogenetic and molecular techniques (FISH), reflecting the underlying genetic instability. Our report emphasize the importance of both cellular and molecular approaches in onco-hematology, in order to accurately identify and refine genetic aberrations. As a consequence, better diagnosis and prognosis assessment is achieved, as well as understanding of pathogenic mechanisms