Chromosome 12q24.31-q24.33 deletion causes multiple dysmorphic features and developmental delay: First mosaic patient and overview of the phenotype related to 12q24qter defects

<p>Abstract</p> <p>Background</p> <p>Genomic imbalances of the 12q telomere are rare; only a few patients having 12q24.31-q24.33 deletions were reported. Interestingly none of these were mosaic. Although some attempts have been made to establish phenotype/genotype interaction for the deletions in this region, no clear relationship has been established to date.</p> <p>Results</p> <p>We have clinically screened more than 100 patients with dysmorphic features, mental retardation and normal karyotype using high density oligo array-CGH (aCGH) and identified a ~9.2 Mb hemizygous interstitial deletion at the 12q telomere (Chromosome 12: 46,XY,del(12)(q24.31q24.33) in a severely developmentally retarded patient having dysmorphic features such as low set ears, microcephaly, undescended testicles, bent elbow, kyphoscoliosis, and micropenis. Parents were found to be not carriers. MLPA experiments confirmed the aCGH result. Interphase FISH revealed mosaicism in cultured peripheral blood lymphocytes.</p> <p>Conclusions</p> <p>Since conventional G-Banding technique missed the abnormality; this work re-confirms that any child with unexplained developmental delay and systemic involvement should be studied by aCGH techniques. The FISH technique, however, would still be useful to further delineate the research work and identify such rare mosaicism. Among the 52 deleted genes, <it>P2RX2, ULK1, FZD10, RAN, NCOR2 STX2, TESC, FBXW8</it>, and <it>TBX3 </it>are noteworthy since they may have a role in observed phenotype.</p

Genomic and transcriptomic analyses distinguish classic Rett and Rett-like syndrome and reveals shared altered pathways

AbstractRett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by derangements in nervous system especially in cognition and behavior. The present study aims to understand the molecular underpinnings of two subtypes of RTT, classic RTT and Rett-like, and to elucidate common pathways giving rise to common RTT phenotype using genomic and transcriptomic approaches. Mutation screening on selected nuclear genes revealed only MECP2 mutations in a subset of classic RTT patients. MLPA assays and mtDNA screenings were all negative. Genome-wide copy number analysis indicated a novel duplication on X chromosome. Transcriptional profiling revealed blood gene signatures that clearly distinguish classic RTT and RTT-like patients, as well as shared altered pathways in interleukin-4 and NF-κB signaling pathways in both subtypes of the syndrome. To our knowledge, this is the first report on investigating common regulatory mechanisms/signaling pathways that may be relevant to the pathobiology of the “common RTT” phenotype

Autism: a review

This is a review of autism spectrum disorders. It presents the symptoms of the disease discussing the age of diagnosis and first symptoms encountered. It is a polygenic disease that occurs mainly in boys. The importance of early diagnosis is emphasized. The assessment scales used for early diagnosis are discussed. The anatomic basis of the disease is detailed. The molecular genetic aspects, and the techniques employed are reviewed. Special emphasis is placed in chromosome abnormalities observed in autism. Its incidence worldwide is increasing dramatically. This is considered to be due to epigenetic events. Several hypotheses for such epigenetic processes are discussed. Finally the state of intervention in autism and its paradigms are detailed. (J Pediatr Neurol 2003; 1(2): 55-67)

Atlas of metabolic diseases / William L. Nyhan , Bruce A. Barshop , Pinar T. Ozand.

Includes bibliographical references and indexes.xii, 788 pages

Biotin-Responsive Basal Ganglia Disease Maps to 2q36.3 and Is Due to Mutations in SLC19A3

Biotin-responsive basal ganglia disease (BBGD) is a recessive disorder with childhood onset that presents as a subacute encephalopathy, with confusion, dysarthria, and dysphagia, and that progresses to severe cogwheel rigidity, dystonia, quadriparesis, and eventual death, if left untreated. BBGD symptoms disappear within a few days with the administration of high doses of biotin (5–10 mg/kg/d). On brain magnetic resonance imaging examination, patients display central bilateral necrosis in the head of the caudate, with complete or partial involvement of the putamen. All patients diagnosed to date are of Saudi, Syrian, or Yemeni ancestry, and all have consanguineous parents. Using linkage analysis in four families, we mapped the genetic defect near marker D2S2158 in 2q36.3 (LOD=5.9; θ=0.0) to a minimum candidate region (∼2 Mb) between D2S2354 and D2S1256, on the basis of complete homozygosity. In this segment, each family displayed one of two different missense mutations that altered the coding sequence of SLC19A3, the gene for a transporter related to the reduced-folate (encoded by SLC19A1) and thiamin (encoded by SLC19A2) transporters

Integrative and comparative genomics analysis of early hepatocellular carcinoma differentiated from liver regeneration in young and old

<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths worldwide. It is often diagnosed at an advanced stage, and hence typically has a poor prognosis. To identify distinct molecular mechanisms for early HCC we developed a rat model of liver regeneration post-hepatectomy, as well as liver cells undergoing malignant transformation and compared them to normal liver using a microarray approach. Subsequently, we performed cross-species comparative analysis coupled with copy number alterations (CNA) of independent early human HCC microarray studies to facilitate the identification of critical regulatory modules conserved across species.</p> <p>Results</p> <p>We identified 35 signature genes conserved across species, and shared among different types of early human HCCs. Over 70% of signature genes were cancer-related, and more than 50% of the conserved genes were mapped to human genomic CNA regions. Functional annotation revealed genes already implicated in HCC, as well as novel genes which were not previously reported in liver tumors. A subset of differentially expressed genes was validated using quantitative RT-PCR. Concordance was also confirmed for a significant number of genes and pathways in five independent validation microarray datasets. Our results indicated alterations in a number of cancer related pathways, including p53, p38 MAPK, ERK/MAPK, PI3K/AKT, and TGF-β signaling pathways, and potential critical regulatory role of <it>MYC, ERBB2, HNF4A</it>, and <it>SMAD3 </it>for early HCC transformation.</p> <p>Conclusions</p> <p>The integrative analysis of transcriptional deregulation, genomic CNA and comparative cross species analysis brings new insights into the molecular profile of early hepatoma formation. This approach may lead to robust biomarkers for the detection of early human HCC.</p