Silver-Russell syndrome following in vitro fertilization

[No abstract available

Genetic prediction of common complex disorders assessed by next generation sequencing and genome wide analysis

Insight into the biological make-up of complex disorders can improve their diagnosis, lead to the discovery of new targets for therapy, increase awareness of genome-environment interactions in health and disease, and open the door to predictive medicine. More than 1 600 genome-wide association studies (GWASs) have been published, and have identified hundreds of polymorphisms associated with more than 250 common diseases or traits. However, for most of the genomic variants identified so far only inconclusive associations with complex diseases have been reported and for many of them their predictive value reaches the same level as the traditional risk. The limited value of these results is probably due to regulatory elements in 2-3% of the encoding genome, whose function has only recently been partially decrypted. Nevertheless, genomic sequencing is an attractive tool for personalized medicine. During the last few years several commercial ventures have begun marketing GWASs directly to consumers for medical, genealogic, and even recreational purposes. Although these tests show promise for the future, consumers should be aware of the unreliability of most of their results at the present time. The development of methods integrating clinical and genetic data together with a better understanding of the heritability of complex diseases will be necessary in the endeavour to progress towards a personalized medicine. In order to achieve maximum benefits from GWASs while keeping the disadvantages to a minimum, guidelines will be necessary to manage the technical advances and to meet the challenges involved in the clinical application of whole genomic sequencing

Grouping of Multiple-Lentigines/LEOPARD and Noonan Syndromes on the PTPN11 Gene

Multiple-lentigines (ML)/LEOPARD (multiple lentigines, electrocardiographic-conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome is an autosomal dominant condition—characterized by lentigines and café au lait spots, facial anomalies, cardiac defects—that shares several clinical features with Noonan syndrome (NS). We screened nine patients with ML/LEOPARD syndrome (including a mother-daughter pair) and two children with NS who had multiple café au lait spots, for mutations in the NS gene, PTPN11, and found, in 10 of 11 patients, one of two new missense mutations, in exon 7 or exon 12. Both mutations affect the PTPN11 phosphotyrosine phosphatase domain, which is involved in <30% of the NS PTPN11 mutations. The study demonstrates that ML/LEOPARD syndrome and NS are allelic disorders. The detected mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the ML/LEOPARD-syndrome subtype of NS

Fluorescence in situ hybridization analysis of allelic losses involving the long arm of chromosome 17 in NF1-associated neurofibromas

Neurofibromatosis type 1 (NF1) is a common autosomal dominant condition associated with germline mutations of the NF1 gene located at chromosome band 17q11.2. Molecular analysis of a number of NF1-specific tumors has shown the inactivation of both NF1 alleles during tumorigenesis, supporting the tumor suppressor hypothesis for the NF1 gene. Using interphase dual-color fluorescence in situ hybridization (FISH) technique on paraffin-embedded tissues, we studied I I plexiform, 4 cutaneous, and 6 subcutaneous neurotibromas. Cytogenetic analysis was conducted using two probes, one specific for the NFI region (RP 11-229K15) and one for the centromeric region of chromosome 17 as control. No large somatic deletions were found. Only in one of the plexiform neurofibromas loss of a whole chromosome 17 was observed. If we assume that dual-color FISH analysis is sensitive enough to detect the majority of large somatic deletions present, then other mutational mechanisms affecting the NF1 gene are probably involved in neurofibroma formation, and other tumor suppressor genes may play an important role in NF1 tumorigenesis. (C) 2004 Elsevier Inc. All rights reserved

Exclusion of Cx43 gene mutation as a major cause of criss-cross heart anomaly in man

[No abstract available

RDDR: a dysmorphology diagnostic network for newborns in central Italy

In 2011, the RDDR network was developed in central Italy to provide support in the diagnosis of dysmorphic newborns. RDDR has been developed as an online electronic system that currently links 20 neonatology centres in central Italy, representing the submitting nodes that transmit patient clinical histories and the relevant photographical documentation to the software, which is password-protected. Accepted cases appropriate for the RDDR are reviewed by the RDDR's dysmorphology experts who, through a forum section, provide diagnostic suggestions and recommendations for further investigation and patient management. Their remarks are summarised in clinical expert reports and sent to the submitting nodes. The results of the first 22 submitted cases are reviewed in this paper. The RDDR was developed on the basis of a related European tool, Dyscerne, a network of centres of expertise for dysmorphology

Nonsyndromic pulmonary valve stenosis and the PTPN11 gene

[No abstract available

NF1 gene analysis based on DHPLC.

The high mutation rate at the NF1 locus results in a wide range of molecular abnormalities. The majority of these mutations are private and rare, generating elevated allelic diversity with a restricted number of recurrent mutations. In this study, we have assessed the efficacy of denaturing high-performance liquid chromatography (DHPLC), for detecting mutation in the NF1 gene. DHPLC is a fast and highly sensitive technique based on the detection of heteroduplexes in PCR products by ion pair reverse-phase HPLC under partially denaturing conditions. We established theoretical conditions for DHPLC analysis of all coding exons and splice junctions of the NF1 gene using the WAVEmaker software version 4.1.40 and screened for mutations a panel of 40 unrelated NF1 patients (25 sporadic and 15 familial), genetically uncharacterized. Disruptive mutations were identified in 29 individuals with an overall mutation detection rate of 72.5%. The mutations included eight deletions (exons 4b, 7, 10a, 14, 26, and 31), one insertion (exon 8), nine nonsense mutation (exons 10a, 13, 23.1, 27a, 29, 31, and 36), six missense mutations (exons 15, 16, 17, 24, and 31), four splice errors (exons 11, 14, 36, and 40) and a complex rearrangement within exon 16. Eighteen (62%) of the identified disruptive mutations are novel. Seven unclassified and three previously reported polymorphisms were also detected. None of the missense mutations identified in this study were found after screening of 150 controls. Our results suggest that DHPLC provides an accurate method for the rapid identification of NF1 mutations. Copyright 2003 Wiley-Liss, Inc