Phenotypic and molecular assessment of seven patients with 6p25 deletion syndrome: Relevance to ocular dysgenesis and hearing impairment

BACKGROUND: Thirty-nine patients have been described with deletions involving chromosome 6p25. However, relatively few of these deletions have had molecular characterization. Common phenotypes of 6p25 deletion syndrome patients include hydrocephalus, hearing loss, and ocular, craniofacial, skeletal, cardiac, and renal malformations. Molecular characterization of deletions can identify genes that are responsible for these phenotypes. METHODS: We report the clinical phenotype of seven patients with terminal deletions of chromosome 6p25 and compare them to previously reported patients. Molecular characterization of the deletions was performed using polymorphic marker analysis to determine the extents of the deletions in these seven 6p25 deletion syndrome patients. RESULTS: Our results, and previous data, show that ocular dysgenesis and hearing impairment are the two most highly penetrant phenotypes of the 6p25 deletion syndrome. While deletion of the forkhead box C1 gene (FOXC1) probably underlies the ocular dysgenesis, no gene in this region is known to be involved in hearing impairment. CONCLUSIONS: Ocular dysgenesis and hearing impairment are the two most common phenotypes of 6p25 deletion syndrome. We conclude that a locus for dominant hearing loss is present at 6p25 and that this locus is restricted to a region distal to D6S1617. Molecular characterization of more 6p25 deletion patients will aid in refinement of this locus and the identification of a gene involved in dominant hearing loss

Mastectomy versus radiotherapy as treatment for stage I-II breast cancer: A prospective randomized trial at the National Cancer Institute

In 1979, the National Cancer Institute in Bethesda, Maryland initiated a randomized, prospective trial to compare surgery versus radiation therapy in the treatment of stages I and II breast cancer. Surgical treatment consists of total mastectomy with axillary lymph node dissection (modified radical mastectomy) and breast reconstruction; radiation treatment consists of gross tumor excision, axillary lymph node dissection, and comprehensive irradiation including a boost dose to the tumor bed. All patients with pathologically positive axillary nodes receive 11 cycles of adjuvant Adriamycin ® /Cytoxan ® chemotherapy. As of December 1984, there have been 175 patients entered in the study. Twenty-three patients have developed disease recurrence (12 mastectomy, 11 radiation), but it is too early to obtain definitive treatment-related results. En 1979 l'Institut National du Cancer de Bethesda a lancé une étude prospective randomisée permettant de comparer les résultats respectifs de la chirurgie et de la radiothérapie en ce qui concerne les stades I et II du cancer du sein. Le traitement chirurgical consiste en la mastectomie totale complétée par le curage ganglionnaire axillaire (mastectomie totale modifiée); le traitement dit radiothérapique consiste en l'exérèse large de la tumeur associée au curage ganglionnaire axillaire et à l'administration d'une dose élevée de rayons au niveau du lit tumoral. Toutes les opérées dont les ganglions sont envahis reçoivent en outre 11 cycles d'une combinaison d'Adriamycine et Cytoxan. De 1979 à Décembre 1984, 175 malades ont fait l'objet de cette étude. Vingt-trois ont accusé une récidive (12 après mastectomie et 11 après traitement dit radiothérapique) mais il est encore trop tôt pour tirer des conclusions définitives de ces résultats. El Instituto Nacional de Cáncer de Bethesda inició en 1979 un ensayo prospectivo y aleatorio orientado a comparar el tratamiento quirúrgico versus radioterapia en el manejo del cáncer mamario en estados I y II. El tratamiento quirúrgico consistió de mastectomía total con disección ganglionar axilar (mastectomía radical modificada) y reconstrucción mamaria; el manejo radioterapéutico consistió de resección del tumor, disección de los ganglios linfáticos axilares e irradiación comprensiva incluyendo una dosis de refuerzo al lecho tumoral. Todos los pacientes con ganglios axilares histológicamente positivos recibieron 11 ciclos de quimioterapia adyuvante con Adriamicina/Citoxán. Hasta diciembre de 1984, 175 pacientes habían entrado al estudio. Veintitrés pacientes han desarrollado recurrencia de la enfermedad (12 mastectomía, 11 irradiación), pero es todavía muy temprano para derivar resultados definitivos.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41319/1/268_2005_Article_BF01655179.pd

Fifteen years of research on oral–facial–digital syndromes: from 1 to 16 causal genes

Oral–facial–digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231 and WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype

supravalvular Aortic Stenosis. Autosomal Dominant Form of Congenital Cardiopathy

We describe a family in which two generations are affected: two brothers and one of their maternal uncles. One of their two half-sisters (same mother) is also suspected of having the same cardiopathy. This observation confirms the autosomal dominant transmission of the disease and shows its variable expressivity in the family under study

Surrogate Model Based on the POD Combined With the RBF Interpolation of Nonlinear Magnetostatic FE Model

International audienceThe Proper Orthogonal Decomposition (POD) is an interesting approach to compress into a reduced basis numerous solutions obtained from a parametrized Finite Element (FE) model. In order to obtain a fast approximation of a FE solution, the POD can be combined with an interpolation method based on Radial Basis Functions (RBF) to interpolate the coordinates of the solution into the reduced basis. In this paper, this POD-RBF approach is applied to a nonlinear magnetostatic problem and is used with a single phase transformer and a three-phase inductance