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PubMed | Seattle Childrens Hospital, University of Antwerp, Sophia Genetics, Pediatrics and Medical Genetics and 28 more.
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2016

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.


PubMed | St George's, University of London, Great Ormond Street Hospital, University of Tromsø, Istanbul University and 26 more.
Type: Journal Article | Journal: Journal of medical genetics | Year: 2014

Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing.Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as NIPBL-like. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases.Future diagnostic testing in mutation-negative CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.


News Article | December 12, 2016
Site: www.eurekalert.org

Media Invited to register now to attend the American College of Medical Genetics and Genomics Annual Clinical Genetics Meeting, March 21-25, 2017 in Phoenix, AZ Named one of the fastest growing meetings in the USA by the Trade Show Executive Magazine, the ACMG Annual Clinical Genetics Meeting continues to provide the genetics community with groundbreaking education and research. Join genetics professionals from around the world March 21-25,2017 in Phoenix for the opportunity to learn more about the rapidly evolving genetics and genomics field. Connect with doctors, laboratory professionals, and genetic counselors to hear firsthand about advances in medical genetics. The meeting's focus is on the clinical practice of genetics and genomics in healthcare today and in the future. It provides attendees with the knowledge they need to apply genetics and genomics into their medical practice. From CRISPR to Care Models for Patients with Secondary Findings - the ACMG Meeting continues to provide genetics professionals with insightful information, resources, and tools for best healthcare practices. Due to the diverse range of topics and sessions, all meeting attendees will find a meeting session of interest. Topics range from common conditions to rare diseases and from ethical to technological issues. Whether you are interested in learning more about how clinical geneticists are approaching challenging diagnostic dilemmas or curious to see the newest technology in the field, there will be something for everyone at the ACMG Meeting. To give you an idea of the ACMG Meeting schedule, please see below. To see the complete program please visit http://www. to learn more. Note - Photo/TV Opportunity: The ACMG Foundation for Genetic and Genomic Medicine will present bicycles to local children with rare genetic diseases at the Annual Day of Caring during the meeting on Friday, March 24th from 10:30 AM - 11:00 AM at the Phoenix Convention Center. Credentialed media representatives on assignment are invited to attend the ACMG Annual Meeting on a complimentary basis. Contact Kathy Ridgely Beal, MBA at kbeal@acmg.net for the Press Registration Access Code. Social Media for the 2017 ACMG Annual Meeting: As the ACMG Meeting approaches, journalists can stay up-to-date on new sessions and information by following the ACMG Social Media pages on Facebook and Twitter and by using the NEW Twitter hashtag #ACMGMtg17 for Meeting-related tweets. About the American College of Medical Genetics and Genomics (ACMG) and ACMG Foundation Founded in 1991, ACMG is the only nationally recognized medical society dedicated to improving health through the clinical practice of medical genetics and genomics. The American College of Medical Genetics and Genomics provides education, resources and a voice for nearly 2000 biochemical, clinical, cytogenetic, medical and molecular geneticists, genetic counselors and other healthcare professionals, nearly 80% of whom are board certified in the medical genetics specialties. The College's mission is to develop and sustain genetic initiatives in clinical and laboratory practice, education and advocacy. Three guiding pillars underpin ACMG's work: 1) Clinical and Laboratory Practice: Establish the paradigm of genomic medicine by issuing statements and evidence-based or expert clinical and laboratory practice guidelines and through descriptions of best practices for the delivery of genomic medicine. 2) Education: Provide education and tools for medical geneticists, other health professionals and the public and grow the genetics workforce. 3) Advocacy: Work with policymakers and payers to support the responsible application of genomics in medical practice. Genetics in Medicine, published monthly, is the official ACMG peer-reviewed journal. ACMG's website offers a variety of resources including Policy Statements, Practice Guidelines, Educational Resources, and a Find a Geneticist tool. The educational and public health programs of the American College of Medical Genetics and Genomics are dependent upon charitable gifts from corporations, foundations, and individuals through the ACMG Foundation for Genetic and Genomic Medicine.


Bacigaluppi S.,IRCCS Azienda Ospedaliero | Piccinelli M.,Emory University | Antiga L.,Mario Negri Institute for Pharmacological Research | Veneziani A.,Emory University | And 10 more authors.
Neurosurgical Review | Year: 2014

Unruptured intracranial aneurysms represent a decisional challenge. Treatment risks have to be balanced against an unknown probability of rupture. A better understanding of the physiopathology is the basis for a better prediction of the natural history of an individual patient. Knowledge about the possible determining factors arises from a careful comparison between ruptured versus unruptured aneurysms and from the prospective observation and analysis of unbiased series with untreated, unruptured aneurysms. The key point is the correct identification of the determining variables for the fate of a specific aneurysm in a given individual. Thus, the increased knowledge of mechanisms of formation and eventual rupture of aneurysms should provide significant clues to the identification of rupture-prone aneurysms. Factors like structural vessel wall defects, local hemodynamic stress determined also by peculiar geometric configurations, and inflammation as trigger of a wall remodeling are crucial. In this sense the study of genetic modifiers of inflammatory responses together with the computational study of the vessel tree might contribute to identify aneurysms prone to rupture. The aim of this article is to underline the value of a unifying hypothesis that merges the role of geometry, with that of hemodynamics and of genetics as concerns vessel wall structure and inflammatory pathways. © 2013 Springer-Verlag Berlin Heidelberg.


Vetro A.,University of Pavia | Ciccone R.,University of Pavia | Giorda R.,Molecular Biology | Patricelli M.G.,Clinical Genetics | And 4 more authors.
Journal of Medical Genetics | Year: 2011

Background: SOX9 is a widely expressed transcription factor playing several relevant functions during development and essential for testes differentiation. It is considered to be the direct target gene of the protein encoded by SRY and its overexpression in an XX murine gonad can lead to male development in the absence of Sry. Recently, a family was reported with a 178 kb duplication in the gene desert region ending about 500 kb upstream of SOX9 in which 46,XY duplicated persons were completely normal and fertile whereas the 46,XX ones were males who came to clinical attention because of infertility. Methods and results: We report a family with two azoospermic brothers, both 46,XX, SRY negative, having a 96 kb triplication 500 kb upstream of SOX9. Both subjects have been analyzed trough oligonucleotide array-CGH and the triplication was confirmed and characterised through qPCR, defining the minimal region of amplification upstream of SOX9 associated with 46,XX infertile males, SRY negative. Conclusions: Our results confirm that even in absence of SRY, complete male differentiation may occur, possibly driven by overexpression of SOX9 in the gonadal ridge, as a consequence of the amplification of a gene desert region. We hypothesize that this region contains gonadal specific long-range regulation elements whose alteration may impair the normal sex development. Our data show that normal XX males, with alteration in copy number or, possibly, in the critical sequence upstream to SOX9 are a new category of infertility inherited in a dominant way with expression limited to the XX background.


Searle C.,Clinical Genetics | Mavrogiannis L.A.,St James's Hospital | Bennett C.P.,Clinical Genetics | Charlton R.S.,St James's Hospital
Genetic Testing and Molecular Biomarkers | Year: 2012

TMC1, a second-tier deafness gene below GJB2, is an appreciable cause of recessive nonsyndromic hearing loss (DFNB7/11) in North Africa, the Middle East, and parts of South Asia. Additionally, a single founder mutation, c.100C>T (p.Arg34X), dominates the TMC1 mutation spectrum. We investigated the frequency of TMC1 c.100C>T in a large set of British Asians with hearing loss, collectively a group with high prevalence of genetic deafness and limited routine clinical testing options beyond GJB2, on a candidate basis. An estimate of 0.21% (95% confidence interval, 0.04%-1.18%) was gained, indicating no significant enrichment in our set. Identification of the common non-GJB2 deafness genes and mutations in British Asian communities would require data from autozygosity mapping and/or massively parallel sequencing of gene panels. © 2012 Mary Ann Liebert, Inc.


PubMed | Clinical Genetics and Neonatal Intensive Care Unit
Type: Journal Article | Journal: Clinical case reports | Year: 2014

We report the case of a premature, very low birth weight, newborn with stigmata of Jeune syndrome, a rare skeletal dysplasia, and marked renal involvement (i.e. remarkable prenatal oligohydramnios, histologic nephronophthisis-like pattern, macroscopic renal cysts, and renal failure), expanding the phenotype consistent with the continuum of syndromic ciliopathies.

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