for Journals by Title or ISSN
for Articles by Keywords
help

Publisher: Elsevier   (Total: 2556 journals)

 A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  

  First | 19 20 21 22 23 24 25 26     

The end of the list has been reached. Please navigate to previous pages.

  First | 19 20 21 22 23 24 25 26     

European Journal of Medical Genetics    [6 followers]  Follow    
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
     ISSN (Print) 1769-7212
     Published by Elsevier Homepage  [2556 journals]   [SJR: 1.029]   [H-I: 32]
  • Mosaicism for c.431_454dup in ARX causes a mild Partington syndrome
           phenotype
    • Abstract: Publication date: Available online 13 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Karen Grønskov , Birgitte Diness , Michelle Stahlhut , Monica Zilmer , Zeynep Tümer , Anne-Marie Bisgaard , Karen Brøndum-Nielsen
      A common in frame duplication in ARX (c.431_454dup24) was found in a five year-old boy who presented with mild Partington syndrome. The duplication was detected by PCR amplification followed by fragment length analysis and was located in exon 2 spanning the two polyalanine tracts commonly seen to expand. Detection of the duplication by DNA sequencing was difficult due to preferential sequencing of the normal allele, demonstrating the superiority of fragment length analysis in mosaic cases. The clinical symptoms were mild to moderate developmental delay with only the hand dystonia to suggest Partington syndrome. This patient is the first male reported to be mosaic for the duplication, and his clinical features are subtle. This study shows that in males with a phenotype of mild Partington syndrome and in heterozygous females fragment length analysis should be preferred over DNA sequencing.


      PubDate: 2014-04-15T16:23:24Z
       
  • Brain Tumors in Turner Syndrome
    • Abstract: Publication date: Available online 13 April 2014
      Source:European Journal of Medical Genetics
      Author(s): George A. Alexiou , Maria Varela , Efthymios Dimitriadis , Amalia Patereli , Vasilios Papadakis , Kalliopi Stefanaki , George Sfakianos , Neofytos Prodromou



      PubDate: 2014-04-15T16:23:24Z
       
  • Genetics of congenital hypogonadotropic hypogonadism in Denmark
    • Abstract: Publication date: Available online 13 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Johanna Tommiska , Johanna Känsäkoski , Peter Christiansen , Niels Jørgensen , Jacob G. Lawaetz , Anders Juul , Taneli Raivio
      Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterized by incomplete/absent puberty caused by deficiency or defective action of gonadotropin-releasing hormone (GnRH). The phenotypic features of patients with CHH vary from genital hypoplasia and absent puberty to reversal of HH later in life. We examined the genetics and clinical features of CHH in Denmark. Forty-one male patients were screened for mutations in KAL1, FGFR1, FGF8, PROK2, PROKR2, GNRHR, TAC3, TACR3, and KISS1R. CHD7 was screened in two patients with hearing loss. In 12 patients, a molecular genetic cause for CHH was found. Four patients had mutations in KAL1 (C105VfsX13, C53X, ex5-8del, R257X), and five in FGFR1 (G97D, R209C, A512V, R646W, and c.1614C>T, (p.I538I), predicted to affect splicing). All 9 had severe HH (cryptorchidism and/or micropenis), and 2 had cleft lip/palate. One patient with a previously reported homozygous R262Q mutation in GNRHR displayed fascinating temporal variation in his phenotype. Two patients with hearing loss had CHD7 mutations (c.7832_7841del (p.K2611MfsX25) and c.2443-2A>C), confirming that CHH patients with CHARGE syndrome –associated features should be screened for mutations in CHD7.


      PubDate: 2014-04-15T16:23:24Z
       
  • Under-recognition of 22q11.2 deletion in adult Chinese patients with
           conotruncal anomalies: implications in transitional care
    • Abstract: Publication date: Available online 8 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Anthony P.Y. Liu , Pak-Cheong Chow , Pamela P.W. Lee , Gary T.K. Mok , Wing-Fai Tang , Elizabeth T. Lau , Stephen T.S. Lam , Kelvin Y. Chan , Anita S.Y. Kan , Adolphus K.T. Chau , Yiu-Fai Cheung , Yu-Lung Lau , Brian H.Y. Chung
      22q11.2 deletion syndrome (22q11.2DS) is a multi-systemic disorder with high phenotypic variability. Underdiagnosis in adults is common and recognition of facial dysmorphic features can be affected by age and ethnicity. This study aims to determine the prevalence of undiagnosed 22q11.2DS in adult Chinese patients with conotruncal anomalies and to delineate their facial dysmorphisms and extra-cardiac manifestations. We recruited consecutively 156 patients with conotruncal anomalies in an adult congenital heart disease (CHD) clinic in Hong Kong and screened for 22q11.2DS using fluorescence-PCR and fluorescence in-situ hybridization. Assessment for dysmorphic features was performed by a cardiologist at initial screening and then by a clinical geneticist upon result disclosure. Clinical photographs were taken and childhood photographs collected. Eighteen patients (11.5%) were diagnosed with 22q11.2DS, translating into 1 previously unrecognized diagnosis of 22q11.2DS in every 10 adult patients with conotruncal anomalies. While dysmorphic features were detected by our clinical geneticist in all patients, only two-thirds were considered dysmorphic by our cardiologist upon first assessment. Evolution of facial dysmorphic features was noted with age. Extra-cardiac manifestations included velopharyngeal incompetence or cleft palate (44%), hypocalcemia (39%), neurodevelopmental anomalies (33%), thrombocytopenia (28%), psychiatric disorders (17%), epilepsy (17%) and hearing loss (17%). We conclude that under-diagnosis of 22q11.2DS in Chinese adults with conotruncal defects is common and facial dysmorphic features may not be reliably recognized in the setting of adult CHD clinic, referral for genetic evaluation and molecular testing for 22q11.2DS should be offered to patients with conotruncal defects.


      PubDate: 2014-04-10T16:16:32Z
       
  • A Newly Recognized Syndrome of Severe Growth Deficiency, Microcephaly,
           Intellectual Disability, and Characteristic Facial Features
    • Abstract: Publication date: Available online 5 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Chana Vinkler , Esther Leshinsky-Silver , Marina Michelson , Dorothea Haas , Tally Lerman-Sagie , Dorit Lev
      Genetic syndromes with proportionate severe short stature are rare. We describe two sisters born to nonconsanguineous parents with severe linear growth retardation, poor weight gain, microcephaly, characteristic facial features, cutaneous syndactyly of the toes, high myopia, and severe intellectual disability. During infancy and early childhood, the girls had transient hepatosplenomegaly and low blood cholesterol levels that normalized later. A thorough evaluation including metabolic studies, radiological, and genetic investigations were all normal. Cholesterol metabolism and transport were studied and no definitive abnormality was found. No clinical deterioration was observed and no metabolic crises were reported. After due consideration of other known hereditary causes of post-natal severe linear growth retardation, microcephaly, and intellectual disability, we propose that this condition represents a newly recognized autosomal recessive multiple congenital anomaly-intellectual disability syndrome.


      PubDate: 2014-04-10T16:16:32Z
       
  • Methylation Analysis In Tongue Tissue Of Bws Patients Identifies The
           (EPI)Genetic Cause In 3 Patients With Normal Methylation Levels In Blood
    • Abstract: Publication date: Available online 2 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Mariëlle Alders , Saskia M. Maas , Daniël J.M. Kadouch , Karin van der Lip , Jet Bliek , Chantal M.A.M. van der Horst , Marcel M.A.M. Mannens
      The Beckwith-Wiedemann syndrome is caused by disturbed imprinting of genes at 11p15.5. Routine diagnostic testing for Beckwith-Wiedemann syndrome (BWS) includes methylation analysis of the imprinting centers ICR1 and ICR2 in DNA extracted from lymphocytes. In approximately 15% of BWS patients the diagnosis cannot be molecularly confirmed. In this study we determined the methylation status in resected tongue tissue of 11 BWS patients and compared this to the genetic defects found by routine diagnostic screening of blood lymphocytes. In all three patients with normal methylation levels in blood, aberrant methylation patterns were found in tongue tissue. In two patients a UPD was detected and the third case had hypermethylation of ICR1. This result shows that tissue specific mosaic (epi)genetic changes, not present in blood, is the underlying defect in at least a subset of BWS patients without a molecular diagnosis after standard genetic testing.


      PubDate: 2014-04-05T11:18:13Z
       
  • A Novel Homozygous Mutation In ALS2 Gene In Four Siblings With
           Infantile-Onset Ascending Hereditary Spastic Paralysis
    • Abstract: Publication date: Available online 3 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Hatice Koçak Eker , Süleyman Ersin Ünlü , Fatema Al-Salmi , Andrew H. Crosby
      Autosomal recessive early onset forms of motor neuron disorders including infantile-onset ascending hereditary spastic paraplegia (OMIM #607225) are due to homozygous mutations in the ALS2 gene. Here, we report on a novel splice-site mutation of the ALS2 (c.2351+2C>A) in four children of a consanguineous union with infantile-onset ascending hereditary spastic paraplegia.


      PubDate: 2014-04-05T11:18:13Z
       
  • Mosaicism for maternal uniparental disomy 15 in a boy with some clinical
           features of Prader-Willi syndrome
    • Abstract: Publication date: Available online 2 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Olga Žilina , Tiina Kahre , Inga Talvik , Eve Õiglane-Shlik , Vallo Tillmann , Katrin Õunap
      Prader-Willi syndrome (PWS) is caused by the lack of paternal expression of imprinted genes in the human chromosomal region 15q11.2-q13.2, which can be due to an interstitial deletion at 15q11.2-q13 of paternal origin (65-75%), maternal uniparental disomy (matUPD) of chromosome 15 (20-30%), or an imprinting defect (1-3%). The majority of PWS-associated matUPD15 cases represent a complete heterodisomy of chromosome 15 or a mixture of hetero- and isodisomic regions across the chromosome 15. Pure maternal isodisomy is observed in only a few matUPD15 patients. Here we report a case of an 18-year-old boy with some clinical features of Prader-Willi syndrome, such as overweight, muscular hypotonia, facial dysmorphism and psychiatric problems, but there was no reason to suspect PWS in the patient based solely on the phenotype estimation. However, chromosomal microarray analysis (CMA) revealed mosaic loss of heterozygosity of the entire chromosome 15. Methylation-specific multiplex ligation-dependant probe amplification (MS-MLPA) analysis showed hypermethylation of the SNRPN and NDN genes in the PWS/AS critical region of chromosome 15 in this patient. Taking into consideration the MS-MLPA results and the presence of PWS features in the patient, we concluded that it was matUPD15, although the patient’s parents were not enrolled in the study. According to CMA and karyotyping, no trisomic or monosomic cells were present. To the best of our knowledge, only two PWS cases with mosaic maternal isodisomy 15 and without trisomic/monosomic cell lines have been reported so far.


      PubDate: 2014-04-05T11:18:13Z
       
  • Arthrogryposis (Multiple Congenital Contractures): Diagnostic Approach to
           Etiology, Classification, Genetics, and General Principles
    • Abstract: Publication date: Available online 3 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Judith G. Hall
      Arthrogryposis has been the term used to describe multiple congenital contractures for over a century. It is a descriptive term and present in over 400 specific conditions. Responsible gene abnormalities have been found for more than 150 specific types of arthrogryposis. Decreased fetal movement is present in all affected individuals which leads to a variety of secondary deformations. Decreased fetal movement (fetal akinesia) is associated with increased connective tissue around the immobilized joint, skin dimpling overlying the immobilized joint, disuse atrophy of the muscles that mobilize the joint and abnormal surface of the joint depending on the immobilized position. Other frequently observed features include: micrognathia, mildly shortened limbs, intrauterine growth restriction, pulmonary hypoplasia and short and/or immature gut. Primary etiologies include neuropathic processes; myopathic processes; end-plate abnormalities; maternal illness, trauma and drugs; limitation of fetal space; vascular compromise; and metabolic disorders to the developing embryo/fetus.


      PubDate: 2014-04-05T11:18:13Z
       
  • SOX9 Dimerization Domain Mutation Mimicking Type 2 Collagen Disorder
           Phenotype
    • Abstract: Publication date: Available online 3 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Toshiki Takenouchi , Yohei Matsuzaki , Kazuka Yamamoto , Keisuke Kosaki , Chiharu Torii , Takao Takahashi , Kenjiro Kosaki
      The classification of bone dysplasia has relied on a clinical/radiographic interpretation and the identification of specific genetic alterations. The clinical presentation of the SOX9 mutation and type 2 collagen disorders overlap with the Pierre-Robin sequence and talipes equinovarus, but the former is often accompanied by the bent long bones. In its milder form, the SOX9 mutation is not necessarily associated with the bent long bones. Here, we report a patient with the Pierre-Robin sequence and talipes equinovarus who did not exhibit either bent long bones or scapular hypoplasia; thus, this patient was instead classified as having a type 2 collagen disorder. Despite this phenotypic presentation, the proposita was found to have a de novo SOX9 mutation. The peculiar location of the mutation within the dimerization domain might account for the relatively mild phenotypic effect of the SOX9 mutation to a degree that is compatible with a clinical diagnosis of type 2 collagen disorder, except for a developmental delay. We concluded that mutations in SOX9 can mimic a type 2 collagen disorder-like phenotype.


      PubDate: 2014-04-05T11:18:13Z
       
  • Cranio facial bony defect with developmental abnormality of facial bones,
           dental malalignment and ectopic neural tissue in the internal auditory
           meati - a new syndrome'
    • Abstract: Publication date: Available online 4 April 2014
      Source:European Journal of Medical Genetics
      Author(s): G.C. Colleran , R. Hayes , G. Kearns , P. Kavanagh , E. Moylett , S.A. Lynch
      We present a previously undescribed skeletal dysplasia with dental anomalies and ectopic neural tissue in the internal auditory meati.


      PubDate: 2014-04-05T11:18:13Z
       
  • Turner syndrome and meningioma: Support for a possible increased risk of
           neoplasia in Turner syndrome
    • Abstract: Publication date: Available online 25 March 2014
      Source:European Journal of Medical Genetics
      Author(s): Danielle B. Pier , Fabio P. Nunes , Scott R. Plotkin , Anat O. Stemmer-Rachamimov , James C. Kim , Helen A. Shih , Priscilla Brastianos , Angela E. Lin
      Neoplasia is uncommon in Turner syndrome, although there is some evidence that brain tumors are more common in Turner syndrome patients than in the general population. We describe a woman with Turner syndrome (45,X) with a meningioma, in whom a second neoplasia, basal cell carcinomas of the scalp and nose, developed five years later in the absence of therapeutic radiation. Together with 7 cases of Turner syndrome with meningioma from a population-based survey in the United Kingdom, and 3 other isolated cases in the literature, we review this small number of patients for evidence of risk factors related to Turner syndrome, such as associated structural anomalies or prior treatment. We performed histological and fluorescent in situ hybridization (FISH) of 22q (NF2 locus) analyses of the meningeal tumor to search for possible molecular determinants. We are not able to prove causation between these two entities, but suggest that neoplasia may be a rare associated medical problem in Turner syndrome. Additional case reports and extension of population-based studies are needed.


      PubDate: 2014-03-26T12:15:36Z
       
  • Birth Defects Epidemiology
    • Abstract: Publication date: Available online 19 March 2014
      Source:European Journal of Medical Genetics
      Author(s): Suzan L. Carmichael
      This article provides background information about epidemiologic methods and how they can be used to further our understanding of what causes birth defects. It briefly describes basic study designs and advantages and disadvantages of each, provides examples of how epidemiologic studies contribute to our current understanding of the etiologies of birth defects, and makes recommendations for future research.


      PubDate: 2014-03-21T12:15:37Z
       
  • Microdeletion of 1p32-p31 involving NFIA in a Patient with Hypoplastic
           Corpus Callosum, Ventriculomegaly, Seizures and Urinary Tract Defects
    • Abstract: Publication date: Available online 18 March 2014
      Source:European Journal of Medical Genetics
      Author(s): Jianling Ji , Noriko Salamon , Fabiola Quintero-Rivera



      PubDate: 2014-03-21T12:15:37Z
       
  • Review of Genetic and Environmental Factors Leading to Hypospadias
    • Abstract: Publication date: Available online 21 March 2014
      Source:European Journal of Medical Genetics
      Author(s): Erin M. Shih , John M. Graham Jr.
      Hypospadias is one of the most common congenital malformations, affecting about 4-6 males per 1,000 male births, and ranging in severity from a urethral meatus that is slightly off-center to a meatus in the perineal area. Over the past three decades its prevalence may have increased due to changes in reporting of mild cases and/or increased survival of low birth weight infants due to improved neonatal care. However, despite the increasing numbers of males with hypospadias, the overall etiology remains unclear and likely multifactorial in nature. The purpose of this review article is to provide a comprehensive overview of the various factors implicated in hypospadias etiology, including genetic and environmental factors. In addition, we list syndromes in which hypospadias is a relatively common association and delineate the areas that require further investigation in an effort to understand this condition.


      PubDate: 2014-03-21T12:15:37Z
       
  • Variable levels of tissue mosaicism can confound the interpretation of
           chromosomal microarray results from peripheral blood
    • Abstract: Publication date: Available online 15 March 2014
      Source:European Journal of Medical Genetics
      Author(s): Chandni V. Pal , Tanya N. Eble , Weimin Bi , Ankita Patel , Luis M. Franco
      Chromosomal microarray analysis (CMA) has significantly increased the ability to diagnose medical conditions caused by copy-number variation in the human genome. Given that the regions involved in copy-number abnormalities often encompass multiple genes, it has been common practice in recent years to compare the phenotypes of individuals with specific copy-number alterations identified by CMA, with the goal of identifying the critical regions for particular elements of a disease phenotype. It is rarely mentioned that this practice relies heavily on the assumption that the absence of mosaicism on CMA from a peripheral blood sample (the most common source of DNA in current clinical practice) reflects the absence of mosaicism in other tissues. We report here a case that violates that assumption. A 28-year-old male with Charcot-Marie-Tooth disease was found by CMA to have a duplication of 17p12 along with two other abnormalities: A duplication of 12p13.33 translocated to the long arm of chromosome 3 and an interstitial duplication of 12p11.23. The patient did not have any clinical features suggestive of 12p duplication syndrome. Chromosomal microarray analysis on skin fibroblasts revealed the duplications at 17p12 and 12p11.23, but not the terminal duplication of 12p13.33. FISH analysis on skin fibroblasts confirmed the presence of very low levels of mosaicism for the terminal 12p duplication. The case illustrates how the absence of mosaicism in blood is not always indicative of the absence of mosaicism in other tissues. Even in an era of high-throughput, highly accurate DNA-based tests, it is important to remember the limitations of testing before drawing conclusions about the relationship between a test results and a clinical phenotype.


      PubDate: 2014-03-16T12:15:49Z
       
  • Twins with hereditary sensory and autonomic neuropathy type IV with
           preserved periodontal sensation
    • Abstract: Publication date: Available online 12 March 2014
      Source:European Journal of Medical Genetics
      Author(s): Yeliz Guven , Umut Altunoglu , Oya Aktoren , Zehra Oya Uyguner , Hulya Kayserili , Massupa Kaewkahya , Piranit Nik Kantaputra
      Turkish twin brothers affected with hereditary sensory and autonomic neuropathy type IV (HSAN IV) are reported. Their clinical findings were generally typical for HSAN IV. Interestingly they both had preserved periodontal sensation. Mutation analysis of the NTRK1 gene showed a homozygous c.2001C>T substitution in exon 15 in both twins. This base substitution is predicted to change a polar, positively charged amino acid arginine to the highly active amino acid cystein at position 654 (p.Arg654Cys). The parents were heterozygous for the mutation. This mutation has been reported previously in one Japanese and one Arab patients. The preserved periodontal sensation has not previously been reported in patients affected with HSAN IV. This preserved sensation in our patients might have been through Ruffini endings, the periodontal mechanoreceptors which have been reported to be present in TrkA knockout mice. Here we report the first twins affected with HSAN IV and the observation that periodontal sensation is not affected by mutation in NTRK1.


      PubDate: 2014-03-16T12:15:49Z
       
  • A maternal de novo non-reciprocal translocation results in a 6q13-q16
           deletion in one offspring and a 6q13-q16 duplication in another
    • Abstract: Publication date: Available online 12 March 2014
      Source:European Journal of Medical Genetics
      Author(s): Christian Wentzel , Göran Annerén , Ann-Charlotte Thuresson
      Here we report a case of two siblings with reciprocal aberrations, one presenting with a deletion and the other carrying two novel duplications at 6q13q16.1. Interestingly, both alterations were inherited from a healthy mother carrying a non-reciprocal translocation of 6q13q16 to 15q11. Deletions at 6q13q16.1 have been previously described; however this is the first characterisation of a 6q13q16.1 duplication. In this report we provide a comprehensive molecular and phenotypical characterisation of the affected siblings and discuss the profiles of previously identified patients carrying 6q deletions.


      PubDate: 2014-03-16T12:15:49Z
       
  • Is there a link between ovarian cancer and tooth agenesis'
    • Abstract: Publication date: Available online 12 March 2014
      Source:European Journal of Medical Genetics
      Author(s): John Bonds , Sarah Pollan-White , Lilin Xiang , Gabriele Mues , Rena D'Souza
      An epidemiologic study from the year 2008 found a highly significant increase of congenital tooth agenesis in women with ovarian cancer suggesting that a common genetic etiology may predispose women to both conditions. The finding was reminiscent of a previously described family harboring an AXIN2 mutation which could be shown to segregate with both the tooth agenesis and the predisposition to colon cancer transmitted in this family. Since tooth agenesis as a marker for susceptibility to ovarian cancer would be of great relevance to both oncologists and women with inborn missing teeth, the relationship between the two disorders requires a thorough assessment. We examined DNA samples from the ovarian cancer patients who participated in the original study, to look for a possible genetic connection between their ovarian malignancies and tooth agenesis. MSX1, PAX9, AXIN2, EDA, WNT10A, BARX and BRCA1 genes were selected for sequence analysis as they may cause tooth agenesis, are expressed in the female reproductive system, and/or are involved in tumorigenesis in general or specifically in the ovary. Our study revealed evidence that one half of the dually affected patients had an independent causation of the two conditions, thus reducing the previously estimated ovarian cancer risk for women with congenital tooth agenesis quite significantly.


      PubDate: 2014-03-16T12:15:49Z
       
  • Neonatal progeroid variant of Marfan syndrome with congenital
           lipodystrophy results from mutations at the 3’ end of FBN1 gene
    • Abstract: Publication date: Available online 6 March 2014
      Source:European Journal of Medical Genetics
      Author(s): Adeline Jacquinet , Alain Verloes , Bert Callewaert , Christine Coremans , Paul Coucke , Anne de Paepe , Uwe Kornak , Frederic Lebrun , Jacques Lombet , Gérald E. Piérard , Peter N. Robinson , Sofie Symoens , Lionel Van Maldergem , François-Guillaume Debray
      We report a 16-year-old girl with neonatal progeroid features and congenital lipodystrophy who was considered at birth as a possible variant of Wiedemann-Rautenstrauch syndrome. The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb) lead to consider the diagnosis of the progeroid variant of Marfan syndrome. A de novo donor splice-site mutation (c.8226+1G>A) was identified in FBN1. We show that this mutation leads to exon 64 skipping and to the production of a stable mRNA that should allow synthesis of a truncated profibrillin-1, in which the C-terminal furin cleavage site is altered. FBN1 mutations associated with a similar phenotype have only been reported in four other patients. We confirm the correlation between marfanoid phenotype with congenital lipodystrophy and neonatal progeroid features (marfanoid-progeroid-lipodystrophy syndrome) and frameshift mutations at the 3’ end of FBN1. This syndrome should be considered in differential diagnosis of neonatal progeroid syndromes.


      PubDate: 2014-03-06T12:15:01Z
       
  • A new Turkish infant with clinical features of CS/CISS1 syndrome and
           homozygous CRLF1 mutation
    • Abstract: Publication date: Available online 5 March 2014
      Source:European Journal of Medical Genetics
      Author(s): Stephanie Moortgat , Valérie Benoit , Marie Deprez , Anne Charon , Isabelle Maystadt
      Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder characterized by profuse sweating at cold environmental temperatures, facial dysmorphism and skeletal features. The infantile presentation of CISS, referred to as Crisponi syndrome (CS), is characterized by facial muscular contractures in response to slight tactile stimuli or during crying, by life-threatening feeding difficulties caused by suck and swallow inabilities, and by intermittent hyperthermia. High febrile crises can lead to death within the first months of life. In preadolescence, surviving patients develop kyphoscoliosis and abnormal sweating. CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 in more than 90 percent of patients (CISS1) and by mutations in CLCF1 in the remaining patients (CISS2). It is now well demonstrated that all patients with an infantile-onset CS will develop CISS, confirming that CS and CISS are not “allelic disorders” but the same clinical entity described at different ages of affected patients. Here we report on a Turkish patient with a phenotype consistent with CS/CISS1 and a nonsense homozygous mutation (c.829C>T, p.R277X) in the CRLF1 gene. This mutation has already been reported in another Turkish patient with CS/CISS1.


      PubDate: 2014-03-06T12:15:01Z
       
  • Next-generation sequencing (NGS) as a fast molecular diagnosis tool for
           Left Ventricular Noncompaction in an infant with compound mutations in the
           MYBPC3 gene
    • Abstract: Publication date: Available online 3 March 2014
      Source:European Journal of Medical Genetics
      Author(s): Elise Schaefer , Pauline Helms , Luc Marcellin , Philippe Desprez , Philippe Billaud , Valérie Chanavat , Robert Rousson , Gilles Millat
      Left ventricular noncompaction (LVNC) is a clinically heterogeneous disorder characterized by a trabecular meshwork and deep intertrabecular myocardial recesses that communicate with the left ventricular cavity. LVNC is classified as a rare genetic cardiomyopathy. Molecular diagnosis is a challenge for the medical community as the condition shares morphologic features of hypertrophic and dilated cardiomyopathies. Several genetic causes of LVNC have been reported, with variable modes of inheritance, including autosomal dominant and X-linked inheritance, but relatively few responsible genes have been identified. In this report, we describe a case of a severe form of LVNC leading to death at 6 months of life. NGS sequencing using a custom design for hypertrophic cardiomyopathy panel allowed us to identify compound heterozygosity in the MYBPC3 gene (p.Lys505del, p.Pro955fs) in 3 days, confirming NGS sequencing as a fast molecular diagnosis tool. Other studies have reported neonatal presentation of cardiomyopathies associated with compound heterozygous or homozygous MYBPC3 mutations. In this family and in families in which parental truncating MYBPC3 mutations are identified, preimplantation or prenatal genetic screening should be considered as these genotypes leads to neonatal mortality and morbidity.


      PubDate: 2014-03-06T12:15:01Z
       
  • Novel SOST gene mutation in a sclerosteosis patient from Morocco:
           A case report
    • Abstract: Publication date: Available online 1 March 2014
      Source:European Journal of Medical Genetics
      Author(s): Mohamed Reda Belkhribchia , Corinne Collet , Jean-Louis Laplanche , Redouane Hassani
      Sclerosteosis (OMIM 269500) is a rare autosomal recessive condition characterized by increased bone density associated with syndactyly. It is linked to a genetic defect in the SOST gene coding for sclerostin. So far, seven different loss-of-function mutations in SOST have been reported in patients with sclerosteosis. Recently, two mutations in LRP4 gene underlying sclerosteosis were identified, reflecting the genetic heterogeneity of this disease. We report here a 30-years-old Moroccan man presented with typical clinical and radiological features of sclerosteosis who carries a novel homozygous mutation in the SOST gene, characterized as a nonsense mutation (c.79C > T; p.Gln27∗) in exon 1 of the SOST gene. This is to our knowledge the first case of sclerosteosis reported from Morocco and North Africa.


      PubDate: 2014-03-06T12:15:01Z
       
  • Descriptive and risk factor analysis for choanal atresia: The National
           Birth Defects Prevention Study, 1997–2007
    • Abstract: Publication date: Available online 24 February 2014
      Source:European Journal of Medical Genetics
      Author(s): Vijaya Kancherla , Paul A. Romitti , Lixian Sun , John C. Carey , Trudy L. Burns , Anna Maria Siega-Riz , Charlotte M. Druschel , Angela E. Lin , Richard S. Olney
      Choanal atresia causes serious posterior nasal obstruction. This defect is the leading cause of nasal surgery in newborns, although its etiology is largely unknown. Data from the National Birth Defects Prevention Study, a population-based case–control study, were used to examine associations between maternal self-reports of exposures and occurrence of choanal atresia in their offspring. Overall, 117 case and 8350 control mothers with deliveries from 1997 to 2007 provided telephone interview reports of pre-pregnancy (one year before conception) and periconceptional (one month before through three months after conception) exposures. Exposures analyzed were pre-pregnancy dietary intake, pre-pregnancy and periconceptional caffeine consumption, and periconceptional cigarette smoking, alcohol drinking, and medication use. Independent associations between each exposure and all choanal atresia cases combined (n = 117) and isolated choanal atresia cases (those without additional unrelated major defects; n = 61) were examined. Odds ratios (ORs), both unadjusted (uORs) and adjusted (aORs) for potential confounders, and 95% confidence intervals (CI)s were estimated using unconditional logistic regression analysis. For all choanal atresia cases combined, positive associations were observed with maternal pre-pregnancy intake in the highest quartile for vitamin B-12 (aOR = 1.9; CI = 1.1,3.1), zinc (aOR = 1.7; CI = 1.0,3.1), and niacin (aOR = 1.8; CI = 1.0,3.1), and intake in the lowest quartile for methionine (aOR = 1.6; CI = 1.0,2.6) and vitamin D (aOR = 1.6; CI = 1.0,2.4) compared to intake in the two intermediate quartiles combined. Further, a positive association was observed with periconceptional use of thyroid medications (uOR = 2.6; CI = 1.0,6.3) compared to no use of such medications. Among isolated choanal atresia cases, negative associations were observed for pantothenic acid (aOR = 0.4; CI = 0.2,0.9) and fat (aOR = 0.5; 95% CI = 0.2,1.0) intake in the lowest quartile compared to that in the intermediate quartiles, and positive associations were observed for periconceptional cigarette smoking (aOR = 2.3; CI = 1.1,4.7) compared to no smoking and pre-pregnancy daily coffee intake of 3 or more cups (aOR = 2.5; CI = 1.1,5.6) compared to intake of less than 1 cup per day. The positive association for periconceptional exposure to thyroid medications also persisted for isolated choanal atresia cases (uOR = 4.0; CI = 1.1,11.2). Because of the large number of associations tested, these findings may be due to chance. Alternatively, they may contribute new hypotheses regarding the etiology of choanal atresia; thus, requiring replication in additional studies.


      PubDate: 2014-03-01T07:31:45Z
       
  • Presenting symptoms in adults with the 22q11 deletion syndrome
    • Abstract: Publication date: Available online 24 February 2014
      Source:European Journal of Medical Genetics
      Author(s): Annick Vogels , Sara Schevenels , Richard Cayenberghs , Eddy Weyts , Griet Van Buggenhout , Ann Swillen , Hilde Van Esch , Thomy de Ravel , Pieter Corveleyn , Koen Devriendt
      A definitive molecular diagnosis of 22q11 Deletion Syndrome (22q11DS) even if occurring later in life, has important genetic, medical and emotional impact on the patients and their families. The aim of this study is to describe presenting symptoms and age at diagnosis in an adult 22q11DS population. A retrospective study was performed on 65 individuals diagnosed with 22q11DS at adult age. Data were collected on adults referred to the genetic clinic or actively recruited through systematic diagnostic examination in both institutions and a psychiatric unit for intellectually disabled. Presenting symptoms were categorized into seven groups: familial occurrence, intellectual disability, cardiac anomalies, palatal anomalies, facial dysmorphic features, psychiatric problems and ‘other’ (comprising all other features associated with 22q11DS). Age at diagnosis was defined as the age at which the 22q11.2 deletion was detected by fluorescence in situ hybridization or comparative genomic hybridization. Ascertainment subgroups were different in presenting symptoms and age at diagnosis. Adults were referred to the genetic clinic mainly because of familial occurrence, cardiac defects and psychiatric disorders whereas adults diagnosed in institutions for intellectually disabled presented mainly with moderate to severe intellectual disability and psychotic disorders. Adults diagnosed at the psychiatric unit for intellectually disabled had a variety of psychiatric disorders but none of them had additional physical features. This emphasizes the need to stay alert for presenting symptoms such as conotruncal heart defects or moderate to severe intellectual disability in combination with a history of psychiatric disorders, even in the absence of obvious physical features.


      PubDate: 2014-03-01T07:31:45Z
       
  • KDM5C mutational screening among males with intellectual disability
           suggestive of X-Linked inheritance and review of the literature
    • Abstract: Publication date: Available online 27 February 2014
      Source:European Journal of Medical Genetics
      Author(s): Thainá Fernandez Gonçalves , Andressa Pereira Gonçalves , Natalia Fintelman Rodrigues , Jussara Mendonça dos Santos , Márcia Mattos Gonçalves Pimentel , Cíntia Barros Santos-Rebouças
      An increasing number of neurodevelopmental diseases have been associated with disruption of chromatin remodeling in eukaryotes. Lysine(K)-specific demethylase 5C (KDM5C) is a versatile epigenetic regulator that removes di- and tri-methyl groups of lysine 4 on histone H3 (H3K4) from transcriptional targets and is essential for neuronal survival and dendritic growth. Mutations in KDM5C gene, located at Xp11.22, have been reported as an important cause of both syndromic and non-syndromic X-linked intellectual disability (XLID) in males. The aim of this study was to evaluate the prevalence and spectrum of KDM5C mutations among Brazilian patients with XLID. To access the impact of KDM5C variants on XLID, a cohort of 143 males with a family history of intellectual disability (ID) suggestive of X-linked inheritance were enrolled. Common genetic causes of XLID were previously excluded and the entire coding and flanking intronic sequences of KDM5C gene were screened by direct Sanger sequencing. Seven nucleotide changes were observed: one pathogenic mutation (c.2172C>A, p.Cys724*), one novel variant with unknown value (c.633G>C, p.Arg211Arg) and five apparently benign sequence changes. In silico analysis of the variants revealed a putative creation of an Exonic Splicing Enhancer sequence by the silent c.633G>C mutation, which co-segregates with the ID phenotype. Our results point out to a KDM5C pathogenic mutational frequency of 0.7% among males with probable XLID. This is the first KDM5C screening among ID males from a country in Latin America and provides new clues about the significance of KDM5C mutations for genetic counseling.


      PubDate: 2014-03-01T07:31:45Z
       
  • Novel De Novo SPOCK1 Mutation in a Proband with Developmental Delay,
           Microcephaly and Agenesis of Corpus Callosum
    • Abstract: Publication date: Available online 27 February 2014
      Source:European Journal of Medical Genetics
      Author(s): Radhika Dhamija , John M. Graham Jr. , Nizar Smaoui , Erik Thorland , Salman Kirmani
      Whole exome sequencing made it possible to identify novel de novo mutations in genes that might be linked to human syndromes (genotype first analysis). We describe a female patient with a novel de novo SPOCK1 variant, which has not been previously been associated with a human phenotype. Her features include intellectual disability with dyspraxia, dysarthria, partial agenesis of corpus callosum, prenatal-onset microcephaly and atrial septal defect with aberrant subclavian artery. Previous genetic, cytogenomic and metabolic studies were unrevealing. At age 13 years, exome sequencing on the patient and her parents revealed a de novo novel missense mutation in SPOCK1 (coding for Testican-1) on chromosome 5q31: c.239A>T (p.D80V). This mutation affects a highly evolutionarily conserved area of the gene, replacing a polar aspartic acid with hydrophobic nonpolar valine, and changing the chemical properties of the protein product, likely representing a pathogenic variant. Previous microdeletions of 5q31 including SPOCK1 have suggested genes on 5q31 as candidates for intellectual disability. No mutations or variants in other genes potentially linked to her phenotype were identified. Testicans are proteoglycans belonging to the BM-40/SPARC/osteonectin family of extracellular calcium-binding proteins. Testican-1 is encoded by the SPOCK1 gene, and mouse models have been shown it to be strongly expressed in the brain and to be involved in neurogenesis. We hypothesize that because this gene function is critical for neurogenesis, mutations could potentially lead to a phenotype with developmental delay and microcephaly.


      PubDate: 2014-03-01T07:31:45Z
       
  • Neuropsychological Impairments in Elderly Neurofibromatosis type 1
           Patients
    • Abstract: Publication date: Available online 18 February 2014
      Source:European Journal of Medical Genetics
      Author(s): Danielle de Souza Costa , Jonas Jardim de Paula , Nilton Alves de Rezende , Luiz Oswaldo Carneiro Rodrigues , Leandro Fernandes Malloy-Diniz , Marco Aurélio Romano-Silva , Débora Marques de Miranda
      Cognitive performance is compromised in Neurofibromatosis type 1 (NF1) patients, but neuropsychological data including elderly NF1 are extremely sparse. We compared the cognitive performance of a small elderly NF1 group (n=5) with an age-matched healthy control group (n=49). NF1 group performed worse than control group on a global cognitive impairment task, verbal working memory, and visuospatial functioning. The results suggest that cognitive impairment is an important feature of NF1 across lifespan, including elderly individuals. Future studies approaching the NF1 cognitive profile might benefit from looking at the mechanisms linked to the age-related aspects of cognitive decline.


      PubDate: 2014-02-19T07:23:00Z
       
  • Implementation of genomic arrays in prenatal diagnosis: the Belgian
           approach to meet the challenges
    • Abstract: Publication date: Available online 15 February 2014
      Source:European Journal of Medical Genetics
      Author(s): Olivier Vanakker , Catheline Vilain , Katrien Janssens , Nathalie Van der Aa , Guillaume Smits , Claude Bandelier , Bettina Blaumeiser , Saskia Bulk , Jean-Hubert Caberg , Anne De Leener , Marjan De Raedemaker , Thomy de Ravel , Julie Desir , Anne Destree , Annelies Dheedene , Stéphane Gaillez , Bernard Grisart , Ann-Cécile Hellin , Sandra Janssens , Kathelijn Keymolen , Björn Menten , Bruno Pichon , Marie Ravoet , Nicole Revencu , Sonia Rombout , Catherine Staessens , Ann Van Den Bogaert , Kris Van Den Bogaert , Joris R. Vermeesch , Frank Kooy , Yves Snajer , Koen Devriendt
      After their successful introduction in postnatal testing, genome-wide arrays are now rapidly replacing conventional karyotyping in prenatal diagnostics. While previous studies have demonstrated the advantages of this method, we are confronted with difficulties regarding the technology and the ethical dilemmas inherent to genomic arrays. These include indication for testing, array design, interpretation of variants and how to deal with variants of unknown significance and incidental findings. The experiences with these issues reported in the literature are most often from single centres. Here, we report on a national consensus approach how microarray is implemented in all genetic centres in Belgium. These recommendations are subjected to constant re-evaluation based on our growing experience and can serve as a useful tool for those involved in prenatal diagnosis.


      PubDate: 2014-02-19T07:23:00Z
       
  • A three-generation family with terminal microdeletion involving 5p15.33-32
           due to a whole-arm 5;15 chromosomal translocation with a steady phenotype
           of atypical cri du chat syndrome
    • Abstract: Publication date: Available online 18 February 2014
      Source:European Journal of Medical Genetics
      Author(s): Amira Elmakky , Diana Carli , Licia Lugli , Paola Torelli , Battista Guidi , Cristina Falcinelli , Sergio Fini , Fabrizio Ferrari , Antonio Percesepe
      Cri du chat syndrome is characterized by cat-like cry, facial dysmorphisms, microcephaly, speech delay, intellectual disability and slow growth rate, which are present with variable frequency. The typical cri du chat syndrome, due to 5p15.2 deletion, includes severe intellectual disability, facial dysmorphisms, neonatal hypotonia and pre- and post-natal growth retardation, whereas more distal deletions in 5p15.3 lead to cat-like cry and speech delay and produce the clinical picture of the atypical cri du chat syndrome, with minimal or absent intellectual impairment. In this article we report a three-generation family with an unbalanced whole arm translocation between chromosome 5 and 15 and a microdeletion of 5,5 Mb involving 5p15.33-32. By reporting the smallest terminal deletion of 5p15.3 described so far and by reviewing the literature we discuss the genotype/phenotype correlations of the distal region of the cri du chat syndrome. The previously described critical region for the speech delay may be narrowed down and microcephaly, growth retardation and dysmorphic facial features can be included in the phenotypic expression of the atypical cri du chat syndrome due to 5p15.3 deletions.


      PubDate: 2014-02-19T07:23:00Z
       
  • Deletion of the entire POU4F3 gene in a familial case of autosomal
           dominant non-syndromic hearing loss
    • Abstract: Publication date: Available online 18 February 2014
      Source:European Journal of Medical Genetics
      Author(s): Érika L. Freitas , Jeanne Oiticica , Amanda G. Silva , Roseli S.M. Bittar , Carla Rosenberg , Regina C. Mingroni-Netto
      In 20% of cases, hereditary non-syndromic hearing loss presents autosomal dominant inheritance (ADNSHL). To date, more than 50 loci for ADNSHL have been mapped to different chromosomal regions. In order to verify whether genomic alterations contribute to the hearing loss etiology and to search for novel deafness candidate locus, we investigated probands from families with ADNSHL by oligonucleotide array-CGH. A deletion in the 5q32 region encompassing only one gene, POU4F3, which corresponds to DFNA15, was detected in one family. POU4F3 protein has an important role in the maturation, differentiation and survival of cochlear hair cells. Defects in these cells may therefore explain sensorineural hearing loss. Mutations in this gene had already been associated with autosomal dominant hearing loss but this is the first description of a germline POUF4F3 deletion associated with hearing impairment.


      PubDate: 2014-02-19T07:23:00Z
       
  • Overlapping microdeletions involving 15q22.2 narrow the critical region
           for intellectual disability to NARG2 and RORA
    • Abstract: Publication date: Available online 11 February 2014
      Source:European Journal of Medical Genetics
      Author(s): Toshiyuki Yamamoto , Maria Antonietta Mencarelli , Chiara Di Marco , Mucciolo Mafalda , Marina Vascotto , Paolo Balestri , Marion Gérard , Michèle Mathieu-Dramard , Joris Andrieux , Martijn Breuning , Mariëtte J.V. Hoffer , Claudia A.L. Ruivenkamp , Shino Shimada , Noriko Sangu , Keiko Shimojima , Ryoji Umezu , Hiroshi Kawame , Mari Matsuo , Kayoko Saito , Alessandra Renieri , Francesca Mari
      Microdeletions in the 15q22 region have not been well documented. We collected genotype and phenotype data from five patients with microdeletions involving 15q22.2, which were between 0.7 Mb and 6.5 Mb in size; two were of de novo origin and one was of familial origin. Intellectual disability and epilepsy are frequently observed in patients with 15q22.2 deletions. Genotype-phenotype correlation analysis narrowed the critical region for such neurologic symptoms to a genomic region of 654 Kb including the NMDA receptor-regulated 2 gene (NARG2) and the PAR-related orphan receptor A gene (RORA), either of which may be responsible for neurological symptoms commonly observed in patients with deletions in this region. The neighboring regions, including the forkhead box B1 gene (FOXB1), may also be related to the additional neurological features observed in the patients with larger deletions.


      PubDate: 2014-02-14T22:22:50Z
       
  • Atypical Alstrom syndrome with novel ALMS1 mutations precluded by current
           diagnostic criteria
    • Abstract: Publication date: Available online 3 February 2014
      Source:European Journal of Medical Genetics
      Author(s): Jillian Casey , Paul McGettigan , Donal Brosnahan , Emma Curtis , Eileen Treacy , Sean Ennis , Sally Ann Lynch
      We report on clinical and genetic studies in a non-consanguineous Irish sib-pair with infantile dilated cardiomyopathy and retinopathy. A diagnosis of Alström Syndrome (AS) was considered and diagnostic testing pursued. The Alströms gene (ALMS1) is very large (23 exons) and diagnostic testing of mutational hotspots (exon 6, 8 and 10) was negative. Furthermore the siblings were tall and did not have the typical phenotype of nystagmus, photophobia, obesity or hearing loss and so the AS diagnosis was removed. We then sought to identify the causative gene in this family using whole exome sequencing. Unexpectedly, the exome analysis identified novel compound heterozygous ALMS1 mutations in exon 5 (c.777delT:p.D260fs*26) and exon 20 (c.12145_12146insC:p.S4049fs*36) that segregated with the phenotype. Although the siblings show some clinical overlap with AS, their phenotype is not classical. It is plausible that their atypical presentation may be due to the location of the ALMS1 mutations outside the usual mutational hotspots. Our findings show how atypical cases of AS may be missed under the current diagnostic guidelines and support consideration of complete ALMS1 sequencing in children with two or more features, even if all of the core clinical features of AS are not present.


      PubDate: 2014-02-05T07:18:42Z
       
  • Report on 3 patients with 12p duplication including GRIN2B
    • Abstract: Publication date: Available online 3 February 2014
      Source:European Journal of Medical Genetics
      Author(s): Celine Poirsier , Emilie Landais , Nathalie Bednarek , Jean-Marie Nobecourt , Maroun Khoury , Pascal Schmidt , Patrice Morville , Nadine Gruson , Sandrine Clomes , Nicole Michel , Anita Riot , Christelle Manjeongean , Dominique Gaillard , Martine Doco Fenzy
      The duplication of the short arm (p) of chromosome 12 is a rare chromosomal abnormality, and most reported cases result from malsegregation of a balanced parental translocation associated with other chromosomal imbalances. Of the reported cases, only 15 involve a pure and complete 12p duplication and only 10 involve a pure and partial duplication overlapping the 12p12.3p13.1 region, including a single instance of an inherited duplication in two related individuals. Here, we report three new patients with a pure 12p duplication, detected by conventional cytogenetic studies and characterized by array-comparative genomic hybridization (array-CGH) and fluorescence in situ hybridization (FISH). The first patient was a child carrying a de novo inverted duplication of the short arm of chromosome 12. His phenotype was similar to that of the “trisomy 12p syndrome”, characterized by developmental delays and craniofacial abnormalities including a high forehead, a short nose with anteverted nostrils and an everted lower lip. The second and third patients were a mother and son with a direct 12p12.3p13.1 duplication, exhibiting a milder phenotype characterized by moderate developmental delays, dysmorphic facial features, behavioral problems and obesity. The present data, including the rarity of the familial cases, should contribute to our knowledge of the genotype/phenotype correlation in trisomy 12p patients.


      PubDate: 2014-02-05T07:18:42Z
       
  • A novel microdeletion involving the 13q31.3-q32.1 region in a patient with
           normal intelligence
    • Abstract: Publication date: Available online 4 February 2014
      Source:European Journal of Medical Genetics
      Author(s): Juan Manuel Valdes-Miranda , Jose Ramon Soto-Alvarez , Jaime Toral-Lopez , Luz González-Huerta , Adrian Perez-Cabrera , Georgina Gonzalez-Monfil , Olga Messina-Bass , Sergio Cuevas-Covarrubias
      Microdeletions of the long arm of chromosome 13 lead to a characteristic facial appearance with systemic affection; 13q deletion shows a wide phenotypic spectrum that varies with respect to the location and size of the deletion region. The main clinical features are mental retardation, growth retardation, craniofacial dysmorphy and various congenital defects. In the present study we describe the case of an adult female of Mexican origin with microcephaly, facial dysmorphism, short stature, hand anomalies and normal intelligence associated with a de novo 13q31.3-q32.1 microdeletion that involved several genes including the MIR17HG and the GPC5 genes.


      PubDate: 2014-02-05T07:18:42Z
       
  • Recent progress in the genetics of motor neuron disease
    • Abstract: Publication date: Available online 4 February 2014
      Source:European Journal of Medical Genetics
      Author(s): Josef Finsterer , Jean-Marc Burgunder
      Background genetic background and pathogenesis of motor neuron diseases (MNDs) have been increasingly elucidated over recent years. Aims to give an overview about publications during the last year concerning the genetic background and phenotypic manifestations of MNDs, such as familial or sporadic amyotrophic lateral sclerosis (fALS, sALS), spinal muscular atrophies (SMA), bulbospinal muscular atrophy (BSMA), and unclassified MNDs. Methods Pubmed search for literature about ALS, SMA, and BSMA for the period 10/2012 to 9/2013. Results an increasing number of mutated genes is recognised in fALS but also sALS patients. Genes mutated in sALS include C9orf72, SOD1, TARDBP, FUS, UBQL2, SQSTM1, DCTN1, and UNC13A. Juvenile (onset <20y) and adult ALS (early onset 20-60y, late onset >60y) are differentiated. Juvenile fALS is most frequently caused by mutations in ALS2, SETX, spatacsin, or Sigmar1 and adult fALS by mutations in C9orf72, SOD1, TARDBP, and FUS. Onset, phenotype, progression, and outcome of ALS are variable between different mutations, different genes, and different countries. Differentiation between sALS and fALS cases becomes artificial. Conclusions further progress has been made over the last year in the clarification and understanding of the etiology and pathogenesis of MNDs. However, further effort is needed to answer the many remaining questions.


      PubDate: 2014-02-05T07:18:42Z
       
  • Postnatal diagnosis of 9q interstitial imbalances involving PTCH1,
           resulting from a familial intrachromosomal insertion
    • Abstract: Publication date: Available online 30 January 2014
      Source:European Journal of Medical Genetics
      Author(s): Marina Blanchard , Christèle Dubourg , Laurent Pasquier , Sylvie Odent , Josette Lucas , Chloé Quélin , Erika Launay , Catherine Henry , Marc-Antoine Belaud-Rotureau , Frédéric Dugay , Sylvie Jaillard
      Insertions are rare chromosomal rearrangements resulting from a three breaks mechanism. The risk of chromosomal imbalance in the offspring is estimated to be 15-50%. We have identified a familial history of direct, paracentric intrachromosomal 9q insertion, balanced in healthy members. For intrachromosomal insertions, unbalanced products in the offspring are always recombinants and in our case, reciprocal deletion and duplication of the inserted segment (9q22.31-9q31.1) were observed. These imbalances involved several genes, including PTCH1. PTCH1 haploinsufficiency causes Gorlin syndrome, an autosomal dominant disorder usually linked to the gene mutation but sometimes due to a 9q deletion. Clinical findings are different in 9q deletions and duplications including PTCH1, notably concerning the predisposition to benign and malignant tumors reported in the Gorlin syndrome. Furthermore, some features may be reciprocal. This history of intrachromosomal insertion highlights the importance of morphological cytogenetic analyses to provide an accurate genetic counseling.


      PubDate: 2014-01-31T22:18:32Z
       
  • A novel missense mutation in CACNA1A evaluated by in silico protein
           modeling is associated with non-episodic spinocerebellar ataxia with slow
           progression
    • Abstract: Publication date: Available online 29 January 2014
      Source:European Journal of Medical Genetics
      Author(s): Katrin Bürk , Frank J. Kaiser , Stephanie Tennstedt , Ludger Schöls , Friedmar R. Kreuz , Thomas Wieland , Tim M. Strom , Thomas Büttner , Ronja Hollstein , Diana Braunholz , Jens Plaschke , Gabriele Gillessen-Kaesbach , Christine Zühlke
      Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are allelic disorders of the gene CACNA1A encoding the P/Q subunit of a voltage gated calcium channel. While SCA6 is related to repeat expansions affecting the C-terminal part of the protein, EA2 and FHM phenotypes are usually associated with nonsense and missense mutations leading to impaired channel properties. In three unrelated families with dominant cerebellar ataxia, symptoms cosegregated with CACNA1A missense mutations of evolutionary highly conserved amino acids (exchanges p.E668K, p.R583Q and p.D302N). To evaluate pathogenic effects, in silico, protein modeling analyses were performed which indicate structural alterations of the novel mutation p.E668K within the homologous domain 2 affecting CACNA1A protein function.The phenotype is characterised by a very slowly progressive ataxia, while ataxic episodes or migraine are uncommon. These findings enlarge the phenotypic spectrum of CACNA1A mutations.


      PubDate: 2014-01-31T22:18:32Z
       
  • A Novel Heterozygous Mutation Of Three Consecutive Nucleotides Causing
           Apert Syndrome In A Congolese Family
    • Abstract: Publication date: Available online 28 January 2014
      Source:European Journal of Medical Genetics
      Author(s): Aimé Lumaka , Gerrye Mubungu , Papino Mukaba , Pierre Mutantu , Gertrude Luyeye , Anniek Corveleyn , Bruno-Paul Tady , Prosper lukusa Tshilobo , Koenraad Devriendt
      Apert syndrome (OMIM 101200) is a rare genetic condition characterized by craniosynostosis and syndactyly of hands and feet with clinical variability. Two single nucleotides mutations in the linker between the immunoglobulin-like domains II and IIIa of the ectodomainin the Fibroblast Growth Factor Receptor 2 gene (FGFR2, OMIM 176943) are responsible of the vast majority of cases: c.755C>G; p.Ser252Trp (65%) and c.758C>G; p.Pro253Arg (34%. Three exceptional cases carry multiple substitutions of adjacent nucleotides in the linker region. Here we present a Congolese male patient and his mother, both affected with Apert syndrome of variable severity, carrying a previously undescribed heterozygous mutation of three consecutive nucleotides (c.756_758delGCCinsCTT) in the IgII-IgIIIa linker region. This is the fourth live-born patient to carry a multiple nucleotide substitution in the linker region and is the second alternative amino acid substitutions of the Pro253. Remarkably, this novel mutation was detected in the first Central African patient ever to be tested molecularly for the Apert syndrome. To discriminate between a hitherto unreported mutation and an ethnic specific polymorphism, we tested 105 Congolese controls, and no variation was detected.


      PubDate: 2014-01-31T22:18:32Z
       
  • SALL4 and NFATC2: two major actors of interstitial 20q13.2 duplication
    • Abstract: Publication date: Available online 29 January 2014
      Source:European Journal of Medical Genetics
      Author(s): A. Briand-Suleau , J. Martinovic , L. Tosca , B. Tou , S. Brisset , J. Bouligand , V. Delattre , I. Giurgea , J. Bachir , P. Folliot , C. Goumy , C. Francannet , A. Guiochon-Mantel , A. Benachi , J. Vermeesch , G. Tachdjian , P. Vago , M. Goossens , C. Métay
      Interstitial duplication within the long arm of chromosome 20 is an uncommon chromosome structural abnormality. We report here the clinical and molecular characterization associated with pure 20q13.2 duplication in three unrelated patients. The most frequent clinical features were developmental delay, facial dysmorphism, cardiac malformation and skeletal anomalies. All DNA gains occurred de novo, ranging from 1.1 Mb to 11.5 Mb. Compared with previously reported conventional cytogenetic analyses, oligonucleotides array CGH allowed us to refine breakpoints and determine the genes of interest in the region. Involvement of SALL4 in cardiac malformations and NFATC2 gene disruption in both cardiac and skeletal anomalies are discussed.


      PubDate: 2014-01-31T22:18:32Z
       
  • Consanguinity profile in the Gaza Strip of Palestine: Large-scale
           community-based study
    • Abstract: Publication date: Available online 25 January 2014
      Source:European Journal of Medical Genetics
      Author(s): Mahmoud Sirdah
      Consanguineous marriages which have been practiced throughout history continue to be practiced within different ethnic, religious and social groups to varying degrees with highest prevalences in North Africa, Middle East and central and south Asia. In the Gaza Strip of Palestine, little is known about the consanguinity profile, so the present large-scale study aims to explore the consanguinity profile of two generations using data from the β-thalassemia premarital screening program. Sociodemographic data analysis included 156,635 (141,200 males and 15,435 females) persons and their parents, representing 141,200 couples who were referred to the Thalassemia and Hemophilia Center for premarital testing. In addition, the consanguinity characteristics of parents of 217 transfusion-dependent β-thalassemic non-sibling patients were analyzed. Results revealed a significant decrease in the overall prevalence of consanguineous (first and second-cousin) marriages between the previous (fathers') generation (45.2%) and the current (groom/bride) generation (39.9%). Among the five governorates of the Gaza Strip, records of Gaza Governorate revealed the lowest occurrence (36.9% current generation and 42.1% previous generation) of consanguineous marriages, as compared to all others. Consanguineous marriages are significantly higher in semi-urban areas (41.6%) than in urban areas (39.1%) in the current generation (previous generation, 46.4% vs 44.7%, respectively). Compound consanguinity (two-generation) and a single level of consanguinity were seen in 20.7% and 43.7%, respectively, of the cases. The average age of those with first-cousin marriages is significantly lower (22.4±4.4 years) than those with second-cousin marriages (24.3±6.1 years) and the non-consanguineous (26.5±8.2 years). The rate of consanguineous marriages among never married people (42.2%) is significantly much higher than the rate of people with multiple marriages (18.1%). About 74.7% of the non-sibling thalassemic patients of the Gaza Strip are associated with consanguineous parents, of them 54.4% first-cousins and 20.3% second-cousins. In conclusion, although there is a decline in the consanguinity profile in the present compared to previous generation, consanguineous marriages are still a common practice in the Gaza Strip, which rationalizes the necessity for more awareness and counseling efforts about the potential health-related risks of consanguinity on individual lives and the population overall.


      PubDate: 2014-01-27T12:17:37Z
       
  • Corrigendum to “Post-axial polydactyly type A2, overgrowth and
           autistic traits associated with a chromosome 13q31.3 microduplication
           encompassing miR-17-92 and GPC5” [Eur J Med Genet 56 (8) (2013)
           452–457]
    • Abstract: Publication date: Available online 23 January 2014
      Source:European Journal of Medical Genetics
      Author(s): P. Kannu , A.B. Campos-Xavier , D. Hull , D. Martinet , D. Ballhausen , L. Bonafé



      PubDate: 2014-01-27T12:17:37Z
       
  • An intragenic deletion of the NFIA gene in a patient with a hypoplastic
           corpus callosum, craniofacial abnormalities and urinary tract defects
    • Abstract: Publication date: Available online 22 January 2014
      Source:European Journal of Medical Genetics
      Author(s): Anupam Rao , Sheridan O’Donnell , Nicole Bain , Cliff Meldrum , Damon Shorter , Himanshu Goel
      Background Chromosome 1p31 deletion (OMIM #613735) involving the NFIA gene (OMIM 600727) is characterised by variable defects in the formation of the corpus callosum, craniofacial abnormalities and urinary tract defects. A review of current literature suggests only seven cases have been reported, none of which had an isolated NFIA gene defect. Methods We submit the clinical and molecular features of an 8-year-old female patient with a microdeletion of chromosome 1p31.3 who has developmental delay, metopic synostosis and macroscopic haemoglobinuria. She was investigated with karyotyping, subtelomeric FISH and microarray CGH. Results Array CGH identified a single 120kb microdeletion of 1p31.3 involving exons 4-9 of the NFIA gene. Her brain MRI showed hypoplasia of the corpus callosum especially in the posterior areas. Karyotype was normal, ruling out structural chromosomal abnormalities. Conclusion In this study, we confirmed that a microdeletion in the chromosome region 1p31.3 involving the NFIA gene is associated with hypoplasia of the corpus callosum, developmental delay, metopic synostosis and urinary tract abnormalities. Furthermore, we propose a mechanism by which disruptions in the NFIA gene causes craniofacial abnormalities. This report presents the first case of an intragenic deletion within the NFIA gene that is still consistent with classic clinical phenotypes present in previously reported cases of chromosome 1p31.3 related deletion. This finding will help clarify the role of the NFIA gene in the normal formation of parts of the CNS, the craniofacial complex and the urinary tract.


      PubDate: 2014-01-23T03:34:15Z
       
  • Clinical assessment of five patients with BRWD3 mutation at Xq21.1 gives
           further evidence for mild to moderate intellectual disability and
           macrocephaly
    • Abstract: Publication date: Available online 22 January 2014
      Source:European Journal of Medical Genetics
      Author(s): Sarah Grotto , Valérie Drouin-Garraud , Katrin Õunap , Helen Puusepp-Benazzouz , Janneke Schuurs-Hoeijmakers , Nathalie Le Meur , Pascal Chambon , Séverine Fehrenbach , Hans van Bokhoven , Thierry Frébourg , Arjan P.M. de Brouwer , Pascale Saugier-Veber
      Truncating mutations of the BRWD3 gene have been reported in two distinct families with in total four patients so far. By using array-CGH, we detected a 74 Kb de novo deletion encompassing exons 11 through 41 of BRWD3 at Xq21.1 in a 20 year old boy presenting with syndromic intellectual disability. In addition, by using exome sequencing, we ascertained a family with a BRWD3 nonsense mutation, p.Tyr1131*, in four males with intellectual disability. We compared the clinical presentation of these five patients to that of the four patients already described in the literature for further delineation of the clinical spectrum in BRWD3-related intellectual disability. The main symptoms are mild to moderate intellectual disability (n=9/9) with speech delay (n=8/8), behavioral disturbances (n=7/8), macrocephaly (n=7/9), dysmorphic facial features (n=9/9) including prominent forehead, pointed chin, deep-set eyes, abnormal ears, and broad hands and feet (n=6/6), and skeletal symptoms (n=7/7) like pes planus, scoliosis, kyphosis and cubitus valgus.


      PubDate: 2014-01-23T03:34:15Z
       
  • Confirmation and Further Delineation of the 3q26.33-3q27.2 Microdeletion
           Syndrome
    • Abstract: Publication date: Available online 22 January 2014
      Source:European Journal of Medical Genetics
      Author(s): Majed Dasouki , Jennifer Roberts , Angela Santiago , Irfan Saadi , Karine Hovanes
      Recently, 3 unrelated children with a potentially novel 3q26.33-3q27.2 microdeletion syndrome were reported. We now report a new 9 ½ years old Caucasian boy with a 2 Mb deletion of the same genomic region in combination with Klinefelter syndrome. He presented with facial dysmorphism, developmental delay, Asperger syndrome, thrombocytopenia, recurrent infections and hypogammaglobulinemia. The deletion in our patient improves upon the minimum region of the novel 3q26.33-3q27.2 microdeletion, and provides additional insights into the underlying genetic basis of the observed phenotypes. Consistent with two of three previously described patients, our patient also presents with thrombocytopenia, which we postulate is caused by haploinsufficiency of THPO. In addition, haploinsufficiency of LAMP3, a lymphoid and dendritic cell expressed protein that is implicated in bacterial and viral infections, pulmonary surfactant protein transport and amelogenin degradation, may be a novel cause for the immune deficiency, lung disease and dental abnormalities respectively as seen in these patients.


      PubDate: 2014-01-23T03:34:15Z
       
  • Modification of severe insulin resistant diabetes in response to lifestyle
           changes in Alström syndrome
    • Abstract: Publication date: Available online 22 January 2014
      Source:European Journal of Medical Genetics
      Author(s): Richard B. Paisey , Tarekeng Geberhiwot , Michael Waterson , Robert Cramb , Rick Steeds , Kathleen Williams , Alison White , Carol Hardy
      Background Alström syndrome is a recessively inherited condition characterised by severe insulin resistance and metabolic syndrome with progression to type 2 diabetes, hepatic dysfunction and coronary artery disease. The metabolic responses to lifestyle changes in the syndrome have not been reported. Case Reports We describe the effects on glycaemia of intense cycling in two insulin treated Alström patients with diabetes, and the effects of opposite lifestyle changes over one year in two others. Methods After practise and clinical assessment two patients aged 21 and 39 years undertook a 380 kilometre cycle ride over 4 days by tandem. The effects of planned reductions in insulin therapies and increased regular carbohydrate ingestion were monitored by frequent capillary blood glucose measurements. Two other patients, siblings aged 22 and 25 years underwent assessment of glycaemia, serum lipids, hepatic function and ultrasound, Enhanced Liver Fibrosis test and measures of insulin resistance before and after significant improvement in lifestyle in one and deterioration in the other. Results Aerobic exercise strikingly improved blood glucose control despite reduction in insulin dose and increased carbohydrate intake. Increase in exercise and exclusion of fast foods improved all aspects of the metabolic syndrome and induced remission of diabetes in one sibling. Reduction in exercise and consumption of high energy foods in the other resulted in development of type 2 diabetes, severe metabolic syndrome and fatty liver in the other. Conclusions Despite dual sensory loss and genetic basis for insulin resistance, Alström patients can successfully ameliorate the metabolic syndrome with lifestyle changes.


      PubDate: 2014-01-23T03:34:15Z
       
  • Distinct phenotype of PHF6 deletions in females
    • Abstract: Publication date: Available online 28 December 2013
      Source:European Journal of Medical Genetics
      Author(s): N. Di Donato , B. Isidor , S. Lopez Cazaux , C. Le Caignec , B. Klink , C. Kraus , E. Schrock , K. Hackmann
      We report on two female patients carrying small overlapping Xq26.2 deletions of 100 kb and 270 kb involving the PHF6 gene. Mutations in PHF6 have been reported in individuals with Borjeson-Forssman-Lehmann syndrome, a condition present almost exclusively in males. Two very recent papers revealed de novo PHF6 defects in seven female patients with intellectual disability and a phenotype resembling Coffin-Siris syndrome (sparse hair, bitemporal narrowing, arched eyebrows, synophrys, high nasal root, bulbous nasal tip, marked clinodactyly with the hypoplastic terminal phalanges of the fifth fingers and cutaneous syndactyly of the toes, Blaschkoid linear skin hyperpigmentation, dental anomalies and occasional major malformations). The clinical presentation of these patients overlaps completely with our first patient, who carries a germline deletion involving PHF6. The second patient has a mosaic deletion and presented with a very mild phenotype of PHF6 loss in females. Our report confirms that PHF6 loss in females results in a recognizable phenotype overlapping with Coffin-Siris syndrome and distinct from Borjeson-Forssman-Lehmann syndrome. We expand the clinical spectrum and provide the first summary of the recommended medical evaluation.


      PubDate: 2013-12-31T22:22:53Z
       
  • A Prenatal Case of Split-hand Malformation Associated with 17p13.3
           triplication – A dilemma in genetic counselling
    • Abstract: Publication date: Available online 28 December 2013
      Source:European Journal of Medical Genetics
      Author(s): H.M. Luk , Vincent C.H. Wong , Ivan F.M. Lo , Kelvin Y.K. Chan , Elizabeth T. Lau , Anita S.Y. Kan , Mary H.Y. Tang , W.F. Tang , Wandy M.K. She , Yoyo W.Y. Chu , W.K. Sin , Brian H.Y. Chung
      Copy number gain of 17p13.3 has been shown to be associated with developmental delay/autism and Split-Hand-Foot malformation. We report a case of fetus with bilateral split-hand malformation detected on prenatal ultrasound. Array comparative genomic hybridization detected 2 maternally inherited copy number gains in the 17p13.3 region with one of them involving the BHLHA9 gene and part of the YWHAE gene. The mother is normal in intelligence with mild right foot anomaly only. Although the BHLHA9 copy gain is known to be associated with split-hand-foot malformation, the penetrance and expressivity is highly variable. More challenging is the effect of partial YWHAE copy number gain on neurodevelopment is inconclusive based on current literature. This case highlights the difficulties of prenatal genetic counselling in array comparative genomic hybridization findings in clinical situation with incomplete understanding of genotype-phenotype correlation.


      PubDate: 2013-12-31T22:22:53Z
       
  • Transforming growth factor-β (TGF-β) pathway abnormalities in
           tenascin-X deficiency associated with CAH-X syndrome
    • Abstract: Publication date: Available online 28 December 2013
      Source:European Journal of Medical Genetics
      Author(s): Rachel Morissette , Deborah P. Merke , Nazli B. McDonnell
      Patients with congenital adrenal hyperplasia (CAH) with tenascin-X deficiency (CAH-X syndrome) have both endocrine imbalances and characteristic Ehlers Danlos syndrome phenotypes. Unlike other subtypes, tenascin-X-related Ehlers Danlos syndrome is caused by an extracellular matrix protein deficiency rather than a defect in fibrillar collagen or a collagen-modifying enzyme, and the understanding of the disease mechanisms is limited. We hypothesized that transforming growth factor-β pathway dysregulation may, in part, be responsible for connective tissue phenotypes observed in CAH-X, due to this pathway’s known role in connective tissue disorders. Fibroblasts and direct tissue from human skin biopsies from CAH-X probands and age- and sex-matched controls were screened for transforming growth factor-β biomarkers known to be dysregulated in other hereditary disorders of connective tissue. In CAH-X fibroblast lines and dermal tissue, pSmad1/5/8 was significantly upregulated compared to controls, suggesting involvement of the bone morphogenetic protein pathway. Additionally, CAH-X samples compared to controls exhibited significant increases in fibroblast-secreted TGF-β3, a cytokine important in secondary palatal development, and in plasma TGF-β2, a cytokine involved in cardiac function and development, as well as palatogenesis. Finally, MMP-13, a matrix metalloproteinase important in secondary palate formation and tissue remodeling, had significantly increased mRNA and protein expression in CAH-X fibroblasts and direct tissue. Collectively, these results demonstrate that patients with CAH-X syndrome exhibit increased expression of several transforming growth factor-β biomarkers and provide a novel link between this signaling pathway and the connective tissue dysplasia phenotypes associated with tenascin-X deficiency.


      PubDate: 2013-12-31T22:22:53Z
       
  • Molecular genetics of congenital nuclear cataract
    • Abstract: Publication date: Available online 30 December 2013
      Source:European Journal of Medical Genetics
      Author(s): Hao Deng , Lamei Yuan
      A cataract is defined as opacification of the normally transparent crystalline lens. Congenital cataract (CC) is a type of cataract that presents at birth or during early childhood. CC is one of the most common causes of visual impairment or blindness in children worldwide. Approximately 50% of all CC cases may have a genetic cause which is quite heterogeneous. CC occurs in a variety of morphologic configurations, including polar/subcapsular, nuclear, lamellar, sutural, cortical, membranous/capsular and complete. Nuclear cataract refers to the opacification limited to the embryonic and/or fetal nuclei of the lens. Although congenital nuclear cataract can be caused by multiple factors, genetic mutation remains to be the most common cause. It can be inherited in one of the three patterns: autosomal dominant, autosomal recessive, or X-linked transmission. Autosomal dominant inheritance is the most frequent mode with high penetrance. There may be no obvious correlation between the genotype and phenotype of congenital nuclear cataract. Animal models have been established to study the pathogenesis of congenital nuclear cataract and to identify candidate genes. In this review, we highlight identified genetic mutations that account for congenital nuclear cataract. Our review may be helpful for genetic counseling and prenatal diagnosis.


      PubDate: 2013-12-31T22:22:53Z
       
 
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-2014