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Journal Cover European Journal of Medical Genetics
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   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1769-7212
   Published by Elsevier Homepage  [2817 journals]
  • A template for broad consent in biobank research. Results and explanation
           of an evidence and consensus-based development process
    • Abstract: Publication date: Available online 26 April 2016
      Source:European Journal of Medical Genetics
      Author(s): D. Strech, S. Bein, M. Brumhard, W. Eisenmenger, C. Glinicke, T. Herbst, R. Jahns, S. von Kielmansegg, G. Schmidt, J. Taupitz, H.D. Tröger
      Background Biobanks increasingly presume long-term storage of biomaterials and data that shall be used for future research projects which are today unspecified. Appropriate consent documents for sample donors must therefore explain the breadth of consent and other elements of the biobank governance framework. Recent reviews demonstrated high variability in what issues these documents mention or not and how the issues are explained. This might undermine the protection of sample donors, complicate networked biobank research, create research waste and impact on public trust. Methods A systematic analysis of international research guidelines and existing broad consent templates was performed. Based on this information an interdisciplinary expert group from the AKMEK (Permanent Working Party of German RECs) developed a draft template and organized a comprehensive stakeholder consultation. After revision the final template was consented by all 53 German RECs. Results This paper briefly explores the spectrum of potentially relevant issues for broad consent forms. It then elaborates the template and how it was designed to be applicable in different types of biobanks. Discussion To further improve the validity and applicability of broad consent forms in biobank and other big data research, practice evaluations are needed. We hope that in this regard the presented template supports the development of new consent forms as well as the evaluation and revision of existing ones.


      PubDate: 2016-04-30T14:26:26Z
       
  • Partial deletion of TCF4 in three generation family with non-syndromic
           intellectual disability, without features of Pitt-Hopkins syndrome
    • Abstract: Publication date: Available online 28 April 2016
      Source:European Journal of Medical Genetics
      Author(s): Mira Kharbanda, Kaja Kannike, Anne Lampe, Jonathan Berg, Tõnis Timmusk, Mari Sepp
      Mutations in TCF4 (basic helix-loop-helix transcription factor 4), a gene with complex organization and multiple transcription initiation sites, are usually associated with Pitt-Hopkins syndrome (PTHS). However, a translocation encompassing the 5′ end of TCF4 and several point mutations have been linked to non-syndromic intellectual disability (NSID). Here we describe a family with autosomal dominantly inherited NSID in seven relatives with a partial deletion of TCF4, disrupting the 5′ end of the gene, predicted to result in the reduction of the number of mRNAs that can be produced by alternative transcription initiation. Functional studies indicate that it leads to reduced levels of transcripts coding for TCF4 protein isoforms with a nuclear localization signal, which may be relevant to the phenotype. The findings in our family support the notion that the position of the mutation in TCF4 is relevant to the phenotype, with those mutations in the 5′ region, cassette exons and regions not affecting the important functional domains being linked to NSID rather than PTHS. We suggest that screening for mutations in TCF4 could be considered in the investigation of NSID.


      PubDate: 2016-04-30T14:26:26Z
       
  • Progressive osseous heteroplasia is not a Mendelian trait but a type 2
           segmental manifestation of GNAS inactivation disorders: A hypothesis
    • Abstract: Publication date: Available online 4 April 2016
      Source:European Journal of Medical Genetics
      Author(s): Rudolf Happle
      Progressive osseous heteroplasia (POH) is a segmental disorder characterized by progeressive heterotopic ossification that extends from dermal and subcutaneous tissues to deeper structures. So far, it has been taken as a rarely occurring bone disease with autosomal dominant inheritance. Here, arguments are presented in favor of the alternative concept that the disorder is merely a type 2 segmental manifestation of autosomal dominant GNAS inactivation disorders. Type 2 segmental mosaicism arises, in a heterozygous embryo, from a somatic mutational event that occurs at an early developmental stage, resulting in loss of the corresponding wild-type allele and giving rise to a homozygous or hemizygous cell clone. As a characteristic feature, such type 2 segmental involvement is far more pronounced than the type 1 segmental mosaicism as noted in otherwise healthy individuals. The concept of type 2 segmental mosaicism has been proven at the molecular level in six human traits including neurofibromatosis 1, Hailey-Hailey disease, and Gorlin syndrome. In POH, molecular proof of principle is so far lacking. The following lines of reasoning, however, support the hypothesis that POH can be explained by a similar mechanism. Firstly, POH has been found to be associated with different phenotypes caused by inactivating GNAS mutations, which is why it cannot be categorized as one distinct Mendelian trait. Secondly, POH occurs as a rather rare complication of these autosomal dominant traits, which is not compatible with the assumption of a separate Mendelian disorder. Thirdly, in a case of plate-like osteoma that represents a more superficial variant of POH, molecular proof of the concept of type 2 segmental manifestation has already been provided, and the available literature suggests that POH can be best explained by a similar mechanism. Moreover, findings obtained in animal experiments support the assumption that human POH represents such superimposed segmental manifestation of GNAS inactivation disorders.


      PubDate: 2016-04-09T07:21:03Z
       
  • Neoplasia in Turner syndrome. The importance of clinical and screening
           practices during follow-up
    • Abstract: Publication date: Available online 4 April 2016
      Source:European Journal of Medical Genetics
      Author(s): Daniela Larizza, Michela Albanesi, Annalisa De Silvestri, Giulia Accordino, Valeria Brazzelli, Gabriella Carnevale Maffè, Valeria Calcaterra
      Aim of the study Turmer syndrome (TS) patients show increased morbidity due to metabolic, autoimmune and cardiovascular disorders. A risk of neoplasia is also reported. Here, we review the prevalence of neoplasia in a cohort of Turner patients. Methods We retrospectively evaluated 87 TS women. Follow-up included periodic ultrasound of the neck, abdominal and pelvic organs, dermatologic evaluation and fecal occult blood test. Karyotype was 45,X in 46 patients. During follow-up, 63 girls were treated with growth hormone, 65 with estro-progestin replacement therapy and 20 with L-thyroxine. Autoimmune diseases were present in 29 TS. Results A total of 17 neoplasms in 14 out of 87 patients were found. Six skin neoplasia, 3 central nervous system tumors, 3 gonadal neoplasia, 2 breast tumors, 1 hepatocarcinoma, 1 carcinoma of the pancreas and 1 follicular thyroid cancer were detected. Age at tumor diagnosis was higher in 45,X pts than in those with other karyotypes (p=0.003). Adenomioma gallbladdder (AG) was detected in 15.3% of the patients, with a lower age in girls at diagnosis with an associated neoplasia in comparison with TS without tumors (p=0.017). No correlation between genetic make up, treatment, associated autoimmune diseases and neoplastia was found. Conclusion In our TS population an increased neoplasia prevalence was reported. A high prevalence of AG was also noted and it might be indicative of a predisposition to neoplasia. Further studies are needed to define the overall risk for neoplasia, and to determine the role of the loss of the X-chromosome and hormonal therapies.


      PubDate: 2016-04-09T07:21:03Z
       
  • A novel Xq22.1 deletion in a male with multiple congenital abnormalities
           and respiratory failure
    • Abstract: Publication date: Available online 16 March 2016
      Source:European Journal of Medical Genetics
      Author(s): Yang Cao, Umut Aypar
      Here we report the first male case of a novel Xq22.1 deletion. An 8-week-old boy with multiple congenital abnormalities and respiratory failure was referred to the Mayo Clinic Cytogenetics laboratory for testing. Chromosomal microarray analysis identified a novel 1.1 Mb deletion at Xq22.1. A similar deletion has only been described once in the literature in a female patient and her mother; both have intellectual disability and dysmorphic facial features. In addition, the mother had a son who died at 15 days due to breathing failure. Recently, a mouse model revealed that a 0.35 Mb sub-region, containing 4 genes, is sufficient to cause majority of the Xq22.1 deletion phenotypes. The deleted intervals in our male patient and the female patients contain 15 common genes, including the four described in the 0.35 Mb sub-region. Male mice with deletion of the 0.35 Mb sub-region died perinatally from respiratory failure due to pulmonary hypoplasia, consistent with the breathing problem and potential neonatal fatality in male patients. The phenotypes of the mouse models and the patients are strikingly similar; therefore, the deletion of these five genes (ARMCX5, ARMCX5-GPRASP2, GPRASP1, GPRASP2, and BHLHB9) is likely responsible for the novel Xq22.1 deletion syndrome.


      PubDate: 2016-03-20T13:53:25Z
       
  • A neurocutaneous phenotype with paired hypo- and hyperpigmented macules,
           microcephaly and stunted growth as prominent features
    • Abstract: Publication date: Available online 12 March 2016
      Source:European Journal of Medical Genetics
      Author(s): Piero Pavone, Andrea Domenico Praticò, Giulia Gentile, Raffaele Falsaperla, Rosario Iemmolo, Maria Guarnaccia, Sebastiano Cavallaro, Martino Ruggieri
      Neurocutaneous disorders represent a heterogeneous group of conditions affecting the skin (with pigmentary/vascular abnormalities, hamartomas or tumors) and the central and peripheral nervous systems. In recent years, besides the well-known neurocutaneous diseases (e.g., the different forms of neurofibromatosis, tuberous sclerosis complex, Sturge-Weber syndrome and mosaic pigmentary/hamartomatous disorders), new distinctive syndromes have been characterized, extending our knowledge on the spectrum of these conditions. The concurrent presence of pigmentary abnormalities (both of the hypo- and hyperpigmented type), and primary microcephaly has not been commonly reported.


      PubDate: 2016-03-15T12:38:15Z
       
  • Genetic predisposition and hematopoietic malignancies in children: Primary
           Immunodeficiency
    • Abstract: Publication date: Available online 11 March 2016
      Source:European Journal of Medical Genetics
      Author(s): Jutte van der Werff ten Bosch, Machiel van den Akker
      It is assumed that patients with some forms of primary immunodeficiency (PID) have a markedly increased risk of cancer as compared to the healthy population. This increased incidence is seen in children as well as adult patients. The type of malignancy depends on the underlying genetic defect, but hematopoietic cancers are most frequent in almost any subtype of PID. In some patients, a malignancy can even be the first or only symptom of an underlying genetic defect. The possibility of an underlying PID is important for the pediatric oncologist as this might influence the treatment. Also, patients with a known PID should be screened for the occurrence of cancer. It is therefore important to raise awareness on this subject among clinicians involved in the treatment of children with cancer as well as in the treatment of children with PID.


      PubDate: 2016-03-11T12:17:45Z
       
  • FOCAL CORTICAL DYSPLASIA, MICROCEPHALY AND EPILEPSY IN A BOY WITH
           1q21.1-q21.3 DUPLICATION
    • Abstract: Publication date: Available online 11 March 2016
      Source:European Journal of Medical Genetics
      Author(s): Roberta Milone, Angelo Valetto, Roberta Battini, Veronica Bertini, Giulia Valvo, Giovanni Cioni, Federico Sicca
      The recent advance of new molecular technologies like array - Comparative Genomic Hybridization has fostered the detection of genomic imbalances in subjects with intellectual disability, epilepsy, and/or congenital anomalies. Though some of the rearrangements are relatively frequent, their consequences on phenotypes can be strongly variable. We report on a boy harbouring a de novo 8.3 Mb duplication of chromosome 1q21.1-q21.3 whose complex unusual phenotype deserves attention, due to the presence of focal cortical dysplasia, microcephaly, and epilepsy. Loss-of-function (LOF) effects of genes associated with human disease involved in the rearrangement have been only partially established, and have not been previously associated with brain malformations in several deletion syndromes. Less is known, instead, about the consequences of their duplication on neuronal migration and brain development process. Further advance in neuroimaging and genetic research will help in defining their actual role in neurodevelopment and cerebral cortex malformations.


      PubDate: 2016-03-11T12:17:45Z
       
  • The acute lymphoblastic leukemia of Down Syndrome – Genetics and
           pathogenesis
    • Abstract: Publication date: March 2016
      Source:European Journal of Medical Genetics, Volume 59, Issue 3
      Author(s): Shai Izraeli
      Children with Down Syndrome (DS) are at markedly increased risk for acute lymphoblastic leukemia (ALL). The ALL is of B cell precursor (BCP) phenotype. T-ALL is only rarely diagnosed as well as infant leukemia. Gene expression profiling and cytogenetics suggest that DS-ALL is an heterogeneous disease. More than half of the leukemias are characterized by aberrant expression of the thymic stromal lymphopoietin (TSLP) receptor CRLF2 caused by genomic rearrangements. These rearrangements are often associated with somatic activating mutations in the receptors or in the downstream components of the JAK-STAT pathway. The activation of JAK-STAT pathway suggests that targeted therapy with JAK or downstream inhibitors may be effective for children with DS-ALL. The basis of the increased risk of BCP-ALL and in particular of the CRLF2 aberrations is presently unknown. Neither is it known which genes on the trisomic chromosome 21 are involved.


      PubDate: 2016-02-29T10:57:47Z
       
  • CHD8 intragenic deletion associated with autism spectrum disorder
    • Abstract: Publication date: Available online 26 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Elliot S. Stolerman, Brooke Smith, Alka Chaubey, Julie R. Jones
      Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that are highly heritable. De novo genomic alterations are considered an important cause of autism spectrum disorders. Recent research has shown that de novo loss-of-function mutations in the chromodomain helicase DNA-binding protein 8 (CHD8) gene are associated with an increased risk of ASD. We describe a single case of an intragenic deletion of exons 26-28 in the CHD8 gene in a patient with autism and global developmental delay. Our clinical case supports the hypothesis that CHD8 may play a central role in neuronal cell development and ASD risk.


      PubDate: 2016-02-29T10:57:47Z
       
  • GEMMs addressing Pax5 loss-of-function in childhood pB-ALL
    • Abstract: Publication date: March 2016
      Source:European Journal of Medical Genetics, Volume 59, Issue 3
      Author(s): Franziska Auer, Deborah Ingenhag, Sanil Bhatia, Jürgen Enczmann, Cesar Cobaleda, Isidro Sanchez-Garcia, Arndt Borkhardt, Julia Hauer
      Germline mutations in transcription factors, which are implicated in hematopoiesis in general or specifically in B-cell differentiation have recently been described to confer an inherited risk to pB-ALL with often reduced penetrance. Predicting leukemia development, therapy response and long term follow up of mutation carriers is challenging because experience from large patient cohorts and their long term follow up are not available. Genetically Engineered Murine Models (GEMMs) represent a promising approach to create individualized and precise models reproducing the molecular makeup of the human disease. This review focuses on PAX5 loss-of-function and summarizes techniques of murine model generation, available GEMMs, which mimic Pax5 loss-of-function in leukemia development and discusses the challenges and drawbacks of these models. These aspects are discussed in the context of creating a robust model, which serves not only for validation of the relevance of a genomic alteration in pB-ALL but at the same time as a valid preclinical model.


      PubDate: 2016-02-29T10:57:47Z
       
  • Genetics of Human Isolated Acromesomelic Dysplasia
    • Abstract: Publication date: Available online 27 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Saadullah Khan, Sulman Basit, Muzammil Ahmed Khan, Noor Muhammad, Wasim Ahmad
      Acromesomelic dysplasia is a type of skeletal malformation affecting distal and middle segments of the extremities. It occurs in both isolated (non-syndromic) and syndromic forms. In later case, it shows association with cardiac, respiratory, neurological and genital abnormalities. Acromesomelic dysplasia segregates in autosomal recessive mode of inheritance. Mutations in three genes (GDF5, NPR2, BMPR1B) have been reported to cause different forms of acromesomelic dysplasia. In the present review we have discussed clinical spectrum, genetics and signalopathies of isolated acromesomelic dysplasias.


      PubDate: 2016-02-29T10:57:47Z
       
  • A new familial case of microdeletion syndrome 10p15.3
    • Abstract: Publication date: Available online 24 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Marlene Eggert, Stefan Müller, Uwe Heinrich, Yasmin Mehraein
      In 2012 a small terminal deletion in the short arm of chromosome 10 in the region 10p15.3 was reported as a novel microdeletion syndrome. By now 21 patients, including a single familial case, have been reported. Characteristic findings comprise variable cognitive impairment or developmental delay, disorder of speech development, as well as various dysmorphic signs. We here report on a new patient, an eight year old girl, with a microdeletion syndrome 10p15.3. She is a foster child showing intellectual deficits, disorder of speech development, behavioral problems, congenital heart defect, and several dysmorphic signs. The same microdeletion was subsequently found in the six year old maternal half-sister, showing very similar developmental and cognitive issues, including major speech impairment. The mother has not obtained a school degree. She was described as being a dissocial person with severe alcohol abuse and showing minor cognitive disability. Thus inheritance of the microdeletion from a probably symptomatic mother can be assumed. The patients presented here add up to the as yet small number of reported cases of microdeletion 10p15.3 and thereby might help to establish a more comprehensive clinical spectrum of this rather newly discovered syndrome.


      PubDate: 2016-02-25T10:14:52Z
       
  • The use of two different MLPA kits in 22q11.2 Deletion Syndrome
    • Abstract: Publication date: Available online 24 February 2016
      Source:European Journal of Medical Genetics
      Author(s): L.J.M. Evers, J.J.M. Engelen, L.M.H. Houben, L.M.G. Curfs, T.A.M.J. van Amelsvoort
      22q11.2 deletion syndrome (22q11DS) is one of the most common recurrent copy-number variant disorder, caused by a microdeletion in chromosome band 22q11.2 and occurring with a population prevalence of 1 in 2000. Until today there has been no evidence that the size of the deletion has an influence on the clinical phenotype. Most studies report that 22q11DS is associated with mild or borderline intellectual disability. There are a limited number of reports on 22q11DS subjects with moderate or severe intellectual disability. In this study we describe 63 adult patients with 22q11DS, including 22q11DS patients functioning at a moderate to severe intellectual disabled level. Deletion size was established with an experimental Multiplex ligation-dependent probe amplification (MLPA) mixture (P324) in addition to the commonly used MLPA kit (P250). We compared deletion size with intellectual functioning and presence of psychotic symptoms during life. The use of the experimental MLPA kit gives extra information on deletion size, only when combined with the common MLPA kit. We were able to detect eleven atypical deletions and in two cases the deletion size was shorter than all other “typical ones”. We conclude that the use of the experimental kit P324 gives extra information about the deletion size, but only when used together with the standard P250 kit. We did not found any relation of deletion size with intelligence or presence of psychosis.


      PubDate: 2016-02-25T10:14:52Z
       
  • A novel homozygous splice site mutation in NALCN identified in siblings
           with Cachexia, Strabismus, Severe Intellectual Disability, Epilepsy and
           Abnormal Respiratory Rhythm
    • Abstract: Publication date: Available online 23 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Moran Gal, Daniella Magen, Younan Zahran, Ayelet Eran, Morad Khayat, Chen Gafni, Erez Y. Levanon, Hanna Mandel
      We studied three siblings, born to consanguineous parents who presented with severe intellectual disability, cachexia, strabismus, seizures and episodes of abnormal respiratory rhythm. Whole exome sequencing led to identification of a novel homozygous splice site mutation, IVS29-1G>A in the NALCN gene, that resulted in aberrant transcript in the patients. NALCN encodes a voltage-independent cation channel, involved in regulation of neuronal excitability. Three homozygous mutations in the NALCN gene were previously identified in only eight patients with severe hypotonia, speech impairment, cognitive delay, constipation and Infantile–Neuroaxonal-dystrophy- like symptoms. Our patients broaden the clinical spectrum associated with recessive mutations in NALCN, featuring also disrupted respiratory rhythm mimicking homozygous Nalcn knockout mice.


      PubDate: 2016-02-25T10:14:52Z
       
  • A case of mild CHARGE syndrome associated with a splice site mutation in
           CHD7
    • Abstract: Publication date: Available online 24 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Constance Wells, Natalie Loundon, Noel Garabedian, Sylvette Wiener-Vacher, Marie-Dominique Cordier-Bouvier, Géraldine Goudeffroye, Tania Attie-Bitach, Sandrine Marlin
      CHARGE syndrome (MIM#214800) (Coloboma, Heart defect, Atresia of choanae, Retarded growth and development, Genital hypoplasia, Ear abnormalities/deafness) is caused by heterozygous mutation of CHD7 transmitted in an autosomal dominant manner. In this report, we describe a patient with bilateral hearing impairment, unusually-shaped ears, no intellectual disability and a patent ductus arteriosus. Further investigation showed abnormal semicircular canals and the presence of olfactory bulbs. He does not fulfill the Blake or the Verloes criteria for CHARGE. A de novo mutation at the donor splice site of intron 33 was identified (c.7164+1G>A). It is of importance to diagnose mildly affected patients for appropriate genetic counselling and to better understand the mild end of the phenotypic spectrum of CHARGE syndrome.


      PubDate: 2016-02-25T10:14:52Z
       
  • Immunoglobulin K Light Chain Deficiency: a rare, but probably
           underestimated, humoral immune defect
    • Abstract: Publication date: Available online 4 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Pierguido Sala, Antonio Colatutto, Dora Fabbro, Laura Mariuzzi, Stefania Marzinotto, Barbara Toffoletto, Anna R. Perosa, Giuseppe Damante
      Human immunoglobulin molecules are generated by a pair of identical heavy chains, which identify the immunoglobulin class, and a pair of identical light chains, Kappa or Lambda alternatively, which characterize the immunoglobulin type. In normal conditions, Kappa light chains represent approximately 2/3 of the light chains of total immunoglobulins, both circulating and lymphocyte surface bound. Very few cases of immunoglobulin Kappa or Lambda light chain defects have been reported. Furthermore, the genetic basis of this defect has been extensively explored only in a single case. We report a case of a patient suffering of serious recurrent bacterial infections, which was caused by a very rare form of immunoglobulin disorder, consisting of a pure defect of Kappa light chain. We evaluated major serum immunoglobulin concentrations, as well as total and free Kappa and Lambda light chain concentrations. Lymphocyte phenotyping was also performed and finally we tested the Kappa chain VJ rearrangement as well as the constant Kappa region sequence. Studies performed on VJ rearrangement showed a polyclonal genetic arrangement, whereas the gene sequencing for the constant region of Kappa chain showed a homozygous T to G substitution at the position 1288 (rs200765148). This mutation causes a substitution from Cys to Gly in the protein sequence and, therefore, determines the abnormal folding of the constant region of Kappa chain. We suggest that this defect could lead to an effective reduction of the variability of total antibody repertoire and a consequent defect of an apparently normal immunoglobulin response to common antigens.


      PubDate: 2016-02-12T11:02:47Z
       
  • Seven novel mutations of the SMPD1 gene in four Chinese patients with
           Niemann-Pick disease type A and prenatal diagnosis for four fetuses
    • Abstract: Publication date: Available online 4 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Yuan Ding, Xiyuan Li, Yupeng Liu, Ying Hua, Jinqing Song, Liwen Wang, Mengqiu Li, Yaping Qin, Yanling Yang
      Background Niemann-Pick disease type A (NPD-A) is a rare autosomal recessive lysosomal storage disorder caused by acid sphingomyelinase deficiency. Only a few cases have been documented in mainland China, and prenatal diagnosis has not been performed to date. In this study, the clinical and laboratory features of four Chinese patients with early-onset NPD-A were summarized. Methods Four patients with NPD-A were the firstborns of non-consanguineous parents from four unrelated Chinese families. Bone marrow analysis, acid sphingomyelinase assay and genetic studies were performed. SMPD1 gene studies on amniocytes were performed for the prenatal diagnosis of four fetuses from three families. Results Four patients were admitted at the age of 1 to 10 months due to jaundice, hepatosplenomegaly and psychomotor retardation. Liver histopathological analysis revealed glucolipid accumulation. Massive foamy histiocytes were found in the bone marrow. Acid sphingomyelinase activities of peripheral blood leukocytes were significantly decreased (4.05 to 21.9 nmol/h/mg protein, normal range 216.1 to 950.9 nmol/h/mg protein). Seven novel mutations (c.518-519insT, c.562_563insC, c.792Gdel, c.949G>A, c.1487_1499delACCGTGTGTACCA, c.1495T>C and c.1670T>C) of the SMPD1 gene were identified in four patients. Only one fetus had two mutations of the SMPD1 gene of amniocytes. The results suggested that the fetus was affected by NPD-A. The mother chose artificial abortion. The other three fetuses were not affected by NPD-A. No mutation of the SMPD1 gene was detected in the cultured amniocytes from the mothers. Postnatal genetic analysis and normal development of the three infants confirmed the prenatal diagnosis. Conclusions Seven novel mutations associated with NPD-A were identified in the Chinese population. Prenatal diagnosis for four fetuses of three families was successfully performed by amniocyte gene analysis.


      PubDate: 2016-02-12T11:02:47Z
       
  • Acute lymphoblastic leukemia in the context of RASopathies
    • Abstract: Publication date: Available online 5 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Hélène Cavé, Aurélie Caye, Marion Strullu, Nathalie Aladjidi, Cédric Vignal, Alice Ferster, Françoise Méchinaud, Carine Domenech, Filomena Pierri, Audrey Contet, Valère Cacheux, Julie Irving, Christian Kratz, Jacqueline Clavel, Alain Verloes
      Noonan syndrome is associated with a range of malignancies including acute lymphoblastic leukemia (ALL). However, little information is available regarding the frequency, natural history, characteristics and prognosis of ALL in Noonan syndrome or RASopathies in general. Cross-referencing data from a large prospective cohort of 1176 patients having a molecularly confirmed RASopathy with data from the French childhood cancer registry allowed us to identify ALL in 6 (0.5%) patients including 4/778 (0.5%) with a germline PTPN11 mutation and 2/94 (2.1%) with a germline SOS1 mutation. None of the patients of our series with CFC syndrome (with germline BRAF or MAP2K1/MAP2K2 mutation – n = 121) or Costello syndrome (with HRAS mutation – n = 35) had an ALL. A total of 19 Noonan-ALL were gathered by adding our patients to those of the International Berlin-Munster-Frankfurt (I-BFM) study group and previously reported patients. Strikingly, all Noonan-associated ALL were B-cell precursor ALL, and high hyperdiploidy with more than 50 chromosomes was found in the leukemia cells of 13/17 (76%) patients with available genetics data. Our data suggest that children with Noonan syndrome are at higher risk to develop ALL. Like what is observed for somatic PTPN11 mutations, NS is preferentially associated with the development of hyperdiploid ALL that will usually respond well to chemotherapy. However, Noonan syndrome patients seem to have a propensity to develop post therapy myelodysplasia that can eventually be fatal. Hence, one should be particularly cautious when treating these patients.


      PubDate: 2016-02-12T11:02:47Z
       
  • Maternally inherited autosomal dominant intellectual disability caused by
           16p13.3 microduplication
    • Abstract: Publication date: Available online 9 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Cha Gon Lee, Eunhae Cho, Young-min An
      A 16p13.3 duplication syndrome has been recently suggested to be a novel recognizable syndrome as a reciprocal microduplication disease of Rubinstein-Taybi syndrome. The CREBBP gene is believed to be the dosage-sensitive critical gene responsible for the reciprocal duplication and deletion syndrome. Descriptions so far have been de novo. Here, we report a very rare case of a maternally inherited a -1Mb sized duplication on 16p13.3 identified by SNP array testing. The patient showed moderate intellectual disability, normal growth, and characteristic facial features. The patient’s mother also had mild intellectual disability, normal growth, camptodactyly, proximally implanted small thumbs, and distinctive facial features. The study provides additional information that furthers the understanding and delineation of 16p13.3 duplication syndrome.


      PubDate: 2016-02-12T11:02:47Z
       
  • Neonatal Severe Hyperparathyroidism caused by homozygous mutation in CASR:
           A Rare Cause of Life-Threatening Hypercalcemia
    • Abstract: Publication date: Available online 6 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Heidi Murphy, Jessica Patrick, Eileen Báez-Irizarry, Yves Lacassie, Ricardo Gómez, Alfonso Vargas, Brian Barkemeyer, Sohit Kanotra, Regina M. Zambrano
      Neonatal severe hyperparathyroidism (NSHPT) is a rare, life-threatening condition that presents with severe hypercalcemia, hyperparathyroidism, and osteopenia in the newborn period. Treatment of NSHPT traditionally includes hydration and bisphosphonates; however newer calcimimetic agents, such as cinacalcet, are now being utilized to prevent or delay parathyroidectomy which is technically difficult in the newborn. Medical treatment success is related to calcium sensing receptor (CaSR) genotype. We report a 4-day-old infant who presented with hyperbilirubinemia, poor feeding, weight loss, severe hypotonia and was ultimately diagnosed with NSHPT. The patient’s total serum calcium level of 36.8 mg/dL (reference range: 8.5-10.4 mg/dL) is, to our knowledge, the highest ever documented in this setting. Exome data previously obtained on the infant’s parents was re-analyzed demonstrating bi-parental heterozygosity for a mutation of the CASR gene: c.206G>A, and Sanger sequencing data confirmed the patient was a homozygote for the same mutation. Though a patient with the same CaSR gene mutation described here has responded to cinacalcet, our patient did not respond and required parathyroidectomy. Though this case has previously been published as a surgical case report, a full report of the medical management and underlying genetic etiology is warranted; this case underscores the importance of disclosing bi-parental heterozygosity for a gene causing severe neonatal disease particularly when treatment is available and illustrates the need for further in vitro studies of this CaSR mutation.


      PubDate: 2016-02-12T11:02:47Z
       
  • Incomplete penetrance of biallelic ALDH1A3 mutations
    • Abstract: Publication date: Available online 10 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Julie Plaisancié, Dominique Brémond-Gignac, Bénédicte Demeer, Véronique Gaston, Alain Verloes, Lucas Fares-Taie, Sylvie Gerber, Jean-Michel Rozet, Patrick Calvas, Nicolas Chassaing
      The formation of a properly shaped eye is a complex developmental event that requires the coordination of many induction processes and differentiation pathways. Microphthalmia and anophthalmia (MA) represent the most severe defects that can affect the ocular globe during embryonic development. When genetic, these ocular disorders exhibit large genetic heterogeneity and extreme variable expressivity. Around 20 monogenic diseases are known to be associated with MA as main phenotype and the penetrance of mutations is usually full in the patients. Some of these genes encode proteins involved in the vitamin A pathway, tightly regulated during eye development. One of those retinoic acid synthesis genes is ALDH1A3 and biallelic mutations in that gene have been recently found to lead to MA phenotype in patients. Interestingly, we report here the lack of ocular defect in a girl carrying the same homozygous mutation in the ALDH1A3 gene than the affected members of her family. Thus, this report brings new information for the phenotype-genotype correlation of ALDH1A3 mutations and raises important questions, especially in terms of genetic counselling given to the patients and their families. Furthermore, these data contribute to the more general understanding that we have for the complex genetic inheritance of these MA phenotypes.


      PubDate: 2016-02-12T11:02:47Z
       
  • Pre- and post-natal growth in two sisters with 3-M syndrome
    • Abstract: Publication date: Available online 2 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Licia Lugli, Emma Bertucci, Vincenzo Mazza, Amira Elmakky, Fabrizio Ferrari, Christine Neuhaus, Antonio Percesepe
      3-M syndrome (OMIM #273750) is a rare autosomal recessive growth disorder characterized by severe pre- and post-natal growth restriction, associated with minor skeletal abnormalities and dysmorphisms. Although the 3-M syndrome is well known as a primordial dwarfism, descriptions of the prenatal growth are missing. We report a family with variable phenotypic features of 3-M syndrome and we describe the prenatal and postnatal growth pattern of two affected sisters with a novel homozygous CUL7 mutation (c.3173-1G>C), showing a pre- and post-natal growth deficiency and a normal cranial circumference.


      PubDate: 2016-02-12T11:02:47Z
       
  • Constitutional abnormalities of chromosome 21 predispose to iAMP21-acute
           lymphoblastic leukaemia
    • Abstract: Publication date: Available online 2 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Christine J. Harrison, Claire Schwab
      In addition to Down syndrome, individuals with other constitutional abnormalities of chromosome 21 have an increased risk of developing childhood acute lymphoblastic leukaemia (ALL). Specifically, carriers of the Robertsonian translocation between chromosomes 15 and 21, rob(15;21) (q10; q10)c, have ∼2700 increased risk of developing ALL with iAMP21 (intrachromosomal amplification of chromosome 21). In these patients, chromosome 15 as well as chromosome 21 is involved in the formation of iAMP21, referred to here as der(21)(15;21). Individuals with constitutional ring chromosomes involving chromosome 21, r(21)c, are also predisposed to iAMP21-ALL, involving the same series of mutational processes as seen in sporadic- and der(21)(15;21)-iAMP21 ALL. Evidence is accumulating that the dicentric nature of the Robertsonian and ring chromosome is the initiating factor in the formation of the complex iAMP21 structure. Unravelling these intriguing predispositions to iAMP21-ALL may provide insight into how other complex rearrangements arise in cancer.


      PubDate: 2016-02-12T11:02:47Z
       
  • Somatic mosaicism of the PIK3CA gene identified in a Hungarian girl with
           macrodactyly and syndactyly
    • Abstract: Publication date: Available online 3 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Kornélia Tripolszki, Rachel Knox, Victoria Parker, Robert Semple, Katalin Farkas, Adrien Sulák, Emese Horváth, Márta Széll, Nikoletta Nagy
      Isolated macrodactyly (OMIM 155500) belongs to a heterogeneous group of overgrowth syndromes. It is a congenital anomaly resulting in enlargement of all tissues localized to the terminal portions of a limb and caused by somatic mutations in the phosphatidylinositol 3-kinase catalytic alpha (PIK3CA, OMIM 171834) gene. Here we report a Hungarian girl with macrodactyly and syndactyly. Genetic screening at hotspots in the PIK3CA gene identified a mosaic mutation (c.1624G > A, p.Glu542Lys) in the affected tissue, but not in the peripheral blood. To date, this somatic mutation has been reported in eight patients affected by different forms of segmental overgrowth syndromes. Detailed analysis of the Hungarian child and previously reported cases suggests high phenotypic diversity associated with the p.Glu542Lys somatic mutation. The identification of the mutation provides a novel therapeutic modality for the affected patients: those who carry somatic mutations in the PIK3CA gene are potential recipients of a novel “repurposing” approach of rapamycin treatment.


      PubDate: 2016-02-12T11:02:47Z
       
  • Treatment-related toxicities in children with acute lymphoblastic
           leukaemia predisposition syndromes
    • Abstract: Publication date: Available online 11 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Kjeld Schmiegelow
      Although most children with acute lymphoblastic leukaemia (ALL) do not harbor germline mutations that strongly predispose them to development of this malignancy, large syndrome registries and detailed mapping of exomes or whole genomes of familial leukaemia kindreds have revealed that 3-5% of all childhood ALL cases are due to such germline mutations, but the figure may be higher. Most of these syndromes are primarily characterized by their non-malignant phenotype, whereas ALL may be the dominating or even only striking manifestation of the syndrome in some families. Identification of such ALL patients is important in order to adjust therapy and offer genetic counseling and cancer surveillance to mutation carriers in the family. In the coming years large genomic screening projects are expected to reveal further hitherto unrecognised familial ALL syndromes. The treatment of ALL cases harboring cancer predisposing mutations can be challenging for both the physician and the patient due to their preexisting symptoms, their reduced tolerance to radio- and/or chemotherapy with enhanced risk of life-threatening organ toxicities, and the paucity of data from ALL patients with the same or similar syndromes being treated by contemporary protocols. Recent studies clearly indicate that many of these patients stand a good chance of cure, and that they should be offered chemotherapy with the intention to cure. Some of these syndromes are characterized by reduced tolerance to radiotherapy and/or specific anticancer agents, while others are not. This review summarises our current knowledge on the risk of acute toxicities for these ALL patients and provides guidance for treatment adjustments.


      PubDate: 2016-02-12T11:02:47Z
       
  • A structured assessment of motor function and behavior in patients with
           Kleefstra Syndrome
    • Abstract: Publication date: Available online 22 January 2016
      Source:European Journal of Medical Genetics
      Author(s): Susanne Schmidt, Heidi E. Nag, Bente S. Hunn, Gunnar Houge, Lise B. Hoxmark
      The present study aimed to further our understanding of Kleefstra syndrome, especially regarding motor function and behavioral characteristics. In total, four males and four females between two and 27 years of age with a genetically confirmed diagnosis of Kleefstra syndrome and their parents participated in this study. Four patients had 9q34.3 deletions that caused Euchromatin Histone Methyl Transferase 1 (EHMT1) haplo-insufficiency, and four patients harbored EHMT1 mutations. The motor function was evaluated via systematic observation. Standardized assessments such as the Vineland Adapted Behavior Scales II (VABS II), the Social Communication Questionnaire (SCQ) and the Child or Adult Behavior Checklist (CBCL, ABCL) were used for the behavioral assessment. All patients showed a delayed developmental status. Muscular hypotonia and its manifestations were present in all patients, regardless of their age. The mean values for all VABS II domains (communication, socialization, daily living skills, and motor skills) were significantly lower than the mean of the reference population (p < 0.001), but similar to other rare intellectual disabilities such as Smith-Magenis syndrome and Angelman syndrome. The results from the SCQ indicated that all patient values exceeded the cut-off value, suggesting the possibility of autism spectrum disorder. The behavioral and emotional problems assessed by CBCL and ABCL were less frequent. In conclusion, patients with Kleefstra syndrome present with a broad range of clinical problems in all age groups and are therefore in need of a multidisciplinary follow-up also after their transition into adulthood.


      PubDate: 2016-01-28T00:56:01Z
       
  • Clinical course and therapeutic implications for lymphoid malignancies in
           Nijmegen breakage syndrome
    • Abstract: Publication date: Available online 27 January 2016
      Source:European Journal of Medical Genetics
      Author(s): Agata Pastorczak, Tomasz Szczepanski, Wojciech Mlynarski
      Nijmegen breakage syndrome (NBS, MIM #251260) is an autosomal recessive chromosomal instability disorder. Majority of patients affected are of Slavic origin and share the same founder mutation of 657del5 within the NBN gene encoding protein involved in DNA double-strand breaks repair. Clinically, this is characterized by a microcephaly, immunodeficiency and a high incidence of pediatric malignancies, mostly lymphomas and leukemias. Anticancer treatment among patients with NBS is challenging because of a high risk of life threatening therapy-related toxicity including severe infections, bone marrow failure, cardio- and nephrotoxicity and occurrence of secondary cancer. Based on systemic review of available literature and the Polish acute lymphoblastic leukemia database we concluded that among patients with NBS, these who suffered from clinically proven severe immunodeficiency are at risk of the complications associated with oncological treatment. Thus, in this group it reasonable to reduce chemotherapy up to 50% especially concerning anthracyclines methotrexate, alkylating agents and epipodophyllotoxines, bleomycin and radiotherapy should be omitted. Moreover, infection prophylaxis using intravenous immunoglobulin supplementation together with antifungal and antibacterial agent is recommended. To replace radiotherapy or some toxic anticancer agents targeted therapy using monoclonal antibodies and kinase inhibitors or bone marrow transplantation with reduced-intensity conditioning should be considered in some cases, however, this statement needs further studies.


      PubDate: 2016-01-28T00:56:01Z
       
  • Recognition of genetic predisposition in pediatric cancer patients: An
           easy-to-use selection tool
    • Abstract: Publication date: Available online 26 January 2016
      Source:European Journal of Medical Genetics
      Author(s): Marjolijn C.J. Jongmans, Jan L.C.M. Loeffen, Esmé Waanders, Peter M. Hoogerbrugge, Marjolijn J.L. Ligtenberg, Roland P. Kuiper, Nicoline Hoogerbrugge
      Genetic predisposition for childhood cancer is under diagnosed. Identifying these patients may lead to therapy adjustments in case of syndrome-related increased toxicity or resistant disease and syndrome-specific screening programs may lead to early detection of a further independent malignancy. Cancer surveillance might also be warranted for affected relatives and detection of a genetic mutation can allow for reproductive counseling. Here we present an easy-to-use selection tool, based on a systematic review of pediatric cancer predisposing syndromes, to identify patients who may benefit from genetic counseling. The selection tool involves five questions concerning family history, the type of malignancy, multiple primary malignancies, specific features and excessive toxicity, which results in the selection of those patients that may benefit from referral to a clinical geneticist.


      PubDate: 2016-01-28T00:56:01Z
       
  • Novel VIPAS39 Mutation in a Syndromic Patient with Arthrogryposis, Renal
           Tubular Dysfunction and Intrahepatic Cholestasis
    • Abstract: Publication date: Available online 23 January 2016
      Source:European Journal of Medical Genetics
      Author(s): Majid Aflatounian, Holly Smith, Fatemeh Farahani, Azam Tofighi Naeem, Anna Straatman-Iwanowska, Samaneh Zoghi, Urvi Khatri, Parisa Tajdini, Gholam Hossein Fallahi, Paul Gissen, Nima Rezaei
      ARC syndrome is a rare autosomal recessive disease, characterized by arthrogryposis, renal tubular dysfunction and cholestasis. Herein a 2.5 month old infant with dysmorphic features, including small anterior fontanel, low set ears, beaked nose and high arched palate is presented who was referred because of icterus. He also suffered from some additional anomalies, including unilateral choanal atresia, club foot, and bilateral developmental dislocation of hip, while further studies showed renal tubular acidosis and hearing impairment in addition to cholestasis. Genetic studies showed a homozygous mutation in the VIPAS39 gene. Making the definite diagnosis of the syndrome is important, while increased risk of mutation in other siblings highlights the importance of prenatal diagnosis.


      PubDate: 2016-01-28T00:56:01Z
       
  • Novel frameshift variant in gene SALL4 causing Okihiro syndrome
    • Abstract: Publication date: Available online 11 January 2016
      Source:European Journal of Medical Genetics
      Author(s): Leandro Ucela Alves, Ana Beatriz Alvarez Perez, Luis Garcia Alonso, Paulo Alberto Otto, Regina Célia Mingroni-Netto



      PubDate: 2016-01-13T23:57:35Z
       
  • A family with the Arg103Pro mutation in the NEUROD1 gene detected by
           Next-Generation Sequencing – clinical characteristics of mutation
           carriers
    • Abstract: Publication date: Available online 8 January 2016
      Source:European Journal of Medical Genetics
      Author(s): Magdalena Szopa, Agnieszka H. Ludwig-Galezowska, Piotr Radkowski, Jan Skupien, Julita Machlowska, Tomasz Klupa, Pawel Wolkow, Maciej Borowiec, Wojciech Mlynarski, Maciej T. Malecki
      Until now only a few families with early onset autosomal diabetes due to the NEUROD1 gene mutations have been identified. Moreover, only some of them meet strict MODY (maturity-onset diabetes of the young) criteria. Next-generation sequencing (NGS) provides an opportunity to detect more pathogenic mutations in this gene. Here, we evaluated the segregation of the Arg103Pro mutation in the NEUROD1 gene in a pedigree in which it was detected, and described the clinical characteristics of the mutation carriers. Methods We included 156 diabetic probands of MODY families, among them 52 patients earlier tested for GCK-MODY and/or HNF1A-MODY by Sanger sequencing with negative results. Genetic testing was performed by targeted NGS sequencing using a panel of 28 monogenic diabetes genes. Results As detected by NGS, one patient had the missense Arg103Pro (CGC/CCC) mutation in the gene NEUROD1 changing the amino –acid structure of the DNA binding domain of this transcription factor. We confirmed this sequence difference by Sanger sequencing. This family had previously been tested with negative results for HNF1A gene mutations. 17 additional members of this family were invited for further testing. We confirmed the presence of the mutation in 11 subjects. Seven adult mutation carriers (all but one) from three generations had been already diagnosed with diabetes. There were 3 individuals with the Arg103Pro mutation diagnosed before the age of 30 years in the family. The range of age of the four unaffected mutation carriers (3 minors and 1 adult) was 3–48 years. Interestingly, one mutation carrier had a history of transient neonatal hypoglycemia, of which the clinical course resembled episodes typical for HNF4A-MODY. Conclusions We report a family with autosomal dominant diabetes related to a new NEUROD1 mutation, one of very few meeting MODY criteria. The use of the NGS method will facilitate identification of more families with rare forms of MODY.


      PubDate: 2016-01-08T22:53:54Z
       
  • c.376G&gt;A mutation in WFS1 gene causes Wolfram syndrome without
           deafness
    • Abstract: Publication date: Available online 7 January 2016
      Source:European Journal of Medical Genetics
      Author(s): Behnam Safarpour Lima, Hamid Ghaedi, Narsis Daftarian, Hamid Ahmadieh, Javad Jamshidi, Mehdi Khorrami, Rezvan Noroozi, Nasim Sohrabifar, Farhad Assarzadegan, Omid Hesami, Shaghayegh Taghavi, Azadeh Ahmadifard, Minoo Atakhorrami, Simin Rahimi-Aliabadi, Neda Shahmohammadibeni, Elham Alehabib, Monavvar Andarva, Hossein Darvish, Babak Emamalizadeh
      Wolfram syndrome is one of the rare autosomal recessive, progressive, neurodegenerative disorders, characterized by diabetes mellitus and optic atrophy. Several other features are observed in patients including deafness, ataxia, and peripheral neuropathy. A gene called WFS1 is identified on chromosome 4p, responsible for Wolfram syndrome. We investigated a family consisted of parents and 8 children, which 5 of them have been diagnosed for Wolfram syndrome. WFS1 gene in all family members was sequenced for causative mutations. A mutation (c.376G>A, p.A126T) was found in all affected members in homozygous state and in both parents in heterozygous state. The bioinformatics analysis showed the deleterious effects of this nucleotide change on the structure and function of the protein product. As all of the patients in the family showed the homozygote mutation, and parents were both heterozygote, this mutation is probably the cause of the disease. We identified this mutation in homozygous state for the first time as Wolfram syndrome causation. We also showed that this mutation probably doesn’t cause deafness in affected individuals.


      PubDate: 2016-01-08T22:53:54Z
       
  • Acute lymphoblastic leukemia and lymphoma in the context of constitutional
           mismatch repair deficiency syndrome
    • Abstract: Publication date: Available online 30 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Tim Ripperger, Brigitte Schlegelberger
      Constitutional mismatch repair deficiency (CMMRD) syndrome is one of the rare diseases associated with a high risk of cancer. Causative mutations are found in DNA mismatch repair genes PMS2, MSH6, MSH2 or MLH1 that are well known in the context of Lynch syndrome. CMMRD follows an autosomal recessive inheritance trait and is characterized by childhood brain tumors and hematological malignancies as well as gastrointestinal cancer in the second and third decades of life. There is a high risk of multiple cancers, occurring synchronously and metachronously. In general, the prognosis is poor. About one third of CMMRD patients develop hematological malignancies as primary (sometimes the only) malignancy or as secondary neoplasm. T-cell non-Hodgkin lymphomas, mainly of mediastinal origin, are the most frequent hematological malignancies. Besides malignant diseases, non-neoplastic features are frequently observed, e.g. café-au-lait spots sometimes resembling neurofibromatosis type I, hypopigmented skin lesions, numerous adenomatous polyps, multiple pilomatricomas, or impaired immunoglobulin class switch recombination. Within the present review, we summarize previously published CMMRD patients with at least one hematological malignancy, provide an overview of steps necessary to substantiate the diagnosis of CMMRD, and refer to the recent most relevant literature.


      PubDate: 2015-12-31T22:16:38Z
       
  • Preexisting conditions in pediatric ALL patients: Spectrum, frequency and
           clinical impact
    • Abstract: Publication date: Available online 28 December 2015
      Source:European Journal of Medical Genetics
      Author(s): P. Schütte, A. Möricke, M. Zimmermann, K. Bleckmann, B. Reismüller, A. Attarbaschi, G. Mann, N. Bodmer, F. Niggli, M. Schrappe, M. Stanulla, C.P. Kratz
      Introduction The etiology of acute lymphoblastic leukemia remains undisclosed in the majority of cases. A number of rare syndromic conditions are known to predispose to different forms of childhood cancer including ALL. The present study characterized the spectrum and clinical impact of preexisting diseases in a cohort of ALL patients from Germany, Austria and Switzerland with a focus on genetic diseases predisposing to cancer development. Methods Retrospective database and study chart review included all patients from Germany, Austria and Switzerland (n=4939) enrolled into multicenter clinical trial AIEOP-BFM ALL 2000 between July 1999 and June 2009. Patients enrolled into study AIEOP-BFM ALL 2009 – which was initiated subsequent to AIEP-BFM ALL 2000 – who were reported with a cancer prone syndrome or chromosomal abnormality were additionally included in this study to increase conclusiveness of observations. Results A total of 233 patients with at least one reported condition could be identified. The following conditions were reported in more than one patient: Gilbert’s disease (n=13), neurofibromatosis type I (n=8), ataxia telangiectasia (n=8), thalassemia (n=7), Nijmegen Breakage syndrome (n=6), cystic fibrosis (n=4), glucose-6-phosphate dehydrogenase deficiency (n=4), Noonan syndrome (n=2), Klinefelter syndrome (n=2), alpha-1-antitrypsin deficiency (n=2), primary ciliary dyskinesia (n=2). Especially those syndromes with a known cancer predisposition (NF type I, Ataxia telangiectasia, Nijmegen Breakage syndrome etc.) were associated with certain general and ALL-related characteristics, high therapy-related toxicity and reduced survival. Conclusion The spectrum of underlying diseases within ALL patients is dispersed. A small number of ALL patients are reported with cancer predisposition syndromes at initial diagnosis which are associated with high rates of therapy-related toxicity and a markedly reduced chance of survival. The true prevalence of these conditions within the ALL population remains unknown due to inapparent clinical presentation. A targeted clinical and/or genetic screening for certain diagnoses like NF type I, Ataxia telangiectasia or Nijmegen Breakage syndrome could identify patients who benefit from adjustment of antileukemic therapy or intensification of supportive care.


      PubDate: 2015-12-31T22:16:38Z
       
  • De novo TUBB2B mutation causes fetal akinesia deformation sequence with
           microlissencephaly: an unusual presentation of tubulinopathy
    • Abstract: Publication date: Available online 28 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Annie Laquerriere, Marie Gonzales, Yoann Saillour, Mara Cavallin, Nicole Joyē, Chloé Quēlin, Laurent Bidat, Marc Dommergues, Ghislaine Plessis, Ferechte Encha-Razavi, Jamel Chelly, Nadia Bahi-Buisson, Karine Poirier
      Tubulinopathies are increasingly emerging major causes underlying complex cerebral malformations, particularly in case of microlissencephaly often associated with hypoplastic or absent corticospinal tracts. Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. We report on an early foetal case with FADS and microlissencephaly due to TUBB2B mutation. Neuropathological examination disclosed virtually absent cortical lamination, foci of neuronal overmigration into the leptomeningeal spaces, corpus callosum agenesis, cerebellar and brainstem hypoplasia and extremely severe hypoplasia of the spinal cord with no anterior and posterior horns and almost no motoneurons. At the cellular level, the p.Cys239Phe TUBB2B mutant leads to tubulin heterodimerization impairment, decreased ability to incorporate into the cytoskeleton, microtubule dynamics alteration, with an accelerated rate of depolymerization. To our knowledge, this is the first case of microlissencephaly to be reported presenting with a so severe and early form of FADS, highlighting the importance of tubulin mutation screening in the context of FADS with microlissencephaly.


      PubDate: 2015-12-31T22:16:38Z
       
  • ADDing a piece to the puzzle of cognition in schizophrenia
    • Abstract: Publication date: Available online 24 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Marta Bosia, Alessandro Pigoni, Laura Zagato, Lino Merlino, Nunzia Casamassima, Cristina Lorenzi, Adele Pirovano, Enrico Smeraldi, Paolo Manunta, Roberto Cavallaro
      The biological bases of cognitive impairment in schizophrenia are poorly understood and may lie in insults in neurodevelopment, leading to alterations in critical structures. Synapses proteins are claimed to have etiopathogenic roles and more direct effects on core cognitive functions. Adducins family proteins seem of great interest, as they are fundamental constituents of synapses, involved in actin cytoskeleton assembly-disassembly, responsible of synaptic plasticity. ADD2 is more prominently expressed in brain tissues and influences memory and learning, commonly impaired in schizophrenia. In the present study we tested 342 patients with schizophrenia for three common adducins genetic variants, ADD1 rs4961, ADD2 rs4984 and ADD3 rs3731566, reported to have significant effects on circulatory system in humans. Neuropsychological measures were evaluated with the Brief Assessment of Cognition in Schizophrenia (BACS), a broad battery evaluating core cognitive domains. The analysis showed significant effects of ADD2 genotype on almost every cognitive domain. Moreover, significant interactions between ADD1 and ADD3 were also observed on some BACS subtests, namely Symbol Coding and Verbal Memory. Our findings suggest that adducins are involved in cognitive impairment in schizophrenia. This effect may result both from a direct mechanism affecting synaptic building and plasticity and indirectly as a consequence of vascular insults.


      PubDate: 2015-12-27T21:57:56Z
       
  • Early Infantile Epileptic Encephalopathy with a de novo variant in ZEB2
           identified by exome sequencing
    • Abstract: Publication date: Available online 22 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Natalia Babkina, Joshua L. Deignan, Hane Lee, Eric Vilain, Raman Sankar, Irina Giurgea, David Mowat, John M. Graham
      Early Infantile Epileptic Encephalopathy (EIEE) presents shortly after birth with frequent, severe seizures, a burst-suppression EEG pattern, and progressive disturbance of cerebral function. We present a case of EIEE associated with a de novo missense variant in ZEB2. Heterozygous truncating mutations or deletions in ZEB2 are known to cause Mowat-Wilson syndrome (MWS), which is characterized by seizures with onset in the second year of life, distinctive dysmorphic facial features and malformations that were absent in this patient. This unique case expands the range of phenotypes associated with variants in ZEB2 and indicates that this gene should be included in the molecular investigation of EIEE cases.


      PubDate: 2015-12-23T21:02:03Z
       
  • Genetics and psychotic disorders: a fresh look at consanguinity
    • Abstract: Publication date: Available online 22 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Aicha Dahdouh-Guermouche, Mohammed Taleb, Lisa Blecha, Amine Benyamina
      Consanguineous unions refer to marriages between related individuals who share a common ancestor. These unions are still commonplace in certain regions of the world such as the southern coast of the Mediterranean, throughout the Middle East and South-East Asia. According to available data, couples with second-degree relations or closer and their offspring currently represent 10.4% of the world’s population, thus resulting in increased frequencies of autosomal recessive disorders. Furthermore, consanguinity may be implicated in the increased frequency of multifactorial pathologies such as mental disorders. The few existing epidemiological studies in consanguineous and/or geographically isolated populations confirm that there is a significant association between consanguinity and mental disorders and a higher risk of schizophrenia or bipolar disorders among offspring from consanguineous couples. There exists a strong and complex genetic component in the predisposition to psychotic disorders that has been confirmed in numerous studies. However, the genetic basis of these disorders remains poorly understood. GWAS studies (Genome Wide Association Studies) over the past 10 years have identified a few weak associations, thus refuting the “common diseases–common variants” hypothesis. A model implicating numerous rare variants has been supported by the recent discovery of CNVs (Copy Number Variants) and their statistically significant association with psychiatric disorders such as schizophrenia, bipolar disorders and autism. The study of consanguineous families may contribute to identifying rare variants in homogenous populations who have conserved certain alleles. Major developments in molecular biology techniques would facilitate these studies as well as contributing to identifying major genes. These results emphasize the need for genetic counseling in high-risk communities and the importance of implementing preventive actions and raising awareness concerning the risk of consanguineous unions.


      PubDate: 2015-12-23T21:02:03Z
       
  • Genetic polymorphisms in the DNA repair gene, XRCC1 associate with
           non-Hodgkin lymphoma susceptibility: A systematic review and meta-analysis
           
    • Abstract: Publication date: Available online 23 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Yuying Li, Ou Bai, Jiuwei Cui, Wei Li
      A DNA repair protein, X-ray repair cross-complementing group 1 (XRCC1), has been implicated in the development of multiple cancers, including non-Hodgkin lymphoma (NHL). Recent studies evaluating the association between XRCC1 polymorphisms and NHL risk have been published. However, the published studies are controversial. This systematic review and meta-analysis of case-control studies aimed to evaluate the association between three single nucleotide polymorphisms (SNPs) of XRCC1, Arg194Trp, Arg280His and Arg399Gln, with risk for developing NHL. We conducted a comprehensive literature search using PubMed, Embase, and the Cochrane Library databases for relevant studies regarding the association between XRCC1 SNPs and NHL risk. Thirteen published case-control studies involving the Arg194Trp (3,897 cases and 5,371 controls), Arg280His (2,140 cases and 3,158 controls) and Arg399Gln (2,722 cases and 4,856 controls) SNPs were selected for meta-analysis. The Arg194Trp SNP was associated with increased NHL risk within the Asian population, and increased diffuse large B cell lymphoma (DLBCL) risk within the overall population under dominant model. The Arg399Gln SNP was associated with decreased risk for NHL and DLBCL under heterozygous and dominant models of inheritance. The Arg280His SNP was not associated with NHL risk by overall or subgroup analyses.


      PubDate: 2015-12-23T21:02:03Z
       
  • An Ashkenazi founder mutation in the PKHD1 gene
    • Abstract: Publication date: Available online 23 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Quint Adina, Sagi Michal, Shai Carmi, Daum Hagit, Macarov Michal, Ben Neriah Ziva, Meiner Vardiela, Elpeleg Orly, Lerer Israela
      Autosomal recessive polycystic kidney disease (ARPKD) is usually detected late in pregnancies in embryos with large echogenic kidneys accompanied by oligohydramnios. Hundreds of private pathogenic variants have been identified in the large PKHD1 gene in various populations. Yet, because of the large size of the gene, segregation analysis of microsatellite polymorphic markers residing in the PKDH1 locus has commonly been utilized for prenatal diagnosis. Keeping in mind the limitations of this strategy, we utilized it for testing 7 families with affected fetuses or newborns, of which in 5 at least one parent was Ashkenazi, and identified that the same haplotype was shared by the majority of the Ashkenazi parents (7/9). This led us to suspect that they carry the same founder mutation. Whole Exome analysis of DNA from a fetus of one of the families detected an already known pathogenic variant c.3761_3762delCCinsG, an indel variant resulting in frameshift (p.Ala1254GlyfsX49). This variant was detected in 9 parents (5 families), of them 7 individuals were Ashkenazi and one Moroccan Jew who shared the same haplotype, and one Ashkenazi, who carried the same variant on a recombinant haplotype. Screening for this variant in 364 Ashkenazi individuals detected 2 carriers. These findings suggest that although c.3761_3762delCCinsG is considered one of the frequent variants detected in unrelated individuals, and was thought to have occurred independently on various haplotypes, it is in fact a founder mutation in the Ashkenazi population.


      PubDate: 2015-12-23T21:02:03Z
       
  • Shooting a moving target. Researching autism genes: an interview study
           with professionals
    • Abstract: Publication date: Available online 23 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Kristien Hens, Hilde Peeters, Kris Dierickx
      Background Given the wide variety of the phenotype, the uncertain genetic origins and the discussions surrounding the status of autism itself, genetic research on autism genes generates specific ethical questions that are not completely analogous to the ethical issues of genetic research in general. Method In order to map ethical issues surrounding research on autism genes, as experienced by professionals in the field of autism, we interviewed 15 Belgian professionals. Results We found that respondents believed that the heterogeneity of the autism phenotype affects the ethics of research on several levels. It affects issues regarding who to include in research on autism genes, regarding what the aim is of such studies, and how the research is done. Conclusions Although genetic research on autism genes is proliferating, a systematic ethical reflection and protocol is missing. With this study we have shown that autism professionals in Belgium express both skepticism and hope with regard to genetic research and raise important points with regard to the effect that the complexity of autism has on research aims and methodology.


      PubDate: 2015-12-23T21:02:03Z
       
  • Genetic predisposition to acute lymphoblastic leukemia: Overview on behalf
           of the I-BFM ALL Host Genetic Variation Working Group
    • Abstract: Publication date: Available online 15 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Christian Peter Kratz, Martin Stanulla, Hélène Cavé
      Environmental causes of childhood acute lymphoblastic leukemia (ALL) remain largely undiscovered. In contrast, multiple germline ALL risk variants have been identified in the recent years. Apart from the low-risk common ALL risk alleles identified through genome wide association studies, rare germline mutations that cause cancer prone syndromes have been found to be associated with an increased risk of developing ALL. Here, we review the germline genetic changes known to be associated with ALL.


      PubDate: 2015-12-15T20:42:21Z
       
  • A novel homozygous missense mutation in the insulin receptor gene results
           in an atypical presentation of Rabson-Mendenhall syndrome
    • Abstract: Publication date: Available online 9 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Rim Ben Abdelaziz, Amel Ben Chehida, Hatem Azzouz, Hela Boudabbous, Olivier Lascols, Hadhami Ben Turkia, Néji Tebib
      Leprechaunism (Donohue syndrome) and Rabson-Mendenhall syndrome are caused by mutations in the insulin receptor gene and are associated with extreme insulin resistance. Clinically these syndromes appear to represent points on a continuum of severity of receptor dysfunction, rather than completely distinct syndromes. We investigated a Libyan infant with growth retardation, facial dysmorphism (elfin-like features), acanthosis nigricans and hirsutism. Fasting hypoglycaemia and postprandial hyperglycaemia with persistent hyperinsulinemia were found. A novel homozygous missense mutation was found in exon 2, resulting in a substitution of a glycine-132 for a serine in the INSR α-subunit (c.394G > A; p.Gly132Ser). At age ten, he developed diabetes mellitus. At age eleven, patient is still alive with mental retardation and severe growth retardation.


      PubDate: 2015-12-12T20:30:28Z
       
  • Karyotype is not dead (yet)!
    • Abstract: Publication date: Available online 10 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Laurent Pasquier, Mélanie Fradin, Elouan Chérot, Dominique Martin-Coignard, Estelle Colin, Hubert Journel, Florence Demurger, Linda Akloul, Chloé Quélin, Vincent Jauffret, Josette Lucas, Marc-Antoine Belaud-Rotureau, Sylvie Odent, Sylvie Jaillard
      Background While array-comparative genomic hybridization (a-CGH) and next-generation sequencing (NGS or exome) technologies have swiftly spread throughout the medical field, karyotype has gradually lost its leading role among genetic tests. Several international guidelines recommend starting with a-CGH screening then going on with exome analysis when investigating a patient with intellectual disability (ID) and no precise clinical diagnosis. A-CGH and whole exome sequencing increase etiologic diagnoses rate up to 30% in case of ID. However, physicians have to deal with the lack of qualitative information of the genome. Especially, exome and a-CGH analysis fail to detect chromosomal rearrangements because breakpoints are either located in introns or not associated with a gain or loss of genetic material. If these technologies cannot easily identify chromosomal translocations or inversions which sometimes split a gene, karyotype can. Discussion For the 5 cases described, karyotype provided the right diagnosis for a Mendelian disease while molecular analysis remained unsuccessful. We conclude that when a Mendelian disease is strongly suggested clinically, if molecular analysis is normal, it could be very useful to carry out a karyotype in order to demonstrate a chromosomal rearrangement involving the targeted gene. If this gene is disrupted, the physician can confirm the suspected disease and give appropriate genetic counseling. Summary This article aims at keeping in mind that karyotype, this old-fashioned genetic tool, can still remain powerful and useful within some genetic issues. Even in this modern period of whole exome sequencing, young geneticists should know that karyotype remains a powerful and cheap technology, available throughout the world and can still do a lot for families.


      PubDate: 2015-12-12T20:30:28Z
       
  • First report on concordant monozygotic twins with Silver-Russell syndrome
           and ICR1 hypomethylation
    • Abstract: Publication date: Available online 10 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Angelika Rieß, Gerhard Binder, Julian Ziegler, Matthias Begemann, Lukas Soellner, Thomas Eggermann
      Twin pairs with the imprinting disorder Silver-Russell syndrome (SRS) have rarely been reported. All six monozygotic (MZ) twin pairs described so far were clinically discordant. In two of the four SRS twin pairs with molecularly proven 11p15.5 epimutation, the healthy twin also showed the molecular alteration in blood cells, but not in the other tested tissues. The clinical discordance is a well-known but poorly understood observation because MZ twins derive from the same zygote. For the second 11p15.5-associated imprinting disorder, Beckwith-Wiedemann syndrome, a larger number of twins has been described, here the majority of pairs are MZ but clinically discordant as well. Interestingly, there is a considerable preponderance of females among the MZ twins with BWS, and a functional link between altered imprinting and X chromosome inactivation has been suggested. We now describe two further MZ SRS twins with H19/IGF2:IG-DMR hypomethylation, including the first clinically concordant pair. By summarizing the existing data, an excess of females in MZ twins with SRS is observed, thus confirming the hypothesis that X-chromosome inactivation might trigger the inaccurate methylation of imprinted loci at least in female twin conceptions. The occurrence of a MZ concordant SRS twin pair is exceptional. The detailed molecular characterization of both siblings of a twin pair enables a reliable diagnosis, furthermore it allows insights in the etiology of twinning in association with (aberrant) imprinting marking.


      PubDate: 2015-12-12T20:30:28Z
       
  • Two familial microduplications of 15q26.3 causing overgrowth and variable
           intellectual disability with normal copy number of IGF1R
    • Abstract: Publication date: Available online 12 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Melanie Leffler, Sanna Puusepp, Olga Žilina, Ying Zhu, Kati Kuuse, Nicole Bain, Trent Burgess, Katrin Õunap, Michael Field
      Terminal duplications of 15q26.3 are associated with an overgrowth phenotype, distinct facial features and intellectual disability, with the smallest reported microduplication to date being 3.16 Mb in size. We report two familial 15q26.3 microduplication cases that are less than half this size, re-defining the minimal critical region for this duplication syndrome. In both families the duplication (albeit a complex copy number gain in one family) is associated with tall stature, early speech delay and variable cognitive problems. Neither familial copy number gains encompass the gene encoding for the insulin-like growth factor 1 receptor (IGF1R), the most-cited candidate for the overgrowth phenotype. In one family, whole genome sequence data and break point mapping excludes disruption of known IGF1R regulatory elements due to potential insertion within these elements. These cases highlight the possibility that the distal region of 15q contains another gene regulating human growth, with LRRK1 being a potential candidate.


      PubDate: 2015-12-12T20:30:28Z
       
  • Fanconi anemia with biallelic FANCD1/BRCA2 mutations – case report
           of a family with three affected children
    • Abstract: Publication date: Available online 2 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Karel Svojgr, David Sumerauer, Alena Puchmajerova, Ales Vicha, Ondrej Hrusak, Kyra Michalova, Josef Malis, Petr Smisek, Martin Kyncl, Drahuse Novotna, Eva Machackova, Jan Jencik, Karel Pycha, Miroslav Vaculik, Roman Kodet, Jan Stary
      Fanconi anemia, complementation group D1 with bi-allelic FANCD1 (BRCA2) mutations, is a very rare genetic disorder characterized by early onset of childhood malignancies, including acute leukemia, brain cancer and nephroblastoma. Here, we present a case report of a family with 3 affected children in terms of treatment outcome, toxicity and characterization of the malignancies using comprehensive cytogenetic analysis. The first child was diagnosed with T-cell acute lymphoblastic leukemia when he was 11 months old. During chemotherapy, he suffered from repeated pancytopenia, sepsis and severe vincristine polyneuropathy, and 18 months after primary diagnosis, he succumbed to secondary acute monocytic leukemia. The second child was diagnosed with stage 2 triphasic nephroblastoma (Wilms tumor), when he was 3 years and 11 months old. During chemotherapy, he suffered from vincristine polyneuropathy. Currently, he is in complete remission, 29 months following the initial diagnosis. The third child was diagnosed with medulloblastoma with classical histology, when she was 4 years and 5 months old. After the first cycle of chemotherapy, she suffered from prolonged pancytopenia, sepsis and severe skin and mucosal toxicity. Six weeks after primary diagnosis, a first relapse in the posterior fossa was diagnosed, and at 7 and half months after primary diagnosis, a second relapse was diagnosed that led to the patient’s death. Our case report underscores tumor heterogeneity, treatment toxicity and poor outcome in Fanconi anemia patients of complementation group D1.


      PubDate: 2015-12-03T17:20:22Z
       
  • Interstitial 9p24.3 deletion involving only DOCK8 and KANK1 genes in two
           patients with non-overlapping phenotypic traits
    • Abstract: Publication date: Available online 2 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Elisa Tassano, Andrea Accogli, Marco Pavanello, Claudio Bruno, Valeria Capra, Giorgio Gimelli, Cristina Cuoco
      Chromosome 9p deletion represents a clinically and genetically heterogeneous condition characterized by a wide spectrum of phenotypic manifestations and a variable size of the deleted region. The deletion breakpoint occurs from 9p22 to 9p24 bands, and the large majority of cases have either terminal deletions or translocations involving another chromosome. Here we report on two patients with similar inherited interstitial 9p24.3 deletion involving only DOCK8 and KANK1 genes. Interestingly, the two patients showed non-overlapping phenotypic traits ranging from a complex phenotype in one to only trigonocephaly with minor dysmorphic features and hand anomalies in the other one. The factors underlying the phenotypic variation associated with seemingly identical genomic alterations are not entirely clear, even if smaller variants, single-nucleotide changes, and epigenetic or stochastic factors altering the expression of genes within functionally relevant pathways have been recently shown to contribute to phenotypic variation. We discuss the role of the two genes and propose possible explanations for the clinical heterogeneity of the phenotype of the two patients.


      PubDate: 2015-12-03T17:20:22Z
       
  • Recommendations of the Scientific Committee of the Italian
           Beckwith-Wiedemann Syndrome Association on the diagnosis, management, and
           follow-up of the syndrome
    • Abstract: Publication date: Available online 22 November 2015
      Source:European Journal of Medical Genetics
      Author(s): Alessandro Mussa, Stefania Di Candia, Silvia Russo, Serena Catania, Maurizio De Pellegrin, Luisa Di Luzio, Mario Ferrari, Chiara Tortora, Maria Costanza Meazzini, Roberto Brusati, Donatella Milani, Giuseppe Zampino, Rosario Montirosso, Andrea Riccio, Angelo Selicorni, Guido Cocchi, Giovanni Battista Ferrero
      Beckwith-Wiedemann syndrome (BWS) is the most common (epi)genetic overgrowth-cancer predisposition disorder. Given the absence of consensual recommendations or international guidelines, the Scientific Committee of the Italian BWS Association (www.aibws.org) proposed these recommendations for the diagnosis, molecular testing, clinical management, follow-up and tumor surveillance of patients with BWS. The recommendations are intended to allow a timely and appropriate diagnosis of the disorder, to assist patients and their families, to provide clinicians and caregivers optimal strategies for an adequate and satisfactory care, aiming also at standardizing clinical practice as a national uniform approach. They also highlight the direction of future research studies in this setting. With recent advances in understanding the disease (epi)genetic mechanisms and in describing large cohorts of BWS patients, the natural history of the disease will be dissected. In the era of personalized medicine, the emergence of specific (epi)genotype-phenotype correlations in BWS will likely lead to differentiated follow-up approaches for the molecular subgroups, to the development of novel tools to evaluate the likelihood of cancer development and to the refinement and optimization of current tumor screening strategies. Conclusions: In this article, we provide the first comprehensive recommendations on the complex management of patients with Beckwith-Wiedemann syndrome.


      PubDate: 2015-11-25T17:01:39Z
       
 
 
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