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Journal Cover European Journal of Medical Genetics
  [SJR: 0.814]   [H-I: 35]   [6 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1769-7212
   Published by Elsevier Homepage  [2801 journals]
  • 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
       
  • Rare Interstitial deletion of chromosome 2p11.2p12. Report of a new
           patient with developmental delay and unusual clinical features
    • Abstract: Publication date: Available online 15 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Rosamaria Silipigni, Elisa Cattaneo, Marco Baccarin, Monica Fumagalli, Maria Francesca Bedeschi



      PubDate: 2015-12-15T20:42:21Z
       
  • Renal dysfunction in sibs with band like calcification with simplified
           gyration and polymicrogyria: Report of a new mutation and review of
           literature
    • Abstract: Publication date: Available online 12 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Shagun Aggarwal, Ashish Bahal, Ashwin Dalal
      Band like calcification with simplified gyration and polymicrogyria (BLC-PMG) is a distinct neuroradiological phenotype initially reported as a pseudo-TORCH syndrome and known to result from biallelic mutations in the Occludin(OCLN) gene. This is report of a family of Indian origin with two affected sibs and segregation of a homozygous novel OCLN mutation in the exon 3(NG_028291.1(OCLN_v001):c.252delC). A literature review suggests that renal dysfunction may be an unrecognized phenotypic manifestation of OCLN mutations and monitoring for the same should form part of the clinical care of these individuals.


      PubDate: 2015-12-12T20:30:28Z
       
  • Prenatal diagnosis of Nager syndrome in a 12-week-old fetus with a whole
           gene deletion of SF3B4 by chromosomal microarray
    • Abstract: Publication date: Available online 9 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Ida Charlotte Bay Lund, Else Marie Vestergaard, Rikke Christensen, Niels Uldbjerg, Naja Becher
      Less than one hundred cases of the acrofacial dysostosis, Nager syndrome, have been described. The cardinal features of Nager syndrome are micrognathia, midface retrusion and limb malformations, predominately of the radial ray of upper extremities. Within the past three years haploinsufficiency of SF3B4 has been confirmed as the major cause of Nager syndrome. Different loss-of-function point-mutations in SF3B4 have been found in approximately 2/3 of patients diagnosed with Nager syndrome. Whole gene deletions of SF3B4 have also been suggested to be the cause of Nager syndrome in SF3B4 point mutation negative patients. Only four prenatal cases displaying Nager-like features in the 2nd or 3rd trimester which have been genetically confirmed with SF3B4 point-mutation after birth have been described. We report a case of a 12-week-old fetus with micrognathia, malformed wrists, bilateral club foot and short long bones diagnosed prenatally by chromosomal microarray with a de novo 0.4 Mb deletion at chromosome 1q21.2 involving SF3B4. To our knowledge, this is the first report of Nager syndrome caused by a SF3B4 whole gene deletion. The case presented also shows that high-resolution chromosomal microarray in early pregnancy can confirm Nager syndome caused by SF3B4-deletion prenatally.


      PubDate: 2015-12-12T20:30:28Z
       
  • Haemophilia A and cardiovascular morbidity in a female SHAM syndrome
           carrier due to skewed X chromosome inactivation
    • Abstract: Publication date: Available online 10 December 2015
      Source:European Journal of Medical Genetics
      Author(s): Szymon Janczar, Joanna Kosinska, Rafal Ploski, Agata Pastorczak, Olga Wegner, Beata Zalewska-Szewczyk, Adam J.W. Paige, Maciej Borowiec, Wojciech Mlynarski
      We have recently described a severe hemophilia A and moyamoya (SHAM) syndrome caused by Xq28 deletions encompassing F8 and the BRCC3 familial moyamoya gene. The phenotype includes haemophilia A, moyamoya angiopathy, dysmorphia and hypertension. The genetic analysis of the family of our SHAM patient demonstrated carrier state in proband’s mother and sister. The patient’s mother is apparently well, whereas his currently 18-years-old sister presents with mild haemophilia A, coarctation of the aorta, hypertension, and ventricular arrhythmia. We performed X chromosome inactivation assay based on HpaII methylation analysis of a polymorphic short tandem repeat (STR) in the X linked AR (androgen receptor) gene and used quantitative real-time RT PCR to measure the expression of genes from the deleted region in proband’s family members. We found an extremely skewed X chromosome inactivation pattern in the female members of the family leading to preferential inactivation of the X chromosome without Xq28 deletion in patient’s sister. We demonstrated differential expression of the genes from the deleted region in four members of the family, that tightly correlates with the clinical features. In conclusion, we show that the hematologic and cardiovascular morbidity and the discrepancy between patient’s sister and mother despite the same genetic lesion are due to skewed X chromosome inactivation leading to clinically relevant differential expression of SHAM syndrome genes. This report highlights the role for BRCC3 in cardiovascular physiology and disease, and demonstrates that in some complex hereditary syndromes full diagnostics may require the examination of both genetic and epigenetic events.


      PubDate: 2015-12-12T20:30:28Z
       
  • 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
       
  • Study of the association of IL-1β and IL-1RA gene polymorphisms with
           occurrence and severity of Familial Mediterranean fever
    • Abstract: Publication date: Available online 14 November 2015
      Source:European Journal of Medical Genetics
      Author(s): José-Noel Ibrahim, Eliane Chouery, Jean-Claude Lecron, André Mégarbané, Myrna Medlej-Hashim
      Familial Mediterranean fever (FMF) is a recessive autoinflammatory disorder. The balance between the pro-inflammatory cytokine IL-1β and its receptor antagonist IL-1RA plays an important role in the development of FMF. In order to determine a possible association of polymorphisms in IL-1β and IL-1RA genes with occurrence and/or severity of the disease, 42 genetically confirmed FMF patients and 42 controls were genotyped for IL-1β(-511C/T), IL-1β(-31T/C), IL1-1β(+3954T/C) and IL-1RA VNTR polymorphisms. IL-1β and IL-1RA levels were evaluated by multiplex ELISA in supernatants of PBMC cultures of 30 FMF patients with and without 24h stimulation of monocytes by LPS. The CC genotype and C allele at positions -31 and +3954 of IL-1β gene were more frequent in FMF patients than in controls. FMF patients carriers of IL-1β(-31) CC genotype were associated with a 2-fold increase in LPS-induced IL-1β secretion as well as a higher disease severity score (11.2 ± 2.9) when compared to patients carrying the TC and TT genotypes (6.1 ± 2.1 and 4.5 ± 2.4, respectively). These results indicate that IL-1β gene polymorphisms at positions -31 and +3954 may be associated with an increased risk for FMF. IL-1β(-31) contributes also to the severity of the disease, probably by modulating IL-1β synthesis.


      PubDate: 2015-11-17T16:32:04Z
       
  • Carrier testing in children and adolescents
    • Abstract: Publication date: Available online 10 November 2015
      Source:European Journal of Medical Genetics
      Author(s): D.F. Vears, S.A. Metcalfe
      Many international guidelines recommend that carrier testing in minors should be postponed either until the age of majority or until the child can be actively involved in the decision making process. Although a number of high school programs exist which provide carrier screening to adolescents in at-risk populations, recent guidelines published by the American Society of Human Genetics do not advocate this testing. Despite this, there are some circumstances in which carrier testing does occur in minors. This testing might be intentional, in which identification of carrier status is the goal of the test, or unintentional, where carrier status is identified as a by-product of testing. In this review we outline the situations in which carriers may be identified in childhood and the positions of professional guidelines that address carrier testing in children. We then review the arguments for and against carrier testing presented in the literature and compare this to the empirical evidence in this field.


      PubDate: 2015-11-13T16:11:34Z
       
  • Two rare deletions upstream of the NRXN1 gene (2p16.3) affecting the
           non-coding mRNA AK127244 segregate with diverse psychopathological
           phenotypes in a family
    • Abstract: Publication date: Available online 10 November 2015
      Source:European Journal of Medical Genetics
      Author(s): Linh TT. Duong, Louise K. Hoeffding, Kirsten B. Petersen, Charlotte D. Knudsen, Johan H. Thygesen, Laura L. Klitten, Niels Tommerup, Andrés Ingason, Thomas Werge
      CNVs spanning the 2p16.3 (NRXN1) and the 15q11.2 gene rich region have been associated with severe neuropsychiatric disorders including schizophrenia. Recently, studies have also revealed that CNVs in non-coding regions play an essential role in genomic variability in addition to disease susceptibility. In this study, we describe a family affected by a wide range of psychiatric disorders including early onset schizophrenia, schizophreniform disorder, and affective disorders. Microarray analysis identified two rare deletions immediately upstream of the NRXN1 gene affecting the non-coding mRNA AK127244 in addition to the pathogenic 15q11.2 deletion in distinct family members. The two deletions upstream of the NRXN1 gene were found to segregate with psychiatric disorders in the family and further similar deletions have been observed in patients diagnosed with autism spectrum disorder. Thus, we suggest that non-coding regions upstream of the NRXN1 gene affecting AK127244 might (as NRXN1) contain susceptibility regions for a wide spectrum of neuropsychiatric disorders.


      PubDate: 2015-11-13T16:11:34Z
       
  • Neuroblastoma Amplified Sequence (NBAS) mutation in recurrent acute liver
           failure: Confirmatory report in a sibship with very early onset,
           osteoporosis and developmental delay
    • Abstract: Publication date: Available online 11 November 2015
      Source:European Journal of Medical Genetics
      Author(s): José-Mario Capo-Chichi, Cybel Mehawej, Valerie Delague, Catherine Caillaud, Issam Khneisser, Fadi F. Hamdan, Jacques L. Michaud, Zoha Kibar, André Mégarbané
      Background Recently, biallelic mutations in the Neuroblastoma Amplified Sequence NBAS gene have been identified in ten patients that present Recurrent Acute Liver Failure (RALF) in early infancy. In addition to severe liver dysfunction, some of these individuals also suffered from other comorbidities including cardiomyopathy, neurologic phenotypes and gastrointestinal immune defects. Here we report on a Lebanese consanguineous family with three affected siblings presenting neonatal spontaneous fractures, developmental delay, prominent eyes, generalized hirsutism, gum hypertrophy, and hepato-splenomegaly. Liver dysfunction was also observed and led to the early death of these patients. Methods Whole-genome SNP genotyping in all the patients, followed by exome sequencing was performed in one of the affected siblings. Results A homozygous c.409C>T (p.Arg137Trp) missense mutation in NBAS was identified in all patients. Conclusion Overall, our findings confirm the involvement of NBAS in the pathogenesis of this condition characterized by severe liver dysfunction and help expand its phenotypical spectrum.


      PubDate: 2015-11-13T16:11:34Z
       
  • Associated congenital anomalies among cases with Down syndrome
    • Abstract: Publication date: Available online 11 November 2015
      Source:European Journal of Medical Genetics
      Author(s): Claude Stoll, Beatrice Dott, Yves Alembik, Marie-Paule Roth
      Down syndrome (DS) is the most common congenital anomaly widely studied for at least 150 years. However, the type and the frequency of congenital anomalies associated with DS are still controversial. Despite prenatal diagnosis and elective termination of pregnancy for fetal anomalies, in Europe, from 2008 to 2012 the live birth prevalence of DS per 10,000 was 10. 2. The objectives of this study were to examine the major congenital anomalies occurring in infants and fetuses with Down syndrome. The material for this study came from 402,532 consecutive pregnancies of known outcome registered by our registry of congenital anomalies between 1979 and 2008. Four hundred sixty seven (64%) out of the 728 cases with DS registered had at least one major associated congenital anomaly. The most common associated anomalies were cardiac anomalies, 323 cases (44%), followed by digestive system anomalies, 42 cases (6%), musculoskeletal system anomalies, 35 cases (5%), urinary system anomalies, 28 cases (4%), respiratory system anomalies, 13 cases (2%), and other system anomalies, 26 cases (3.6%). Among the cases with DS with congenital heart defects, the most common cardiac anomaly was atrioventricular septal defect (30%) followed by atrial septum defect (25%), ventricular septal defect (22%), patent ductus arteriosus (5%), coarctation of aorta (5%), and tetralogy of Fallot (3%). Among the cases with DS with a digestive system anomaly recorded, duodenal atresia (67%), Hirschsprung disease (14%), and tracheo-esophageal atresia (10%) were the most common. Fourteen (2%) of the cases with DS had an obstructive anomaly of the renal pelvis, including hydronephrosis. The other most common anomalies associated with cases with DS were syndactyly, club foot, polydactyly, limb reduction, cataract, hydrocephaly, cleft palate, hypospadias and diaphragmatic hernia. Many studies to assess the anomalies associated with DS have reported various results. There is no agreement in the literature as to which associated anomalies are most common in cases with DS with associated anomalies. In this study we observed a higher percentage of associated anomalies than in the other reported series as well as an increase in the incidence of duodenal atresia, urinary system anomalies, musculoskeletal system anomalies, and respiratory system anomalies, and a decrease in the incidence of anal atresia, annular pancreas, and limb reduction defects. In conclusion, we observed a high prevalence of total congenital anomalies and specific patterns of malformations associated with Down syndrome which emphasizes the need to evaluate carefully all cases with Down syndrome for possible associated major congenital anomalies.


      PubDate: 2015-11-13T16:11:34Z
       
  • Spinal Muscular Atrophy Type III: Molecular Genetic Characterization of
           Turkish Patients
    • Abstract: Publication date: Available online 6 November 2015
      Source:European Journal of Medical Genetics
      Author(s): Gamze Bora-Tatar, Ayse Yesbek-Kaymaz, Can Ebru Bekircan-Kurt, Sevim Erdem-Özdamar, Hayat Erdem-Yurter



      PubDate: 2015-11-09T16:01:53Z
       
  • A novel homozygous insertion and review of published mutations in the NNT
           gene causing familial glucocorticoid deficiency (FGD)
    • Abstract: Publication date: Available online 6 November 2015
      Source:European Journal of Medical Genetics
      Author(s): Omid Jazayeri, Xuanzhu Liu, Cleo C. van Diemen, Willie M. Bakker-van Waarde, Birgit Sikkema-Raddatz, Richard J. Sinke, Jianguo Zhang, Conny M.A. van Ravenswaaij-Arts
      Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by low levels of cortisol despite high adrenocorticotropin (ACTH) levels, due to the reduced ability of the adrenal cortex to produce cortisol in response to stimulation by ACTH. FGD is a heterogeneous disorder for which causal mutations have been identified in MC2R, MRAP, MCM4 and TXNRD2. Also mutations in STAR and CYP11A1 can sometimes present with a phenotype resembling FGD. Recently, it has been indicated that FGD can also be caused by mutations in NNT (nicotinamide nucleotide transhydrogenase). We identified a 6.67 Mb homozygous region harboring the NNT gene by SNP haplotyping in a 1-year old Dutch boy presenting with FGD, but without mutations in MC2R and MRAP. Exome-sequencing revealed a novel homozygous mutation (NM_012343.3: c.1259dupG) in NNT that was predicted to be disease-causing. The mutation is located in exon 9 and creates a frameshift leading to a premature stop-codon (p.His421Serfs*4) that is known to result in FGD. Both parents were shown to be heterozygous carriers. We reviewed the literature for all the reported NNT mutations and their clinical presentation. The median age of disease onset in 23 reported patients, including the present patient, was 12 months (range 3 days to 39 months). There was no difference in age of disease onset between truncating and non-truncating NNT mutations. Based on recent literature, we advise to monitor patients with FGD due to NNT mutations for possible combined mineralocorticoid insufficiency and extra-adrenal manifestations.


      PubDate: 2015-11-09T16:01:53Z
       
  • Penetrance of pathogenic mutations in haploinsufficient genes for
           intellectual disability and related disorders
    • Abstract: Publication date: Available online 24 October 2015
      Source:European Journal of Medical Genetics
      Author(s): H. Hilger Ropers, Thomas Wienker



      PubDate: 2015-10-28T17:14:22Z
       
  • TGF-β signalopathies as a paradigm for translational medicine
    • Abstract: Publication date: Available online 24 October 2015
      Source:European Journal of Medical Genetics
      Author(s): Elyssa Cannaerts, Gerarda van de Beek, Aline Verstraeten, Lut Van Laer, Bart Loeys
      This review focusses on impact of a better knowledge of pathogenic mechanisms of Marfan and related disorders on their treatment strategies. It was long believed that a structural impairment formed the basis of Marfan syndrome as deficiency in the structural extracellular matrix component, fibrillin-1 is the cause of Marfan syndrome. However, the study of Marfan mouse models has revealed the strong involvement of the transforming growth factor-β signalling pathway in the pathogenesis of Marfan. Similarly, this pathway was demonstrated to be key in the pathogenesis of Loeys-Dietz and Shprintzen-Goldberg syndrome. The elucidation of the underlying pathogenic mechanisms has led to new treatment strategies, targeting the overactive TGF-β pathway. Various clinical trials are currently investigating the potential new treatment options. A meta-analysis will contribute to a better understanding of the various trial results.


      PubDate: 2015-10-28T17:14:22Z
       
  • A novel mutation in the C7orf11 gene causes nonphotosensitive
           trichothiodystrophy in a multiplex highly consanguineous kindred
    • Abstract: Publication date: Available online 27 October 2015
      Source:European Journal of Medical Genetics
      Author(s): Ben Pode-Shakked, Dina Marek-Yagel, Shoshana Greenberger, Naomi Pode-Shakked, Elon Pras, Aviv Barzilai, Saeed Yassin, Yechezkel Sidi, Yair Anikster
      Trichothiodystrophy (TTD), also known as sulfur-deficient brittle hair syndrome, is a rare autosomal recessive multisystem disorder, which manifests with brittle hair, mental retardation, ichthyosis and decreased fertility. Mutations in the TTDN1 (C7orf11) gene have been shown to cause a nonphotosensitive type of trichothiodystrophy. We report of a 19 years old male, born to consanguineous parents of Arab-Muslim descent, who presented due to severe renal failure, but exhibited additional unique features, including developmental delay, mental retardation, splenomegaly, pancytopenia, hypogonadism and brittle hair. Following the clinical diagnosis of nonphotosensitive TTD, sequencing of the coding exons of C7orf11 was performed and revealed the patient to be homozygous for a novel c.505dupA mutation. As the severe renal failure following which the proband was referred to our care is not typically characteristic of this disorder, its significance is discussed. Molecular diagnosis of this highly affected family should enable genetic counseling and prenatal diagnosis for future pregnancies.


      PubDate: 2015-10-28T17:14:22Z
       
  • Targeted multi-gene panel testing for the diagnosis of Bardet Biedl
           Syndrome: Identification of nine novel mutations across BBS1, BBS2, BBS4,
           BBS7, BBS9, BBS10 genes
    • Abstract: Publication date: Available online 27 October 2015
      Source:European Journal of Medical Genetics
      Author(s): Asli Ece Solmaz, Huseyin Onay, Tahir Atik, Ayca Aykut, Meltem Cerrah Gunes, Ozge Ozalp Yuregir, Veysel Nijat Bas, Filiz Hazan, Ozgur Kirbiyik, Ferda Ozkinay
      Bardet-Biedl Syndrome (BBS) is a rare, autosomal-recessive ciliopathy characterized by obesity, rod-cone dystrophy, postaxial polydactyly, renal abnormalities, genital abnormalities and learning difficulties. To date, mutations in 21 different genes have been described as being responsible for BBS. Recently sequential gene sequencing has been replaced by next generation sequencing (NGS) applications. In this study, 15 patients with clinically diagnosed BBS were investigated using a next generation sequencing panel which included 17 known BBS causing genes (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, NPHP6, WDPCP, SDCCAG8, NPHP1). A genetic diagnosis was achieved in 13 patients (86.6%) and involved 9 novel and 3 previously described pathogenic variants in 6 of 17 BBS causing genes. BBS10 and BBS1 were the most commonly involved genes with frequencies of 31% and 23% respectively. Three of the 13 patients had an affected sibling. All affected siblings were found to be homozygous for the mutation detected in the proband. No evidence of triallelic inheritance was detected. Although limited association between certain genes and phenotypic features has been observed in this study, it is considered that additional studies are needed to better characterize the genotype-phenotype correlation of BBS. Our results demonstrate that NGS panels are feasible and effective method for providing high diagnostic yields in the diseases caused by multiple genes such as BBS.


      PubDate: 2015-10-28T17:14:22Z
       
  • Enzymatic Diagnosis of Fabry Disease Using a Fluorometric Assay on Dried
           Blood Spots: An Alternative Methodology
    • Abstract: Publication date: Available online 28 October 2015
      Source:European Journal of Medical Genetics
      Author(s): Eric Caudron, Patrice Prognon, Dominique P. Germain
      Fabry disease (FD, OMIM#301500) is an X-linked lysosomal storage disorder caused by the functional deficiency of α-galactosidase A, a lysosomal enzyme. A method to screen for FD in large populations has been developed using a fluorometric assay of α-galactosidase A activity in dried blood spots (DBS) on filter paper. However, results can be influenced by quenching of fluorescence by haemoglobin which, together with small sample size, may result in a low light emission signal. An alternative, simple and sensitive fluorometric assay was developed for the determination of α-galactosidase A activity in DBS. The assay uses 4-methylumbelliferyl-α-D-galactose as an artificial substrate. To minimize the risk of false-positives, zinc sulfate was used for protein precipitation to stop the enzymatic reaction and eliminate interfering species (hemoglobin). Samples from 209 individuals (60 hemizygotes, 68 heterozygotes, and 81 controls) were tested to establish reference values for the assay. The mean α-galactosidase A activity of the 81 controls was 9.1 ± 3.3 μmol.h-1.L-1 (mean ± SD). All 60 hemizygotes affected with FD had AGAL activities below 1.7 μmol.h-1.L-1 (0.2 ± 0.3 μmol.h-1.L-1). For the 68 heterozygous females, AGAL activity ranged from 0 to 12.6 μmol.h-1.L-1 (3.5 ± 2.7 μmol.h-1.L-1). Two-thirds of the female patients could be identified using the enzymatic assay and a cut-off level of 40% of the median control value (<3.4 μmol.h-1.L-1). Our fluorometric assay using zinc sulfate protein precipitation was shown to have similar sensitivity and robustness while reducing the risk of false positive results due to quenching of 4-MU fluorescence by haemoglobin.


      PubDate: 2015-10-28T17:14:22Z
       
 
 
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