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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  [2575 journals]   [SJR: 1.029]   [H-I: 32]
  • A familial case with interstitial 2q36 deletion: Variable phenotypic
           expression in full and mosaic state
    • Abstract: Publication date: November 2012
      Source:European Journal of Medical Genetics, Volume 55, Issue 11
      Author(s): Érika L. Freitas , Susan M. Gribble , Milena Simioni , Társis P. Vieira , Elena Prigmore , Ana C. Krepischi , Carla Rosenberg , Peter L. Pearson , Débora G. Melo , Vera Lúcia Gil-da-Silva-Lopes
      Submicroscopic chromosomal anomalies play an important role in the etiology of craniofacial malformations, including midline facial defects with hypertelorism (MFDH). MFDH is a common feature combination in several conditions, of which Frontonasal Dysplasia is the most frequently encountered manifestation; in most cases the etiology remains unknown. We identified a parent to child transmission of a 6.2 Mb interstitial deletion of chromosome region 2q36.1q36.3 by array-CGH and confirmed by FISH and microsatellite analysis. The patient and her mother both presented an MFDH phenotype although the phenotype in the mother was much milder than her daughter. Inspection of haplotype segregation within the family of 2q36.1 region suggests that the deletion arose on a chromosome derived from the maternal grandfather. Evidences based on FISH, microsatellite and array-CGH analysis point to a high frequency mosaicism for presence of a deleted region 2q36 occurring in blood of the mother. The frequency of mosaicism in other tissues could not be determined. We here suggest that the milder phenotype observed in the proband's mother can be explained by the mosaic state of the deletion. This most likely arose by an early embryonic deletion in the maternal embryo resulting in both gonadal and somatic mosaicism of two cell lines, with and without the deleted chromosome. The occurrence of gonadal mosaicism increases the recurrence risk significantly and is often either underestimated or not even taken into account in genetic counseling where new mutation is suspected.
      Highlights ► Midline facial defects with hypertelorism. ► Ocular hypertelorism. ► Array-CGH. ► 2q36 deletion. ► Mosaic state.

      PubDate: 2014-12-14T21:44:24Z
  • Identification of a novel nonsense mutation and a missense substitution in
           the AGPAT2 gene causing congenital generalized lipodystrophy type 1
    • Abstract: Publication date: November 2012
      Source:European Journal of Medical Genetics, Volume 55, Issue 11
      Author(s): Amirreza Haghighi , Maryam Razzaghy-Azar , Ali Talea , Mahnaz Sadeghian , Sian Ellard , Alireza Haghighi
      Congenital generalized lipodystrophy (CGL) is an autosomal recessive disease characterized by the generalized scant of adipose tissue. CGL type 1 is caused by mutations in gene encoding 1-acylglycerol-3-phosphate O-acyltransferase-2 (AGPAT2). A clinical and molecular genetic investigation was performed in affected and unaffected members of two families with CGL type 1. The AGPAT2 coding region was sequenced in index cases of the two families. The presence of the identified mutations in relevant parents was tested. We identified a novel nonsense mutation (c.685G>T, p.Glu229*) and a missense substitution (c.514G>A, p.Glu172Lys). The unaffected parents in both families were heterozygous carrier of the relevant mutation. The results expand genotype–phenotype spectrum in CGL1 and will have applications in prenatal and early diagnosis of the disease. This is the first report of Persian families identified with AGPAT2 mutations.
      Highlights ► First diagnosis of congenital generalized lipodystrophy type 1 in Persian population. ► Molecular analysis identified a novel nonsense mutation and a missense substitution in the AGPAT2. ► The patients did not have diabetes mellitus or hyperinsulinemia. ► The mutations found are candidates for CGL screening. ► The results expand the knowledge about the genotype–phenotype correlations in CGL.

      PubDate: 2014-12-14T21:44:24Z
  • A microduplication of 5p15.33 reveals CLPTM1L as a candidate gene for
           cleft lip and palate
    • Abstract: Publication date: April 2013
      Source:European Journal of Medical Genetics, Volume 56, Issue 4
      Author(s): Giselle Izzo , Érika L. Freitas , Ana Cristina V. Krepischi , Peter L. Pearson , Luciana R. Vasques , Maria Rita S. Passos-Bueno , Débora R. Bertola , Carla Rosenberg
      We report a 10-year-old boy with syndromic cleft lip and palate (CLP) and neuro-psychomotor developmental delay. Oligoarray comparative genomic hybridization (aCGH) detected an approximately 300 kb interstitial microduplication at 5p15.33 encompassing 5 protein-coding genes, including TERT and CLPTM1L, and two microRNA genes. Our findings suggest that the duplicated segment predisposes for cleft lip with or without cleft palate (CL/P), or any of the other phenotypic features presented by the patient. A gene coding a similar protein (CLPMT1) has been implicated in CLP etiology both through linkage studies and by a translocation disrupting the gene, indicating the possible involvement of CLPTM1L with CL/P. This is the first report of a possible connection between CLPTM1L and CLP.
      Highlights ► A boy with syndromic CLP and neuro-psychomotor delay is reported. ► aCGH analysis revealed a rare interstitial microduplication of 5p15.33. ► The CNV has approximately 300 kb and includes 5 protein coding genes. ► Our findings suggest a predisposing region for cleft lip-palate on 5p.

      PubDate: 2014-12-14T21:44:24Z
  • Mutations in PYCR1 gene in three families with autosomal recessive cutis
           laxa, type 2
    • Abstract: Publication date: June 2013
      Source:European Journal of Medical Genetics, Volume 56, Issue 6
      Author(s): D.Z. Scherrer , M.B. Baptista , A.H.B. Matos , C.V. Maurer-Morelli , C.E. Steiner

      PubDate: 2014-12-14T21:44:24Z
  • Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a
           distinct syndromic phenotype
    • Abstract: Publication date: May 2013
      Source:European Journal of Medical Genetics, Volume 56, Issue 5
      Author(s): Michaela Auer-Grumbach , Heiko Bode , Thomas R. Pieber , Maria Schabhüttl , Dirk Fischer , Rainer Seidl , Elisabeth Graf , Thomas Wieland , Reinhard Schuh , Gerda Vacariu , Franz Grill , Vincent Timmerman , Tim M. Strom , Thorsten Hornemann
      Mutations in the serine palmitoyltransferase subunit 1 (SPTLC1) gene are the most common cause of hereditary sensory neuropathy type 1 (HSN1). Here we report the clinical and molecular consequences of a particular mutation (p.S331Y) in SPTLC1 affecting a patient with severe, diffuse muscle wasting and hypotonia, prominent distal sensory disturbances, joint hypermobility, bilateral cataracts and considerable growth retardation. Normal plasma sphingolipids were unchanged but 1-deoxy-sphingolipids were significantly elevated. In contrast to other HSN patients reported so far, our findings strongly indicate that mutations at amino acid position Ser331 of the SPTLC1 gene lead to a distinct syndrome.

      PubDate: 2014-12-14T21:44:24Z
  • Genetic factors in esophageal atresia, tracheo-esophageal fistula and the
           VACTERL association: Roles for FOXF1 and the 16q24.1 FOX transcription
           factor gene cluster, and review of the literature
    • Abstract: Publication date: January–February 2010
      Source:European Journal of Medical Genetics, Volume 53, Issue 1
      Author(s): Charles Shaw-Smith
      Esophageal atresia with/without tracheo-esophageal fistula is a relatively common malformation, occurring in around 1 in 3500 births. In around half of cases, additional malformations are present, forming either a syndrome of known genetic aetiology, or a recognised association, of which the VACTERL association (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal and Limb malformations) is the most recognised. Recently, microdeletions of the FOX gene cluster at 16q24.1, comprising four genes, FOXF1, MTHFSD, FOXC2 and FOXL1, were reported to cause a phenotype resembling VACTERL association, with vertebral anomalies, gastro-intestinal atresias (esophageal, duodenal and anal), congenital heart malformations, and urinary tract malformations, as well as a rare lethal developmental anomaly of the lung, alveolar capillary dysplasia. This article reviews these new data alongside other genetic causes of syndromic esophageal atresia, and also highlights information from relevant mouse models, particularly those for genes in the Sonic Hedgehog pathway.

      PubDate: 2014-12-14T21:44:24Z
  • SNP-array based whole genome homozygosity mapping: A quick and powerful
           tool to achieve an accurate diagnosis in LGMD2 patients
    • Abstract: Publication date: May–June 2011
      Source:European Journal of Medical Genetics, Volume 54, Issue 3
      Author(s): Lea Papić , Dirk Fischer , Slave Trajanoski , Romana Höftberger , Carina Fischer , Thomas Ströbel , Wolfgang M. Schmidt , Reginald E. Bittner , Maria Schabhüttl , Karin Gruber , Thomas R. Pieber , Andreas R. Janecke , Michaela Auer-Grumbach
      A large number of novel disease genes have been identified by homozygosity mapping and the positional candidate approach. In this study we used single nucleotide polymorphism (SNP) array-based, whole genome homozygosity mapping as the first step to a molecular diagnosis in the highly heterogeneous muscle disease, limb girdle muscular dystrophy (LGMD). In a consanguineous family, both affected siblings showed homozygous blocks on chromosome 15 corresponding to the LGMD2A locus. Direct sequencing of CAPN3, encoding calpain-3, identified a homozygous deletion c.483delG (p.Ile162SerfsX17). In a sporadic LGMD patient complete absence of caveolin-3 on Western blot was observed. However, a mutation in CAV3 could not be detected. Homozygosity mapping revealed a large homozygous block at the LGMD2I locus, and direct sequencing of FKRP encoding fukutin-related-protein detected the common homozygous c.826 C>A (p.Leu276Ile) mutation. Subsequent re-examination of this patient's muscle biopsy showed aberrant α-dystroglycan glycosylation. In summary, we show that whole-genome homozygosity mapping using low cost SNP arrays provides a fast and non-invasive method to identify disease-causing mutations in sporadic patients or sibs from consanguineous families in LGMD2. Furthermore, this is the first study describing that in addition to PTRF, encoding polymerase I and transcript release factor, FKRP mutations may cause secondary caveolin-3 deficiency.

      PubDate: 2014-12-14T21:44:24Z
  • A novel microdeletion in the IGF2/H19 imprinting centre region defines a
           recurrent mutation mechanism in familial Beckwith–Wiedemann syndrome
    • Abstract: Publication date: July–August 2011
      Source:European Journal of Medical Genetics, Volume 54, Issue 4
      Author(s): Agostina De Crescenzo , Filomena Coppola , Pietro Falco , Italo Bernardo , Gaetano Ausanio , Flavia Cerrato , Luigi Falco , Andrea Riccio
      The overgrowth disorder Beckwith–Wiedemann syndrome (BWS) is associated with dysregulation of imprinted genes at chromosome 11p15.5. The molecular defects are heterogeneous but most of the cases are associated with defective DNA methylation at either one of two Imprinting Control Regions (IC1 and IC2) or Uniparental paternal Disomy (UPD) at 11p15.5. In rare cases, the BWS phenotype has been found associated with maternal transmission of IC1 microdeletions. We describe a family with a novel 1.8kb deletion that is associated with hypermethylation at IC1. The mutation results from recombination between highly homologous sequences containing target sites for the zinc-finger protein CTCF (CTSs). This finding supports the hypothesis that the function of IC1 and the penetrance of the clinical phenotype depend on the spacing of the CTSs resulting from recombination in the mutant allele.

      PubDate: 2014-12-14T21:44:24Z
  • Unexpected results in the constitution of small supernumerary marker
    • Abstract: Publication date: March 2012
      Source:European Journal of Medical Genetics, Volume 55, Issue 3
      Author(s): Annalisa Vetro , Emmanouil Manolakos , Michael B. Petersen , Loretta Thomaidis , Thomas Liehr , Gianfranco Croci , Fabrizia Franchi , Maria Marinelli , Emanuela Meneghelli , Babara Dal Bello , Stefania Cesari , Angela Iasci , Giulia Arrigo , Orsetta Zuffardi
      Traditional approaches for the classification of Small Supernumerary Marker Chromosomes (sSMC), mostly based on FISH techniques, are time-consuming and not always sufficient to fully understand the true complexity of this class of rearrangements. We describe four supernumerary marker chromosomes that, after array-CGH, were interpreted rather differently in respect to the early classification made by conventional cytogenetics and FISH investigations, reporting two types of complex markers which DNA content was overlooked by conventional approaches: 1. the sSMC contains non-contiguous regions of the same chromosome and, 2. the sSMC, initially interpreted as a supernumerary del(15), turns out to be a derivative 15 to which the portion of another chromosome was attached. All are likely derived from partial trisomy rescue events, bringing further demonstration that germline chromosomal imbalances are submitted to intense reshuffling during the embryogenesis, leading to unexpected complexity and changing the present ideas on the composition of supernumerary marker chromosomes.

      PubDate: 2014-12-14T21:44:24Z
  • Using a combination of MLPA kits to detect chromosomal imbalances in
           patients with multiple congenital anomalies and mental retardation is a
           valuable choice for developing countries
    • Abstract: Publication date: July–August 2011
      Source:European Journal of Medical Genetics, Volume 54, Issue 4
      Author(s): Fernanda Sarquis Jehee , Jean Tetsuo Takamori , Paula F. Vasconcelos Medeiros , Ana Carolina B. Pordeus , Flavia Roche M. Latini , Débora Romeo Bertola , Chong Ae Kim , Maria Rita Passos-Bueno
      Conventional karyotyping detects anomalies in 3–15% of patients with multiple congenital anomalies and mental retardation (MCA/MR). Whole-genome array screening (WGAS) has been consistently suggested as the first choice diagnostic test for this group of patients, but it is very costly for large-scale use in developing countries. We evaluated the use of a combination of Multiplex Ligation-dependent Probe Amplification (MLPA) kits to increase the detection rate of chromosomal abnormalities in MCA/MR patients. We screened 261 MCA/MR patients with two subtelomeric and one microdeletion kits. This would theoretically detect up to 70% of all submicroscopic abnormalities. Additionally we scored the de Vries score for 209 patients in an effort to find a suitable cut-off for MLPA screening. Our results reveal that chromosomal abnormalities were present in 87 (33.3%) patients, but only 57 (21.8%) were considered causative. Karyotyping detected 15 abnormalities (6.9%), while MLPA identified 54 (20.7%). Our combined MLPA screening raised the total detection number of pathogenic imbalances more than three times when compared to conventional karyotyping. We also show that using the de Vries score as a cut-off for this screening would only be suitable under financial restrictions. A decision analytic model was constructed with three possible strategies: karyotype, karyotype + MLPA and karyotype + WGAS. Karyotype + MLPA strategy detected anomalies in 19.8% of cases which account for 76.45% of the expected yield for karyotype + WGAS. Incremental Cost Effectiveness Ratio (ICER) of MLPA is three times lower than that of WGAS, which means that, for the same costs, we have three additional diagnoses with MLPA but only one with WGAS. We list all causative alterations found, including rare findings, such as reciprocal duplications of regions deleted in Sotos and Williams–Beuren syndromes. We also describe imbalances that were considered polymorphisms or rare variants, such as the new SNP that confounded the analysis of the 22q13.3 deletion syndrome.

      PubDate: 2014-12-14T21:44:24Z
  • Array comparative genomic hybridization: Results from an adult population
           with drug-resistant epilepsy and co-morbidities
    • Abstract: Publication date: May 2012
      Source:European Journal of Medical Genetics, Volume 55, Issue 5
      Author(s): Elizabeth C. Galizia , Maithili Srikantha , Rodger Palmer , Jonathan J. Waters , Nicholas Lench , Caroline Mackie Ogilvie , Dalia Kasperavičiūtė , Lina Nashef , Sanjay M. Sisodiya
      Background The emergence of array comparative genomic hybridization (array CGH) as a diagnostic tool in molecular genetics has facilitated recognition of microdeletions and microduplications as risk factors for both generalised and focal epilepsies. Furthermore, there is evidence that some microdeletions/duplications, such as the 15q13.3 deletion predispose to a range of neuropsychiatric disorders, including intellectual disability (ID), autism, schizophrenia and epilepsy. We hypothesised that array CGH would reveal relevant findings in an adult patient group with epilepsy and complex phenotypes. Methods 82 patients (54 from the National Hospital for Neurology and Neurosurgery and 28 from King’s College Hospital) with drug-resistant epilepsy and co-morbidities had array CGH. Separate clinicians ordered array CGH and separate platforms were used at the two sites. Results In the two independent groups we identified copy number variants judged to be of pathogenic significance in 13.5% (7/52) and 20% (5/25) respectively, noting that slightly different selection criteria were used, giving an overall yield of 15.6%. Sixty-nine variants of unknown significance were also identified in the group from the National Hospital for Neurology and Neurosurgery and 5 from the King’s College Hospital patient group. Conclusion We conclude that array CGH be considered an important investigation in adults with complicated epilepsy and, at least at present for selected patients, should join the diagnostic repertoire of clinical history and examination, neuroimaging, electroencephalography and other indicated investigations in generating a more complete formulation of an individual’s epilepsy.
      Highlights ► Copy number variants may predispose to a range of neuropsychiatric disorders. ► Array CGH may reveal relevant findings in adults with complex phenotypes. ► Likely pathogenic copy number changes were identified with a yield of 15.6%. ► Array CGH should join the diagnostic repertoire for adults with complex phenotypes.

      PubDate: 2014-12-14T21:44:24Z
  • The internet is parents' main source of information about psychiatric
           manifestations of 22q11.2 deletion syndrome (22q11.2DS)
    • Abstract: Publication date: August 2013
      Source:European Journal of Medical Genetics, Volume 56, Issue 8
      Author(s): Marianne B.M. van den Bree , Gregory Miller , Elizabeth Mansell , Anita Thapar , Frances Flinter , Michael J. Owen
      With advances in laboratory technology, an increasing number of potentially pathogenic CNVs is recognised. The phenotypic effects of some CNVs are well characterised, however, it remains unclear how much information reaches the parents of affected children and by what route. The 22q11.2 deletion syndrome (del22q11.2) is caused by the deletion of approximately 40 genes from the long arm of chromosome 22 and was first described in 1955 [1]. Our study reports the extent to which parents of an affected child are aware of the various manifestation of the condition and describes how they first learned about these potential problems.

      PubDate: 2014-12-14T21:44:24Z
  • Atypical copy number abnormalities in 22q11.2 region: Report of three
    • Abstract: Publication date: September 2013
      Source:European Journal of Medical Genetics, Volume 56, Issue 9
      Author(s): Miriam Coelho Molck , Társis Paiva Vieira , Ilária Cristina Sgardioli , Milena Simioni , Ana Paula dos Santos , Josiane Souza , Fabíola Paoli Monteiro , Vera Lúcia Gil-da-Silva-Lopes
      The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion syndrome in humans, with a highly variable phenotype. This chromosomal region contains low copy repeat (LCR) sequences that mediate non-allelic homologous recombination which predispose to copy number abnormalities at this locus. This article describes three patients investigated for suspicion of 22q11.2DS presenting atypical copy number abnormalities overlapping or not with the common ∼3 Mb deletion. They were investigated by G-banding karyotype, Multiplex-ligation dependent probe amplification (MLPA) and array Genomic Hibridization (aGH). Clinical and molecular data were compared with literature, in order to contribute to genotype–phenotype correlation. Atypical chromosomal abnormalities were detected: 3.6 Mb deletion at 22q11.21-q11.23 between LCRs B–F in patient 1 and approximately 1.5 Mb deletion at 22q11.21-q11.22 between LCRs D–E in patients 2 and 3. The breakpoints detected in patient 1 have not been previously described. These findings exemplify the complexity and genetic heterogeneity observed in 22q11.2 region and corroborates the idea that genetic modifiers contribute to the phenotypic variability observed in proximal and distal 22q11.2 deletion syndromes.

      PubDate: 2014-12-14T21:44:24Z
  • Novel candidate genes for 46,XY gonadal dysgenesis identified by a
           customized 1 M array-CGH platform
    • Abstract: Publication date: December 2013
      Source:European Journal of Medical Genetics, Volume 56, Issue 12
      Author(s): Ameli Norling , Angelica Lindén Hirschberg , Erik Iwarsson , Bengt Persson , Anna Wedell , Michela Barbaro
      Half of all patients with a disorder of sex development (DSD) do not receive a specific molecular diagnosis. Comparative genomic hybridization (CGH) can detect copy number changes causing gene haploinsufficiency or over-expression that can lead to impaired gonadal development and gonadal DSD. The purpose of this study was to identify novel candidate genes for 46,XY gonadal dysgenesis (GD) using a customized 1 M array-CGH platform with whole-genome coverage and probe enrichment targeting 78 genes involved in sex development. Fourteen patients with 46,XY gonadal DSD were enrolled in the study. Nine individuals were analyzed by array CGH. All patients were included in a follow up sequencing study of candidate genes. Three novel candidate regions for 46,XY GD were identified in two patients. An interstitial duplication of the SUPT3H gene and a deletion of C2ORF80 were detected in a pair of affected siblings. Sequence analysis of these genes in all patients revealed no additional mutations. A large duplication highlighting PIP5K1B, PRKACG and FAM189A2 as candidates for 46,XY GD, were also detected. All five genes are expressed in testicular tissues, and one is shown to cause gonadal DSD in mice. However detailed functional information is lacking for these genes.

      PubDate: 2014-12-14T21:44:24Z
  • The genetics of auricular development and malformation: new findings in
           model systems driving future directions for microtia research
    • Abstract: Publication date: Available online 29 May 2014
      Source:European Journal of Medical Genetics
      Author(s): Timothy C. Cox , Esra D. Camci , Siddharth Vora , Daniela V. Luquetti , Eric E. Turner
      Microtia is a term used to describe a wide array of phenotypic presentations of the outer ear. Although the majority of the cases are isolated in nature, much of our understanding of the causes of microtia has been driven by the identification of genes underlying syndromic forms where the anomaly co-presents with various other craniofacial and extra-craniofacial structural defects. In this review we discuss recent findings in mice deficient in Hoxa2, a key regulator of branchial arch patterning, which has necessitated a revision to the canonical model of pinna morphogenesis. The revised model will likely impact current classification schemes for microtia and, as we argue in this review, the interpretation of the developmental basis for various auricular malformations. In addition, we highlight recent studies in other mammalian species that are providing the first clues as to possible causes of at least some isolated anomalies and thus should now accelerate the search for the more elusive genetic contributions to the many isolated and non-syndromic cases of microtia. These findings, together with the application of new genome-level sequencing technologies and more thorough quantitative assessment of available mutant mouse resources, promise an exciting future for genetic studies in microtia.

      PubDate: 2014-06-01T15:29:50Z
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