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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  [2563 journals]   [SJR: 1.029]   [H-I: 32]
  • Haploinsufficiency of XP01 and USP34 by a de novo 230 kb deletion in 2p15,
           in a patient with mild intellectual disability and cranio-facial
           dysmorphisms
    • Abstract: Publication date: Available online 7 June 2014
      Source:European Journal of Medical Genetics
      Author(s): Madeleine Fannemel , Tuva Barøy , Asbjørn Holmgren , Olaug K. Rødningen , Trine M. Haugsand , Børre Hansen , Eirik Frengen , Doriana Misceo
      2p15p16.1-deletion syndrome was first described in 2007 based on the clinical presentation of two patients. The syndrome is characterized by intellectual disability, autism spectrum disorders, microcephaly, dysmorphic facial features and a variety of congenital organ defects. The precise genotype-phenotype correlation in 2p15- deletion syndrome is not understood. However, greater insight can be obtained by thorough clinical investigation of patients carrying deletions, especially those of small size. We report a 21-year-old male patient with features overlapping the clinical spectrum of the 2p15p16.1 deletion syndrome, such as intellectual disability, dysmorphic facial features, and congenital defects. He carried a 230 kb de novo deletion (chr2:61500346-61733075 bp, hg19), which affects the genes USP34, SNORA70B and XPO1. While there is a lack of functional data on SNORA70B, the involvement of USP34 and XPO1 in the regulation of fundamental developmental processes is well known. We suggest that haploinsuffiency of one or both of these genes is likely to be responsible for the disease in our patient.


      PubDate: 2014-06-07T15:55:31Z
       
  • New mutations and polymorphisms of the ATP7B gene in sporadic Wilson
           disease
    • Abstract: Publication date: Available online 28 May 2014
      Source:European Journal of Medical Genetics
      Author(s): Cong-Xia Lu , Qing -Lin , Wen-Qing Huang , Chi-Meng Tzeng
      Wilson's disease (WD) is a rare autosomal recessive genetic disorder of copper metabolism resulting in brain damage, liver failure, and neurological impairment and psychiatric disturbances, as a result of excessive copper accumulation in the brain, liver, kidneys and eyes. ATP7B, encoding a copper transporter P-ATPase was identified as the causative gene of WD. Mutations in the ATP7B gene lead to the defection of the transmembrane transporter so that it can not metabolize copper effectively. We reported the clinical and molecular features of three unrelated and non-consanguineous WD patients. We performed molecular genetic analysis of the ATP7B gene in all cases by DNA sequencing, and revealed 7 novel single nucleotide polymorphisms (SNPs) and 8 well known mutations. Among them, that novel SNP (c. -520 C>T) and two well known mutations (c. 2310 C>G/p. Leu700Leu, c. 2333 G>T/A/p. Arg778Leu/Gln) coexisted in all patients and they were heterozygous and homozygous in the youngest case, respectively, indicating that they may be correlated to the pathogenesis and potentially used as a genetic biomarker for early WD diagnosis.


      PubDate: 2014-06-01T15:29:50Z
       
  • Severe ipsilateral musculoskeletal involvement in a Cornelia de Lange
           patient with a novel NIPBL mutation
    • Abstract: Publication date: Available online 26 May 2014
      Source:European Journal of Medical Genetics
      Author(s): Carolina Baquero-Montoya , María-Concepción Gil-Rodríguez , María Hernández-Marcos , María-Esperanza Teresa-Rodrigo , Alicia Vicente-Gabas , María-Luisa Bernal , Cesar-Horacio Casale , Gloria Bueno-Lozano , Inés Bueno-Martínez , Ethel Queralt , Olaya Villa , Cristina Hernando-Davalillo , Lluís Armengol , Paulino Gómez-Puertas , Beatriz Puisac , Angelo Selicorni , Feliciano J. Ramos , Juan Pié
      Cornelia de Lange Syndrome (CdLS) is a congenital autosomal dominant (NIPBL, SMC3 and RAD21) or X-linked (SMC1A and HDAC8) disorder characterized by facial dysmorphism, pre and postnatal growth retardation, developmental delay and/or intellectual disability, and multiorgan involvement. Musculoskeletal malformations are usually bilateral and affect mainly the upper limbs; the range goes from brachyclinodactyly to severe reduction defects. Instead lower extremities are usually less and mildly involved. Here, we report on a 3-year-old Senegalese boy with typical craniofacial CdLS features, pre and postnatal growth retardation, atrial septal defect, developmental delay and right ipsilateral limb malformations, consistent with oligodactyly of the 3rd and 4th fingers, tibial agenesis and fibula hypoplasia. Exome Sequencing and Sanger sequencing showed a novel missense mutation in NIPBL gene (c.6647A>G; p.(Tyr2216Cys)), which affects a conserved residue located within NIPBL HEAT repeat elements. Pyrosequencing analysis of NIPBL gene, disclosed similar levels of wild-type and mutated alleles in DNA and RNA samples from all tissues analyzed (oral mucosa epithelial cells, peripheral blood leukocytes and fibroblasts). These findings indicated the absence of somatic mosaicism, despite of the segmental asymmetry of the limbs, and confirmed biallelic expression for NIPBL transcripts, respectively. Additionally, conditions like Split-hand/foot malformation with long-bone deficiency secondary to duplication of BHLHA9 gene have been ruled out by the array-CGH and MLPA analysis. To our knowledge, this is the first CdLS patient described with major ipsilateral malformations of both the upper and lower extremities, that even though this finding could be due to a random event, expands the spectrum of limb reduction defects in CdLS.


      PubDate: 2014-06-01T15:29:50Z
       
  • 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
       
  • Exome sequencing identifies a recessive PIGN splice site mutation as a
           cause of syndromic Congenital Diaphragmatic Hernia
    • Abstract: Publication date: Available online 20 May 2014
      Source:European Journal of Medical Genetics
      Author(s): P.D. Brady , Philippe Moerman , Luc De Catte , J. Deprest , K. Devriendt , J.R. Vermeesch
      Using exome sequencing we identify a homozygous splice site mutation in the PIGN gene in a foetus with multiple congenital anomalies including bilateral diaphragmatic hernia, cardiovascular anomalies, segmental renal dysplasia, facial dysmorphism, cleft palate, and oligodactyly. This finding expands the phenotypic spectrum associated with homozygous loss of function mutations in PIGN, and adds further support for defective GPI anchor biosynthesis as a cause of developmental abnormalities. We demonstrate that exome sequencing is a valuable approach for the identification of a genetic cause in sporadic cases of MCA due to inherited mutations.


      PubDate: 2014-05-25T16:18:42Z
       
  • Interstitial deletion 1p36.32 in two brothers with a distinct phenotype -
           overgrowth, macrocephaly and nearly normal intellectual function
    • Abstract: Publication date: Available online 23 May 2014
      Source:European Journal of Medical Genetics
      Author(s): N. Di Donato , B. Klink , G. Hahn , E. Schrock , K. Hackmann
      We report on two adult patients, who both presented with overgrowth and one of them additionally with macrocephaly while carrying an 1p36 microdeletion of about 2.1 Mb. They are full brothers born to unaffected parents. Although both brothers attended special schools, they lived independently without a legal guardian and were able to succeed in regular jobs. One of the brothers received a professional education. Genetic analysis of the parents revealed neither the microdeletion nor a cryptical translocation or inversion. We suggest that the recurrent deletion is a result of germline mosaicism, a phenomenon reported only once in the context of the 1p36 microdeletion syndrome. Our report confirms the recurrence of the apparently de novo 1p36 microdeletion due to a likely germline mosaicism of one of the parents. Furthermore, it illustrates the possibility of the distinct phenotype with a nearly normal intellectual outcome of the 1p36 microdeletion syndrome that might be due to the region involved in our patients.


      PubDate: 2014-05-25T16:18:42Z
       
  • The Genetic Architecture of Microphthalmia, Anophthalmia and Coloboma
    • Abstract: Publication date: Available online 22 May 2014
      Source:European Journal of Medical Genetics
      Author(s): Kathleen A. Williamson , David R. FitzPatrick
      Microphthalmia, anophthalmia and coloboma (MAC) are distinct phenotypes that represent a continuum of structural developmental eye defects. In severe bilateral cases (anophthalmia or severe microphthalmia) the genetic cause is now identifiable in approximately 80 percent of cases, with de novo heterozygous loss-of-function mutations in SOX2 or OTX2 being the most common. The genetic cause of other forms of MAC, in particular isolated coloboma, remains unknown in the majority of cases. This review will focus on MAC phenotypes that are associated with mutation of the genes SOX2, OTX2, PAX6, STRA6, ALDH1A3, RARB, VSX2, RAX, FOXE3, BMP4, BMP7, GDF3, GDF6, ABCB6, ATOH7, C12orf57, TENM3 (ODZ3), and VAX1. Recently reported mutation of the SALL2 and YAP1 genes are discussed in brief. Clinical and genetic features were reviewed in a total of 283 unrelated MAC cases or families that were mutation-positive from these 20 genes. Both the relative frequency of mutations in MAC cohort screens and the level of confidence in the assignment of disease-causing status were evaluated for each gene.


      PubDate: 2014-05-25T16:18:42Z
       
  • An unusual presentation of Kabuki syndrome: clinical overlap with CHARGE
           syndrome
    • Abstract: Publication date: Available online 23 May 2014
      Source:European Journal of Medical Genetics
      Author(s): Judith M.A. Verhagen , Wilma Oostdijk , Cecilia E.J. Terwisscha van Scheltinga , Nicoline E. Schalij-Delfos , Yolande van Bever
      Kabuki syndrome is a rare genetic disorder characterized by intellectual disability and multiple congenital anomalies, including short stature, peculiar facial appearance, skeletal anomalies, a variety of visceral malformations and abnormal dermatoglyphic patterns. We describe a case of Kabuki syndrome presenting with atypical features, consisting of bilateral microphthalmia, coloboma, anal atresia and panhypopituitarism, showing considerable phenotypic overlap with CHARGE syndrome. This report demonstrates that clinical follow-up and molecular genetic testing can be useful for establishing the correct diagnosis.


      PubDate: 2014-05-25T16:18:42Z
       
  • Atypical breakpoint in a t(6;17) translocation case of acampomelic
           campomelic dysplasia
    • Abstract: Publication date: Available online 10 May 2014
      Source:European Journal of Medical Genetics
      Author(s): Lauren C. Walters-Sen , Devon Lamb Thrush , Scott E. Hickey , Sayaka Hashimoto , Shalini Reshmi , Julie M. Gastier-Foster , Robert E. Pyatt , Caroline Astbury
      Campomelic dysplasia (CD) is a skeletal dysplasia characterized by Pierre Robin sequence (PRS), shortened and bowed long bones, airway instability, and the potential for sex reversal. A subtype of CD, acampomelic CD (ACD), is seen in approximately 10% of cases and preserves long bone straightness. Both syndromes are caused by alterations in SOX9, with translocations and missense mutations being overrepresented in ACD cases. We report a term infant with PRS, severe cervical spine abnormalities, eleven rib pairs, hypoplastic scapulae, and female genitalia. Chromosome analysis identified a 46,XY,t(6;17)(q25;q24) karyotype. FISH analysis with a series of BAC probes localized the translocation breakpoints to 6q27 and a region at 17q24.3 in the range of 459–379 kb upstream of SOX9. Therefore, this case extends the region classified as the proximal breakpoint cluster. In addition, the comorbidity of acampomelia, complete sex reversal, and severe spinal anomalies in our patient underscores the variability in the level of malformation in the CD/ACD family of disorders.


      PubDate: 2014-05-15T06:29:27Z
       
  • Authors' response to the Letter to the Editor “Left ventricular
           noncompaction associated with a compound heterozygous MYBPC3
           mutation”
    • Abstract: Publication date: Available online 13 May 2014
      Source:European Journal of Medical Genetics
      Author(s): Elise Schaefer , Gilles Millat



      PubDate: 2014-05-15T06:29:27Z
       
  • Pectus excavatum and carinatum
    • Abstract: Publication date: Available online 10 May 2014
      Source:European Journal of Medical Genetics
      Author(s): Jan M. Cobben , Roelof-Jan Oostra , Fleur S. van Dijk
      Pectus excavatum and carinatum are the most common morphological chest wall abnormalities. For both pectus excavatum and carinatum the pathogenesis is largely unknown although various hypotheses exist. Usually, exclusion of an underlying syndromal or connective tissue disorder is the reason for referral for genetic evaluation. A detailed anamnesis and family history are needed as well as a complete dysmorphological physical examination. If no features of an underlying disorder are detected, then the pectus excavatum/carinatum can be considered as an isolated abnormality and no further genetic studies seem indicated. Although cases of non-syndromal pectus excavatum/carinatum with a positive family history fitting Mendelian inheritance have been described, it is possible that these pedigrees represent multifactorial inheritance, as no genetic cause for familial isolated pectus excavatum/carinatum has been described yet. The recurrence risk for a non-familial iolated pectus excavatum/carinatum is unknown, but thought to be low. If other symptoms are found then appropriate further diagnostic studies are indicated as pectus excavatum/carinatum can be part of many syndromes. However, the most important and most frequently observed monogenic syndromes with pectus excavatum/carinatum are Marfan Syndrome and Noonan Syndrome.


      PubDate: 2014-05-15T06:29:27Z
       
  • Associated nonurinary congenital anomalies among infants with congenital
           anomalies of kidney and urinary tract (CAKUT)
    • Abstract: Publication date: Available online 10 May 2014
      Source:European Journal of Medical Genetics
      Author(s): Claude Stoll , Beatrice Dott , Yves Alembik , Marie-Paule Roth
      Infants with congenital anomalies of kidney and urinary tract (CAKUT) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CAKUT in a defined population from northeastern France. The associated anomalies in CAKUT were collected in all livebirths, stillbirths and terminations of pregnancy during 26 years in 346,831 consecutive births of known outcome in the area covered by our population based registry of congenital anomalies. Of the 1678 infants with CAKUT born during this period (prevalence at birth of 48.4 per 10,000), 563(34 %) had associated anomalies. There were 119 (7%) patients with chromosomal abnormalities including 33 trisomies 18 (2%), and 168 (10%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognised dysmorphic conditions, but VA(C)TER(L) association (3%). However, other recognised dysmorphic conditions were registered including Meckel-Gruber syndrome (2%), and prune belly syndrome (1%). Two hundred seventy six (16 %) of the patients had multiple congenital anomalies, non syndromic, non chromosomal (MCA). Anomalies in the musculoskeletal, the digestive, the cardiovascular and the central nervous systems were the most common other anomalies. Prenatal diagnosis was obtained in 71 % of dysmorphic syndromes with CAKUT. In conclusion the overall prevalence of associated anomalies, which was one in three infants, emphasizes the need for a thorough investigation of infants with CAKUT. The most commonly associated major nonurinary anomalies involved the musculoskeletal system, followed by the digestive, the cardiovascular and the central nervous systems. A routine screening for other anomalies may be considered in infants and in fetuses with CAKUT. One should be aware that the anomalies associated with CAKUT can be classified into a recognizable anomaly syndrome or pattern in one out of six infants with CAKUT.


      PubDate: 2014-05-10T06:29:26Z
       
  • A novel missense mutation in CACNA1A evaluated by in silico protein
           modeling is associated with non-episodic spinocerebellar ataxia with slow
           progression
    • Abstract: Publication date: April 2014
      Source:European Journal of Medical Genetics, Volume 57, Issue 5
      Author(s): Katrin Bürk , Frank J. Kaiser , Stephanie Tennstedt , Ludger Schöls , Friedmar R. Kreuz , Thomas Wieland , Tim M. Strom , Thomas Büttner , Ronja Hollstein , Diana Braunholz , Jens Plaschke , Gabriele Gillessen-Kaesbach , Christine Zühlke
      Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are allelic disorders of the gene CACNA1A encoding the P/Q subunit of a voltage gated calcium channel. While SCA6 is related to repeat expansions affecting the C-terminal part of the protein, EA2 and FHM phenotypes are usually associated with nonsense and missense mutations leading to impaired channel properties. In three unrelated families with dominant cerebellar ataxia, symptoms cosegregated with CACNA1A missense mutations of evolutionary highly conserved amino acids (exchanges p.E668K, p.R583Q and p.D302N). To evaluate pathogenic effects, in silico, protein modeling analyses were performed which indicate structural alterations of the novel mutation p.E668K within the homologous domain 2 affecting CACNA1A protein function. The phenotype is characterised by a very slowly progressive ataxia, while ataxic episodes or migraine are uncommon. These findings enlarge the phenotypic spectrum of CACNA1A mutations.


      PubDate: 2014-05-05T11:18:38Z
       
  • The genetics of common disorders – Congenital diaphragmatic hernia
    • Abstract: Publication date: Available online 2 May 2014
      Source:European Journal of Medical Genetics
      Author(s): Anne M. Slavotinek
      Congenital diaphragmatic hernia (CDH) is a common birth defect with a high mortality and morbidity. Although numerous chromosomal aberrations and gene mutations have been associated with CDH, the etiology of the diaphragmatic defect is identified in less than 50% of patients. This review discusses the some of the more frequent, recurrent karyotypic abnormalities in which CDH is a feature, including 15q26, 8p23.1 and 4p16.3 deletions and tetrasomy 12p (Pallister–Killian syndrome), together with some of the syndromes in which CDH is a relatively common feature, including Fryns syndrome, Matthew-Wood syndrome, overgrowth syndromes and Donnai–Barrow syndrome. In the era of genomic technologies, our knowledge of the genes and chromosome regions involved in pathogenesis of CDH is likely to advance significantly.


      PubDate: 2014-05-05T11:18:38Z
       
  • Progressive Cognitive Decline in an Adult Patient with Cleidocranial
           Dysplasia
    • Abstract: Publication date: Available online 2 May 2014
      Source:European Journal of Medical Genetics
      Author(s): Toshiki Takenouchi , Wakiro Sato , Chiharu Torii , Kenjiro Kosaki
      Cleidocranial dysplasia is a rare skeletal disorder characterized by a defective skull and defective clavicles caused by RUNX2, an activator of osteoblast differentiation. Consistent with the expression pattern of RUNX2, this disorder typically affects the skeletal system, but not the central nervous system. A 56-year-old man with the prototypic skeletal defects of cleidocranial dysplasia and a RUNX2 deletion presented with a progressive cognitive decline after the age of 40 years. After a failed cranioplasty during childhood, he had worn a protective helmet until young adulthood. His current neuroimaging studies revealed extensive cystic encephalomalacia beneath the defective skull, suggesting that his cognitive decline could likely be attributed to repetitive cerebral contusions. Late-onset progressive cognitive decline in the context of a defective skull accompanied by extensive cystic encephalomalacia illustrates the importance of natural calvarial protection against head injury. Since the majority of patients with cleidocranial dysplasia do not wear protective helmets beyond childhood, mainly for cosmetic reasons, a discussion of whether the social disadvantage outweighs the potential risk of brain parenchymal injury may be necessary.


      PubDate: 2014-05-05T11:18:38Z
       
  • Postnatal diagnosis of 9q interstitial imbalances involving PTCH1,
           resulting from a familial intrachromosomal insertion
    • Abstract: Publication date: April 2014
      Source:European Journal of Medical Genetics, Volume 57, Issue 5
      Author(s): Marina Blanchard , Christèle Dubourg , Laurent Pasquier , Sylvie Odent , Josette Lucas , Chloé Quélin , Erika Launay , Linda Akloul , Catherine Henry , Marc-Antoine Belaud-Rotureau , Frédéric Dugay , Sylvie Jaillard
      Insertions are rare chromosomal rearrangements resulting from a three breaks mechanism. The risk of chromosomal imbalance in the offspring is estimated to be 15–50%. We have identified a familial history of direct, paracentric intrachromosomal 9q insertion, balanced in healthy members. For intrachromosomal insertions, unbalanced products in the offspring are always recombinants and in our case, reciprocal deletion and duplication of the inserted segment (9q22.31–9q31.1) were observed. These imbalances involved several genes, including PTCH1. PTCH1 haploinsufficiency causes Gorlin syndrome, an autosomal dominant disorder usually linked to the gene mutation but sometimes due to a 9q deletion. Clinical findings are different in 9q deletions and duplications including PTCH1, notably concerning the predisposition to benign and malignant tumors reported in the Gorlin syndrome. Furthermore, some features may be reciprocal. This history of intrachromosomal insertion highlights the importance of morphological cytogenetic analyses to provide an accurate genetic counseling.


      PubDate: 2014-05-05T11:18:38Z
       
  • Clinical assessment of five patients with BRWD3 mutation at Xq21.1 gives
           further evidence for mild to moderate intellectual disability and
           macrocephaly
    • Abstract: Publication date: April 2014
      Source:European Journal of Medical Genetics, Volume 57, Issue 5
      Author(s): Sarah Grotto , Valérie Drouin-Garraud , Katrin Õunap , Helen Puusepp-Benazzouz , Janneke Schuurs-Hoeijmakers , Nathalie Le Meur , Pascal Chambon , Séverine Fehrenbach , Hans van Bokhoven , Thierry Frébourg , Arjan P.M. de Brouwer , Pascale Saugier-Veber
      Truncating mutations of the BRWD3 gene have been reported in two distinct families with in total four patients so far. By using array-CGH, we detected a 74 Kb de novo deletion encompassing exons 11 through 41 of BRWD3 at Xq21.1 in a 20 year old boy presenting with syndromic intellectual disability. In addition, by using exome sequencing, we ascertained a family with a BRWD3 nonsense mutation, p.Tyr1131*, in four males with intellectual disability. We compared the clinical presentation of these five patients to that of the four patients already described in the literature for further delineation of the clinical spectrum in BRWD3-related intellectual disability. The main symptoms are mild to moderate intellectual disability (n = 9/9) with speech delay (n = 8/8), behavioral disturbances (n = 7/8), macrocephaly (n = 7/9), dysmorphic facial features (n = 9/9) including prominent forehead, pointed chin, deep-set eyes, abnormal ears, and broad hands and feet (n = 6/6), and skeletal symptoms (n = 7/7) like pes planus, scoliosis, kyphosis and cubitus valgus.


      PubDate: 2014-05-05T11:18:38Z
       
  • Genetic basis of congenital cardiovascular malformations
    • Abstract: Publication date: Available online 30 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Seema R. Lalani , John W. Belmont
      Cardiovascular malformations are a singularly important class of birth defects and, due to dramatic improvements in medical and surgical care, there are now large numbers of adult survivors. The etiologies are complex, but there is strong evidence that genetic factors play a crucial role. Over the last 15 years there has been enormous progress in the discovery of causative genes for syndromic heart malformations and in rare families with Mendelian forms. The rapid characterization of genomic disorders as major contributors to congenital heart defects is also notable. The genes identified encode many transcription factors, chromatin regulators, growth factors and signal transduction pathways– all unified by their required roles in normal cardiac development. Genome-wide sequencing of the coding regions promises to elucidate genetic causation in several disorders affecting cardiac development. Such comprehensive studies evaluating both common and rare variants would be essential in characterizing gene–gene interactions, as well as in understanding the gene–environment interactions that increase the susceptibility to congenital heart defects.


      PubDate: 2014-05-05T11:18:38Z
       
  • Co-Occurrence in Body Site of Malformations and Cancer
    • Abstract: Publication date: Available online 2 May 2014
      Source:European Journal of Medical Genetics
      Author(s): Fonnet E. Bleeker , Saskia M. Hopman , Raoul C. Hennekam
      In many malformation syndromes benign and malignant tumours develop more frequently than in the general population. Malformations result from an abnormal intrinsic developmental process. It can be hypothesized that disturbed regulation of cell growth as can become evident by the presence of benign and malignant tumours, which will occur at the same site of a malformation or at other sites at which the gene involved in the malformation is functioning. The present study aimed to compare the localization of malignant and benign tumours to the localization of major and minor characteristics of syndromes that have either of two malformations, i.e. microtia and hypospadias. To eliminate co-occurrence of a malformation syndrome and tumours by chance we confined evaluations to syndromes which have been described in >100 individuals. We identified 11 syndromes associated with microtia and 26 syndromes associated with hypospadias, for which co-localisation of (benign and malignant) tumours with (major and minor) syndrome characteristics was determined. In both groups of syndromes tumours were found to be localized at the same body site as the major and minor characteristics of the syndromes in two-third of the tumours. There was no significant difference in co-occurrence in site between benign and malignant tumours. We conclude that in two groups of malformation syndromes which go along with a different core malformation, benign and malignant tumours co-localize with the core malformation or with other sites at which the gene involved is functioning. This adds further proof that tumours in malformation syndromes can usually be explained by abnormal functioning of the same gene that has caused the malformation syndrome.


      PubDate: 2014-05-05T11:18:38Z
       
  • Nonmosaic tetrasomy 15q25.2 → qter identified with SNP
           microarray in a patient with characteristic facial appearance and review
           of the literature
    • Abstract: Publication date: Available online 30 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Huihui Xu , Bing Xiao , Xing Ji , Qin Hu , Yingwei Chen , Wenjuan Qiu
      Tetrasomy for the distal chromosome 15q is rare, and only 22 patients (including 6 cases without detailed information) have been described to date in the literature. Here we report on another patient with nonmosaic tetrasomy 15q25.2-qter resulted from an inverted duplication of distal chromosome 15. This patient presents with features of development delay, arachnodactyly, joint contractures and typical facial dysmorphism including frontal bossing, short palpebral fissures, long philtrum, low-set ears, high-arched palate and retrognathia. Unlike most of the related patients, abdominal ultrasound test and brain MRI showed normal. Karyotyping analysis revealed a supernumerary marker chromosome presented in all metaphase cells examined. Parental karyotyping analysis was normal, indicating a de novo chromosome aberration of the patient. SNP microarray analysis found a two copy gain of 17.7 Mb from the distal long arm of chromosome 15 (15q25.2-qter). Further FISH analysis using SureFISH 15q26.3 IGF1R probe proved an inverted duplication of distal long arm of chromosome 15. The segmental duplications which lie in the hotspots of 15q24-26 might increase the susceptibility of chromosome rearrangement. Compared with the George-Abraham' study [2012], ADAMTSL3 might be more related to the cardiac disorders in tetrasomy 15q patients. Considering all patients reported in the literature, different mosaic degrees and segmental sizes don't correlate to the severity of phenotypes. A clear delineation on tetrasomy for distal chromosome 15q could still be investigated.


      PubDate: 2014-05-05T11:18:38Z
       
  • Genotype-phenotype relationship in a child with 2.3 Mb de novo
           interstitial 12p13.33-p13.32 deletion
    • Abstract: Publication date: Available online 26 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Isabella Fanizza , Sara Bertuzzo , Silvana Beri , Elisabetta Scalera , Angelo Massagli , Maria Enrica Sali , Roberto Giorda , Maria Clara Bonaglia
      Microdeletion 12p13.33, though very rare, is an emerging condition associated with variable phenotype including a specific speech delay sound disorder, labeled childhood apraxia of speech (CAS), intellectual disability (ID) and neurobehavioral problems. Here we report a de novo 2.3 Mb interstitial 12p13.33-p13.32 deletion in a 5 year-old child with mild ID, speech delay, microcephaly, muscular hypotonia, and joint laxity. In contrast to previously reported patients with 12p13.33 monosomy, our patient’s interstitial deletion spans the 12p13.33-12p13.32 region with the distal breakpoint within intron 12 of CACNA1C . Phenotype-genotype comparison between our case, previously reported patients, and subjects with 12p13.33 deletions led us to propose that haploinsufficiency of CACNA1C may influence the variability of the patients’ phenotype, since the gene resulted disrupted or entirely deleted in the majority of reported patients. In addition, phenotypic features such as microcephaly, muscular hypotonia, and joint laxity are mainly present in patients with monosomy of 12p13.33 extending to the 12p13.32 portion. A common region of ∼300 Kb, harboring EFCAB4B and PARP11, is deleted in patients with microcephaly while a second region of ∼700 Kb , including TSPAN9 and PMTR8, could be associated with muscle hypotonia and joint laxity. These data reinforce the hypothesis that multiple haploinsufficient genes and age-dependent observation may concur to generate the variable phenotype associated with 12p13.33 deletion.


      PubDate: 2014-04-30T06:28:48Z
       
  • Clinical Utility of Whole-Exome Sequencing in Rare Diseases:
           Galactosialidosis
    • Abstract: Publication date: Available online 24 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Carlos E. Prada , Claudia Gonzaga-Jauregui , Rebecca Tannenbaum , Samantha Penney , James R. Lupski , Robert J. Hopkin , V. Reid Sutton
      Rare genetic disorders can go undiagnosed for years as the entire spectrum of phenotypic variation is not well characterized given the reduced number of patients reported in the literature and the low frequency at which these occur. Moreover, the current paradigm for clinical diagnostics defines disease diagnosis by a specified spectrum of phenotypic findings; when such parameters are either missing, or other findings not usually observed are seen, the phenotype driven approach to diagnosis may result in a specific etiological diagnosis not even being considered within the differential diagnosis. The novel implementation of genomic sequencing approaches to investigate rare genetic disorders is allowing not only the discovery of new genes, but also the phenotypic expansion of known Mendelian genetic disorders. Here we report the detailed clinical assessment of a patient with a rare genetic disorder with undefined molecular diagnosis. We applied whole-exome sequencing to this patient and unaffected parents in order to identify the molecular cause of her disorder. We identified compound heterozygous mutations in the CTSA gene, responsible for causing galactosialidosis; the molecular diagnosis was further confirmed by biochemical studies. This report expands on the clinical spectrum of this rare lysosomal disorder and exemplifies how genomic approaches are further elucidating the characterization and understanding of genetic diseases.


      PubDate: 2014-04-25T11:16:54Z
       
  • ILDR1: Novel mutation and a rare cause of congenital deafness in the Saudi
           Arabian population
    • Abstract: Publication date: Available online 21 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Khushnooda Ramzan , Khalid Taibah , Asma I. Tahir , Nada Al-Tassan , Amal Berhan , Ahmed M. Khater , Selwa A.F. Al-Hazzaa , Mohammed Al-Owain , Faiqa Imtiaz
      Hearing impairment is the common human sensorineural disorder and is a genetically heterogeneous phenotype for which more than 100 genomic loci have been mapped so far. ILDR1 located on chromosome 3q13.33, encodes a putative transmembrane receptor containing an immunoglobulin-like domain. We used a combination of autozygosity mapping and candidate gene sequencing to identify a novel mutation in ILDR1, as a causative gene for autosomal-recessive non-syndromic hearing loss (arNSHL) in a consanguineous Saudi family with three affected children. Autozygosity mapping identified a shared region between the affected individuals encompassing ILDR1 on chromosome 3q13.12-3q22.1. Sequencing revealed homozygous 9 base pair duplication, resulting in an in-frame duplication of three amino acids p.(Asn109_Pro111dup). The mutation was segregating with the disease phenotype and is predicted to be pathogenic by SIFT and PROVEAN. The identified mutation is located in the immunoglobulin-type domain of the ILDR1 protein. In silico analysis using I-TASSER server and PyMOL offers the first predictions on the structural and functional consequences of this mutation. To our knowledge, this is the first ILDR1 mutation identified in a Saudi family. Identification of ILDR1 mutation in only one of 100 Saudi familial and sporadic individuals with hearing loss suggests that this mutation is unique to this family and that ILDR1 should be considered as a rare cause of congenital deafness among Saudi Arabian population. Our data also confirms the evidence for ILDR1 allelic heterogeneity and expands the number of familial arNSHL-associated ILDR1 gene mutations.


      PubDate: 2014-04-25T11:16:54Z
       
  • Genetics of cleft lip and/or cleft palate: Association with other common
           anomalies
    • Abstract: Publication date: Available online 21 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Núria Setó-Salvia , Philip Stanier
      Cleft lip and/or cleft palate (CL/P) collectively are well known as being amongst the most common birth defects but we still have difficulty explaining why the majority of cases occur. In general, sporadic cases with no family history may be more related to environmental risks, while the presence of one or more affected relative in the same family strongly suggests that genetic factors are the main contributor. Orofacial clefts can occur in conjunction with other defects (syndromic CL/P) or as an isolated defect (non-syndromic – NSCL/P). CL/P syndromes have been studied intensively and appear to have a stronger genetic aetiology. Here we report on the relationship between syndromic and NSCL/P as a phenotypic spectrum resulting from coding or non-coding mutations respectively. We review certain abnormalities that are most frequently associated with CL/P, including dental, heart, brain, skin and certain types of cancer and examine some of the genes that are involved. We include the outcome of recent NSCL/P GWAS data and we will discuss how the genes at these loci might contribute towards clarifying the genetics of CL/P.


      PubDate: 2014-04-25T11:16:54Z
       
  • Left ventricular noncompaction associated with a compound heterozygous
           MYBPC3 mutation
    • Abstract: Publication date: Available online 24 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Josef Finsterer , Sinda Zarrouk-Mahjoub



      PubDate: 2014-04-25T11:16:54Z
       
  • Exome sequencing identifies ZFPM2 as a cause of familial isolated
           
    • Abstract: Publication date: Available online 23 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Paul D. Brady , Jeroen Van Houdt , Bert Callewaert , Jan Deprest , Koenraad Devriendt , Joris R. Vermeesch
      Using exome sequencing we identify a heterozygous nonsense mutation in ZFPM2 as a cause of familial isolated congenital diaphragmatic hernia in 2 affected siblings. This mutation displays variable phenotypic expression being present in a third sibling with a mild diaphragmatic eventration and a cardiovascular malformation. The same variant is seen in 2 additional family members, both of whom are asymptomatic, thus highlighting that ZFPM2 haploinsufficiency is associated with reduced penetrance. Our finding adds further evidence for ZFPM2 having a role in diaphragm and cardiovascular development.


      PubDate: 2014-04-25T11:16:54Z
       
  • Mosaicism for c.431_454dup in ARX causes a mild Partington syndrome
           phenotype
    • Abstract: Publication date: Available online 13 April 2014
      Source:European Journal of Medical Genetics
      Author(s): Karen Grønskov , Birgitte Diness , Michelle Stahlhut , Monica Zilmer , Zeynep Tümer , Anne-Marie Bisgaard , Karen Brøndum-Nielsen
      A common in frame duplication in ARX (c.431_454dup24) was found in a five year-old boy who presented with mild Partington syndrome. The duplication was detected by PCR amplification followed by fragment length analysis and was located in exon 2 spanning the two polyalanine tracts commonly seen to expand. Detection of the duplication by DNA sequencing was difficult due to preferential sequencing of the normal allele, demonstrating the superiority of fragment length analysis in mosaic cases. The clinical symptoms were mild to moderate developmental delay with only the hand dystonia to suggest Partington syndrome. This patient is the first male reported to be mosaic for the duplication, and his clinical features are subtle. This study shows that in males with a phenotype of mild Partington syndrome and in heterozygous females fragment length analysis should be preferred over DNA sequencing.


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



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


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


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


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


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


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


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


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


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


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


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


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



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


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


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


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


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


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


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


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


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


      PubDate: 2014-02-19T07:23:00Z
       
  • Report on 3 patients with 12p duplication including GRIN2B
    • Abstract: Publication date: Available online 3 February 2014
      Source:European Journal of Medical Genetics
      Author(s): Celine Poirsier , Emilie Landais , Nathalie Bednarek , Jean-Marie Nobecourt , Maroun Khoury , Pascal Schmidt , Patrice Morville , Nadine Gruson , Sandrine Clomes , Nicole Michel , Anita Riot , Christelle Manjeongean , Dominique Gaillard , Martine Doco Fenzy
      The duplication of the short arm (p) of chromosome 12 is a rare chromosomal abnormality, and most reported cases result from malsegregation of a balanced parental translocation associated with other chromosomal imbalances. Of the reported cases, only 15 involve a pure and complete 12p duplication and only 10 involve a pure and partial duplication overlapping the 12p12.3p13.1 region, including a single instance of an inherited duplication in two related individuals. Here, we report three new patients with a pure 12p duplication, detected by conventional cytogenetic studies and characterized by array-comparative genomic hybridization (array-CGH) and fluorescence in situ hybridization (FISH). The first patient was a child carrying a de novo inverted duplication of the short arm of chromosome 12. His phenotype was similar to that of the “trisomy 12p syndrome”, characterized by developmental delays and craniofacial abnormalities including a high forehead, a short nose with anteverted nostrils and an everted lower lip. The second and third patients were a mother and son with a direct 12p12.3p13.1 duplication, exhibiting a milder phenotype characterized by moderate developmental delays, dysmorphic facial features, behavioral problems and obesity. The present data, including the rarity of the familial cases, should contribute to our knowledge of the genotype/phenotype correlation in trisomy 12p patients.


      PubDate: 2014-02-05T07:18:42Z
       
 
 
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