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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  [2570 journals]   [SJR: 1.029]   [H-I: 32]
  • Sickle cell anemia and α-thalassemia: A modulating factor in
           homozygous HbS/S patients in Oman
    • Abstract: Publication date: Available online 28 September 2014
      Source:European Journal of Medical Genetics
      Author(s): S.M. Hassan , M. Al Muslahi , M. Al Riyami , E. Bakker , C.L. Harteveld , P.C. Giordano
      We report the general phenotype severity and the hematological presentation in a cohort of 125 sickle cell anemia (SCA) patients with identical homozygous HbS/S genotype and categorized by identical βS haplotype, both with and without alpha thalassemia. No clear general phenotype correlation was found when patients were compared regardless of the haplotype but overall, patients with homozygous alpha thalassemia (α–/α–) had the highest Hb, HCT, RBC and the lowest MCV, MCH and MCHC levels. When patients with identical haplotype were compared, the mildest hematological and clinical conditions were observed in patients of the Asian/Asian haplotype, also known as Arab-Indian haplotype, and carriers of α-thalassemia, suggesting an additional ameliorating effect of alpha thalassemia. In conclusion, our results show that alpha thalassemia improves the hematological conditions but amelioration of the general disease severity is only noticed when compared in cohorts of the same haplotype.


      PubDate: 2014-10-03T09:50:45Z
       
  • Root dentin Anomaly and a PLG mutation
    • Abstract: Publication date: Available online 30 September 2014
      Source:European Journal of Medical Genetics
      Author(s): Napaporn Tananuvat , Pimlak Charoenkwan , Atsushi Ohazama , James R. Ketuda Cairns , Massupa Kaewgahya , Piranit Nik Kantaputra
      We report a Thai girl affected with plasminogen deficiency, Type I. Ligneous conjunctivitis was first observed when she was one month old. The newly recognized findings include tapered incisor roots as a result of thin root dentin, generalized short tooth roots, and mandibular prognathism. Mutation analysis of PLG demonstrated homozygous c.1193G>A missense mutation. The parents were heterozygous for c.1193G>A mutation. The c.1193G>A mutation is novel and predicted to cause amino acid substitution p.Cys398Tyr. Thin root dentin in the patient who was affected with PLG mutation and immunolocalization of Plg during early root development in mice imply the role of plasminogen in root dentin formation.


      PubDate: 2014-10-03T09:50:45Z
       
  • Clinico-pathological manifestations of variant late infantile neuronal
           ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene
    • Abstract: Publication date: Available online 28 September 2014
      Source:European Journal of Medical Genetics
      Author(s): Hanna Mandel , Ksenya Cohen Katsanelson , Morad Khayat , Ilana Chervinsky , Eugene Vladovski , Theodor C. Iancu , Margarita Indelman , Yoseph Horovitz , Eli Sprecher , Stavit A. Shalev , Ronen Spiegel
      Neuronal ceroid lipofuscinosis (NCL) refers to a growing heterogeneous group of neurodegenerative disorders characterized by lysosomal accumulation of abnormal autofluorescent material. NCLs are traditionally classified clinically according to their age of onset. Variable late infantile NCL (vLINCL) is the most genetically heterogeneous subtype as it has been shown to be caused by mutations in at least six genes. We report on 5 patients of a consanguineous family who presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration. Disease course was severe; all patients were in a vegetative state by the second decade of life, and eventually die prematurely (except in one case). Ultrastructural studies of brain and rectal mucosa disclosed accumulation of storage material in various patterns including fingerprint, curvilinear, and granular osmiophilic deposits consistent with the diagnosis of NCL. Brain pathologic features from a living patient are first reported here and shed light on disease progression and pathogenesis. Using a combination of whole genome autozygosity mapping and candidate gene direct sequencing, we identified a mutation in MFSD8, c.472G>A (p.Gly158Ser), which was found to segregate with the disease phenotype in the family. This study underscores the importance of a combined clinic-molecular work up in NCLs and other neurodegenerative conditions.


      PubDate: 2014-10-03T09:50:45Z
       
  • A de novo mutation in ZMYND11, a candidate gene for 10p15.3 deletion
           syndrome, is associated with syndromic intellectual disability
    • Abstract: Publication date: Available online 30 September 2014
      Source:European Journal of Medical Genetics
      Author(s): J.M. Cobben , M.M. Weiss , F.S. van Dijk , R. De Reuver , C. de Kruiff , W. Pondaag , R.C. Hennekam , H.G. Yntema
      We report a boy with severe syndromic intellectual disability who has a de novo mutation in the ZMYND11 gene. Arguments for pathogenicity of this mutation are found in cases from the literature, especially several with 10p15.3 deletions, harbouringZMYND11. Additional reports of ZMYND11 mutations in cases with syndromic intellectual disability are needed before the ZMYND11 mutation identified in our case can be considered as definitely pathogenic.


      PubDate: 2014-10-03T09:50:45Z
       
  • First steps in exploring prospective exome sequencing of consanguineous
           couples
    • Abstract: Publication date: Available online 2 October 2014
      Source:European Journal of Medical Genetics
      Author(s): Marieke Teeuw , Quinten Waisfisz , Petra J.G. Zwijnenburg , Erik A. Sistermans , Marjan M. Weiss , Lidewij Henneman , Leo P. ten Kate , Martina C. Cornel , Hanne Meijers-Heijboer
      Consanguinity is one of the most frequent risk factors for congenital disorders. In theory, prospective exome sequencing of consanguineous couples could identify couples who both are carriers of autosomal recessive diseases, and empower such couples to make informed reproductive decisions. To investigate this, we sent blood samples to our laboratory of four pairs of consanguineous parents having one or more children affected by an autosomal recessive disorder, without revealing any diagnostic information. The study was restricted to find identical, previously described, or evidently pathogenic mutations in both parents of each couple, in over 400 genes known to result in severe autosomal recessive disorders. Out of the six autosomal recessive disorders known to the four couples studied, two were correctly identified. Carrier status of one not previously known autosomal recessive disorder was discovered. As expected, given the pipeline used, large deletions, mutations in genes not present in the gene list, mutations outside the exons and consensus splice sites, and mutations that were not evidently pathogenic and previously not reported, were not identified. The restriction to detecting only couples with identical mutations diminishes the risk of revealing unsolicited findings and shortens the time needed for analysis, but also results in missing couples with different mutations in the same gene. In addition to the proposed pipeline, couples should be offered testing for carrier status of frequent disorders that can present themselves by large deletions, non-exonic mutations or compound heterozygous mutations (e.g. thalassemia, spinal muscular atrophy, cystic fibrosis). Even though sensitivity is reduced, offering exome sequencing prospectively will increase reproductive options for consanguineous couples.


      PubDate: 2014-10-03T09:50:45Z
       
  • Atypical hematologic and renal manifestations in Neurofibromatosis type I:
           Coincidence or pathophysiological link'
    • Abstract: Publication date: Available online 16 September 2014
      Source:European Journal of Medical Genetics
      Author(s): Julien Van-Gils , Jérôme Harambat , Charlotte Jubert , Dominique Vidaud , Brigitte Llanas , Yves Perel , Didier Lacombe , Cyril Goizet
      Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder that predisposes to the development of benign and malignant tumours with a birth incidence rate of 1 in 2500-3000. 50% of cases are sporadic. The diagnosis is exclusively based on clinical assessment with clinical diagnostic criteria such as café-au-lait spots, neurofibromas, axillary or groin freckling, Lisch nodules, optic pathway glioma, bony dysplasia and first-degree relative with NF1. We report a family with NF1 in which two members presented atypical clinical features in addition to the classical diagnostic criteria. Three relatives affected by NF1, a father and two of his three sons, are described. The clinical diagnosis was originally worn in all three cases, with the association many spots café-au –lait over the entire body and some axillary freckling as well as first-degree relative. One case presented an Acute Myeloid Leukemia (AML) type 2 at 10 years of age diagnosed before the revelation of bicytopenia associated pallor and isolated asthenia. A second case presented a nephrotic syndrome at 4 years of age due to the association of hydrops with headache and asthenia. Direct sequencing of NF1 led to identify the familial mutation, a previously unreported heterozygous missense mutation c.3443C>A, p.Ala1148Glu in exon 20 which segregated with all three affected patients. The family described in this report confirms the high clinical variability of NF1, even intrafamilial, and raises the question as to whether rare features such as AML and nephrotic syndrome are associated with NF1. Some NF1 patients presenting glomerular diseases or AML have rarely been reported, but due to the small number of cases described the mechanisms underlying these associations are poorly understood. However, it seems important to be aware of the possible occurrence of nephritic syndrome and/or malignant blood diseases in NF1 patients.


      PubDate: 2014-09-20T05:56:38Z
       
  • 19q13.32 microdeletion syndrome: Three new cases
    • Abstract: Publication date: Available online 16 September 2014
      Source:European Journal of Medical Genetics
      Author(s): Angela Castillo , Nancy Kramer , Charles E. Schwartz , Judith H. Miles , Barbara R. DuPont , Jill A. Rosenfeld , John M. Graham Jr.
      A previous report described a unique phenotype associated with an apparently de novo 732 kb 19q13.32 microdeletion, consisting of intellectual disability, facial asymmetry, ptosis, oculomotor abnormalities, orofacial clefts, cardiac defects, scoliosis and chronic constipation. We report three unrelated patients with developmental delay and dysmorphic features, who were all found to have interstitial 19q13.32 microdeletions of varying sizes. Both the previously reported patient and our Patient 1 with a larger, 1.3-Mb deletion have distinctive dysmorphic features and medical problems, allowing us to define a recognizable 19q13.32 microdeletion syndrome. Patient 1 was hypotonic and dysmorphic at birth, with aplasia of the posterior corpus callosum, bilateral ptosis, oculomotor paralysis, down-slanting palpebral fissures, facial asymmetry, submucosal cleft palate, micrognathia, wide-spaced nipples, right-sided aortic arch, hypospadias, bilateral inguinal hernias, double toenail of the left second toe, partial 2–3 toe syndactyly, kyphoscoliosis and colonic atony. Therefore, the common features of the 19q13.32 microdeletion syndrome include facial asymmetry, ptosis, oculomotor paralysis, orofacial clefting, micrognathia, kyphoscoliosis, aortic defects and colonic atony. These findings are probably related to a deletion of some combination of the 20–23 genes in common between these two patients, especially NPAS1, NAPA, ARHGAP35, SLC8A2, DHX34, MEIS3, and ZNF541. These candidate genes are expressed in the brain parenchyma, glia, heart, gastrointestinal tract and musculoskeletal system and likely play a fundamental role in the expression of this phenotype. This report delineates the phenotypic spectrum associated with the haploinsufficiency of genes found in 19q13.32.


      PubDate: 2014-09-20T05:56:38Z
       
  • Exome sequencing identifies a novel homozygous variant in NDRG4 in a
           family with infantile myofibromatosis
    • Abstract: Publication date: Available online 18 September 2014
      Source:European Journal of Medical Genetics
      Author(s): Natália D. Linhares , Maíra C.M. Freire , Raony G.C.C.L. Cardenas , Heloísa B. Pena , Magda Bahia , Sergio D.J. Pena
      Infantile myofibromatosis (IM) is a rare disorder characterized by the development of benign tumors in the skin, muscle, bone, and viscera. The incidence is 1/150,000 live births and the disease is the most common cause of fibrous tumors in infancy. Cases which lack visceral involvement generally have a more benign course, usually with spontaneous regression of the tumors. On the other hand, the prognosis tends to be unfavorable when there is involvement of vital organs, which can lead to significant mortality. The identification of rare variants in genes that may cause IM is the first step towards the possibility of targeted treatments; however, the molecular pathogenesis of IM is poorly understood. In the present study, we report the results of exome sequence analysis of two brothers diagnosed with visceral multicentric infantile myofibromatosis, and their healthy consanguineous parents. In the two brothers we identified novel homozygous variants in NDRG4 gene (N-myc downregulated gene family member 4) and in RLTPR gene (RGD motif, leucine rich repeats, tropomodulin domain and proline-rich containing). The healthy parents were heterozygous for both variants. Consistent with the phenotype of IM, NDRG4 is a tumor-related gene; its expression has been shown to be decreased in numerous tumor types, suggesting that it might be a tumor suppressor gene. Additionally, studies have demonstrated that NDRG4 may have a role in cell survival and tumor invasion. We thus propose that this homozygous variant in NDRG4 may be the causative variant of the autosomal recessive form of IM in the studied family and that it should be investigated in other cases of autosomal recessive infantile myofibromatosis.


      PubDate: 2014-09-20T05:56:38Z
       
  • NGLY1 Mutation Causes Neuromotor Impairment, Intellectual Disability, and
           Neuropathy
    • Abstract: Publication date: Available online 9 September 2014
      Source:European Journal of Medical Genetics
      Author(s): Ahmet Okay Caglayan , Sinan Comu , Jacob F. Baranoski , Yesim Parman , Hande Kaymakçalan , Gozde Tugce Akgumus , Caner Caglar , Duygu Dolen , E. Zeynep Erson Omay , Akdes Serin Harmanci , Ketu Mishra , Hudson H. Freeze , Katsuhito Yasuno , Kaya Bilguvar , Murat Gunel
      N-glycanase 1 (NGLY1) is a conserved enzyme that is responsible for the deglycosylation of misfolded N-glycosylated proteins in the cytoplasm prior to their proteosome-mediated degradation. Disruption of this degradation process has been associated with various neurologic diseases including amyotrophic lateral sclerosis and Parkinson’s disease. Here, we describe two siblings with neuromotor impairment, apparent intellectual disability, corneal opacities, and neuropathy who were found to possess a novel homozygous frame-shift mutation due to a 4 base pair deletion in NGLY1 (c.1533_1536delTCAA, p.Asn511LysfsX51). We hypothesize that this mutation causes the capability of neuronal cells to respond to stress due to accumulation of misfolded proteins, thereby impairing their survival and resulting in progressive loss of neurological function.


      PubDate: 2014-09-12T04:26:44Z
       
  • Phenotypic and Genotypic spectrum of Turkish patients with isovaleric
           acidemia
    • Abstract: Publication date: Available online 8 September 2014
      Source:European Journal of Medical Genetics
      Author(s): Rıza Koksal Ozgul , Mehmet Karaca , Mustafa Kilic , Ozgul Kucuk , Didem Yucel-Yilmaz , Ozlem Unal , Burcu Hismi , Didem Aliefendioglu , Serap Sivri , Aysegul Tokatli , Turgay Coskun , Ali Dursun
      We aim to investigate the genetic basis of isovaleryl-CoA dehydrogenase (IVD) gene mutations and genotype-phenotype correlations in Turkish patients. Accordingly, bi-directional sequencing was performed to screen 26 patients with isovaleric acidemia (IVA). Nine novels (c.145delC, c.234+3G>C, c.506_507insT, p.Glu85Gln, p.Met147Val, p.Ala268Val, p.Ile287Met, p.Gly346Asp and p.Arg382Trp) and six previously reported (c.456+2T>C, p.Arg21His, p.Arg21Pro, p.Arg363Cys, p.Arg363His p.Glu379Lys) pathogenic mutations were identified. Pathogenicity of the novel mutations was supported using computational programs. No clear genotype-phenotype correlation could be determined. One of the cases with the novel c.234+3G>C mutation has portoseptal liver fibrosis, the clinical condition that was first reported for IVA. This study is the first comprehensive report from Turkey related to IVA genetics that provides information about the high number of disease-causing novel mutations.


      PubDate: 2014-09-12T04:26:44Z
       
  • Prevalence and spectrum of Nkx2.6 mutations in patients with congenital
           heart disease
    • Abstract: Publication date: Available online 3 September 2014
      Source:European Journal of Medical Genetics
      Author(s): Lan Zhao , Shi-Hong Ni , Xing-Yuan Liu , Dong Wei , Fang Yuan , Lei Xu , Xin-Li , Ruo-Gu Li , Xin-Kai Qu , Ying-Jia Xu , Wei-Yi Fang , Yi-Qing Yang , Xing-Biao Qiu
      Congenital heart disease (CHD) is the most common form of birth defect and is the most prevalent non-infectious cause of infant death. A growing body of evidence documents that genetic defects are involved in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic basis underpinning CHD in an overwhelming majority of patients remain unclear. In this study, the coding exons and flanking introns of the Nkx2.6 gene, which codes for a homeodomain-containing transcription factor important for normal cardiovascular development, were sequenced in 320 unrelated patients with CHD, and two novel heterozygous Nkx2.6 mutations, p.V176M and p.K177X, were identified in two unrelated patients with CHD, respectively, including a patient with tetralogy of Fallot and a patient with double outlet of right ventricle and ventricular septal defect. The mutations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily across species. Due to unknown transcriptional targets of Nkx2.6, the functional consequences of the identified mutations at transcriptional activity were evaluated by using Nkx2.5 as a surrogate. Alignment between human Nkx2.6 and Nkx2.5 proteins showed that V176M-mutant Nkx2.6 was equivalent to V182M-mutant Nkx2.5 and K177X-mutant Nkx2.6 was equal to K183X-mutant Nkx2.5, and introduction of V182M or K183X into Nkx2.5 significantly diminished its transcriptional activating function when compared with its wild-type counterpart. To our knowledge, this is the first report on the association of Nkx2.6 loss-of-function mutation with increased susceptibility to tetralogy of Fallot or double outlet of right ventricle and ventricular septal defect, providing novel insight into the molecular mechanism of CHD.


      PubDate: 2014-09-06T03:25:25Z
       
  • A syndromic form of Pierre Robin sequence is caused by 5q23 deletions
           encompassing FBN2 and PHAX
    • Abstract: Publication date: Available online 3 September 2014
      Source:European Journal of Medical Genetics
      Author(s): Morad Ansari , Jacqueline K. Rainger , Jennie E. Murray , Isabel Hanson , Helen V. Firth , Felicity Mehendale , Jeanne Amiel , Christopher T. Gordon , Antonio Percesepe , Laura Mazzanti , Alan Fryer , Paola Ferrari , Koenraad Devriendt , I. Karen Temple , David R. FitzPatrick
      Pierre Robin sequence (PRS) is an etiologically distinct subgroup of cleft palate. We aimed to define the critical genomic interval from five different 5q22-5q31 deletions associated with PRS or PRS-associated features and assess each gene within the region as a candidate for the PRS component of the phenotype. Clinical array-based comparative genome hybridisation (aCGH) data were used to define a 2.08 Mb minimum region of overlap among four de novo deletions and one mother-son inherited deletion associated with at least one component of PRS. Commonly associated anomalies were talipes equinovarus (TEV), finger contractures and crumpled ear helices. Expression analysis of the orthologous genes within the PRS critical region in embryonic mice showed that the strongest candidate genes were FBN2 and PHAX. Targeted aCGH of the critical region and sequencing of these genes in a cohort of 25 PRS patients revealed no plausible disease-causing mutations. In conclusion, deletion of ∼2 Mb on 5q23 region causes a clinically recognisable subtype of PRS. Haploinsufficiency for FBN2 accounts for the digital and auricular features. A possible critical region for TEV is distinct and telomeric to the PRS region. The molecular basis of PRS in these cases remains undetermined but haploinsufficiency for PHAX is a plausible mechanism.


      PubDate: 2014-09-06T03:25:25Z
       
  • Co-occurrence of congenital hydronephrosis and FOXL2-associated
           blepharophimosis, ptosis, epicanthus inversus syndrome (BPES)
    • Abstract: Publication date: Available online 2 September 2014
      Source:European Journal of Medical Genetics
      Author(s): Reena Gulati , Hannah Verdin , Dhanapathi Halanaik , B Vishnu Bhat , Elfride De Baere
      Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is an autosomal dominantly inherited congenital malformation of the eyelids. Diagnostic criteria include blepharophimosis, ptosis, epicanthus inversus and telecanthus. Type І BPES has additional features of premature ovarian failure and female infertility, while type ІІ occurs isolated. We report a two-year old male child with typical features of BPES and bilateral congenital hydronephrosis. The child, first-born to non-consanguineous parents, presented to us with hypertension. Congenital hydronephrosis and reduced renal function were confirmed by renal dynamic scan. Pyeloplasty and stent placement were performed with subsequent resolution of hypertension. On follow up, growth and development are appropriate for age. His father has similar but less severe features of BPES. Sequencing of the FOXL2 gene revealed a heterozygous FOXL2 mutation c.672_701dup, which is a recurrent 30-bp duplication leading to expansion of the polyalanine tract (p.Ala225_Ala234dup), in both father and son. Additional atypical clinical features have been reported previously in BPES patients with this mutation. However, this is the first report of a renal congenital anomaly in a BPES patient with this or other mutations. Although a pleiotropic effect of the FOXL2 mutation cannot be excluded, the co-occurrence of congenital hydronephrosis and BPES may represent two different entities.


      PubDate: 2014-09-06T03:25:25Z
       
  • Birth defects epidemiology
    • Abstract: Publication date: August 2014
      Source:European Journal of Medical Genetics, Volume 57, Issue 8
      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: 2014-09-02T02:51:13Z
       
  • Genetics of cleft lip and/or cleft palate: Association with other common
           anomalies
    • Abstract: Publication date: August 2014
      Source:European Journal of Medical Genetics, Volume 57, Issue 8
      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: 2014-09-02T02:51:13Z
       
  • Arthrogryposis (multiple congenital contractures): Diagnostic approach to
           etiology, classification, genetics, and general principles
    • Abstract: Publication date: August 2014
      Source:European Journal of Medical Genetics, Volume 57, Issue 8
      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: 2014-09-02T02:51:13Z
       
  • Genetic basis of congenital cardiovascular malformations
    • Abstract: Publication date: August 2014
      Source:European Journal of Medical Genetics, Volume 57, Issue 8
      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 proteins- 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 susceptibility to congenital heart defects.


      PubDate: 2014-09-02T02:51:13Z
       
  • Review of genetic and environmental factors leading to hypospadias
    • Abstract: Publication date: August 2014
      Source:European Journal of Medical Genetics, Volume 57, Issue 8
      Author(s): Erin M. Shih , John M. Graham Jr.
      Hypospadias is one of the most common congenital malformations, affecting about 4–6 males per 1000 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: 2014-09-02T02:51:13Z
       
  • Constitutional chromoanasynthesis: Description of a rare chromosomal event
           in a patient
    • Abstract: Publication date: Available online 13 August 2014
      Source:European Journal of Medical Genetics
      Author(s): Julie Plaisancie , Pascale Kleinfinger , Claude Cances , Anne Bazin , Sophie Julia , Detlef Trost , Laurence Lohmann , Adeline Vigouroux
      Structural alterations in chromosomes are a frequent cause of cancers and congenital diseases. Recently, the phenomenon of chromosome crisis, consisting of a set of tens to hundreds of clustered genomic rearrangements, localized in one or a few chromosomes, was described in cancer cells under the term chromothripsis. Better knowledge and recognition of this catastrophic chromosome event has brought to light two distinct entities, chromothripsis and chromoanasynthesis. The complexity of these rearrangements and the original descriptions in tumor cells initially led to the thought that it was an acquired anomaly. In fact, a few patients have been reported with constitutional chromothripsis or chromoanasynthesis. Using microarray we identified a very complex chromosomal rearrangement in a patient who had a cytogenetically visible rearrangement of chromosome 18. The rearrangement contained more than 15 breakpoints localized on a single chromosome. Our patient displayed intellectual disability, behavioral troubles and craniofacial dysmorphism. Interestingly, the succession of duplications and triplications identified in our patient was not clustered on a single chromosomal region but spread over the entire chromosome 18. In the light of this new spectrum of chromosomal rearrangements, this report outlines the main features of these catastrophic events and discusses the underlying mechanism of the complex chromosomal rearrangement identified in our patient, which is strongly evocative of a chromoanasynthesis.


      PubDate: 2014-08-16T01:52:34Z
       
  • Analysis of genetic mutations in Chinese patients with systemic primary
           carnitine deficiency
    • Abstract: Publication date: Available online 13 August 2014
      Source:European Journal of Medical Genetics
      Author(s): Lianshu Han , Fei Wang , Yu Wang , Jun Ye , Wenjuan Qiu , Huiwen Zhang , Xiaolan Gao , Zhuwen Gong , Xuefan Gu
      Systemic primary carnitine deficiency (CDSP) is caused by mutations in SLC22A5 gene, which encodes organic cation transporter 2(OCTN2). CDSP leads to skeletal or cardiac myopathy and hepatic encephalopathy. The present study aimed to identify SLC22A5 gene mutations and analyze the potential relationship between genotype and clinical symptoms in 20 Chinese patients with CDSP. The complete coding region of the SLC22A5 gene including intron-exon boundaries were amplified and sequenced in all patients. Eighteen different mutations were found; of which, nine were novel. The mutations clustered in exons 1 and 4 accounted for 66.7% of all mutant alleles (26/39). The c.760C>T (p. R254X) was the most frequent mutation (25.6%, 10/39), suggesting it as an ethnic founder mutation. The relationship between genotype and phenotypewas investigated in patients carrying the R254X mutation. Homozygous patients with R254X were late-onset cases who presented with dilated cardiomyopathy and muscle weakness after 1 year of age. Compound heterozygous patients carrying R254X, combined with other missense mutations occurred in very specific positions, dramatically altered OCTN2 protein function. Based on the analysis of case studies, a clear relationship between free carnitine (C0) levels in plasma and OCTN2 genotype was not found in the present work, however, the low plasma C0 level could not indicate disease severity or genotype. Further functional studies with a large sample size are required to understand the relationship between R254X mutation and CDSP.


      PubDate: 2014-08-16T01:52:34Z
       
  • Familial Co-segregation of Coffin-Lowry syndrome inherited from the mother
           and autosomal dominant Waardenburg type IV syndrome due to deletion of
           EDNRB inherited from the father
    • Abstract: Publication date: Available online 10 August 2014
      Source:European Journal of Medical Genetics
      Author(s): Jacob Loupe , Sri Sampath , Yves Lacassie
      We report an African-American family that was identified after the proposita was referred for diagnostic evaluation at 4½ months with a history of Hirschsprung and dysmorphic features typical of Waardenburg syndrome (WS). Family evaluation revealed that the father had heterochromidia irides and hypertelorism supporting the clinical diagnosis of WS; however, examination of the mother revealed characteristic facial and digital features of Coffin-Lowry syndrome (CLS). Molecular testing of the mother identified a novel 2 bp deletion (c.865_866delCA) in codon 289 of RPS6KA3 leading to a frame-shift and premature termination of translation 5 codons downstream (NM_004586.2:p.Gln289ValfsX5). This deletion also was identified in the proposita and her three sisters with a clinical suspicion of CLS, all of whom as carriers for this X-linked disorder had very subtle manifestations. The molecular confirmation of WS type 4 (Shah-Waardenburg; WS4) was not as straightforward. To evaluate WS types 1-4, multiple sequential molecular tests were requested, including Sanger sequencing of all exons, and deletion/duplication analysis using MLPA for PAX3, MITF, SOX10, EDN3 and EDNRB. Although sequencing did not identify any disease causing variants, MLPA identified a heterozygous deletion of the entire EDNRB in the father. This deletion was also found in the proposita and the oldest child. Since the heterozygous deletion was the only change identified in EDNRB, this family represents one of the few cases of an autosomal dominant inheritance of WS4 involving the endothelin pathway. Altogether, clinical evaluation of the family revealed one child to be positive for WS4 and two positive for CLS, while two children were positive for both diseases simultaneously (including the proposita) while another pair test negative for either disease. This kinship is an example of the coincidence of two conditions co-segregating in one family, with variable phenotypes requiring molecular testing to confirm the clinical diagnoses.


      PubDate: 2014-08-12T01:36:15Z
       
  • NKX2.5 mutation identification on exome sequencing in a patient with
           heterotaxy
    • Abstract: Publication date: Available online 10 August 2014
      Source:European Journal of Medical Genetics
      Author(s): Kosuke Izumi , Sarah Noon , Alisha Wilkens , Ian D. Krantz
      Exome sequencing enables us to screen most of the protein coding genes in an unbiased way, this technique represents an ideal tool to identify previously under- or unappreciated phenotypes associated with known disease genes and genetic disorders. Here we present an illustrative case that required exome sequencing to identify a genetic alteration associated with the clinical features. The phenotype of the proband included heterotaxy, double outlet right ventricle, common atrioventricular canal, total anomalous pulmonary venous connection, asplenia, failure to thrive and short stature. Exome sequencing demonstrated a frameshift mutation c.397_400del (p.P133GfsTer 42) in NKX2.5. Although a single previous case of heterotaxy was reported in a large familial case of NKX2.5, heterotaxy is not clinically appreciated to be a part of the phenotypic spectrum associated with NKX2.5 mutations. This case report demonstrates the utility of exome sequencing in expanding a phenotypic spectrum of a known Mendelian disorder. We predict that this type of unexpected identification of mutations in known-disease associated genes in patients with atypical or expanded phenotypes will occur with increasing frequency as the use of exome and genome sequencing become more common tools in diagnosing patients with syndromic and non-syndromic foms of structural birth defects.


      PubDate: 2014-08-12T01:36:15Z
       
  • Clinical and molecular description of a 17q21.33 microduplication in a
           girl with severe kyphoscoliosis and developmental delay
    • Abstract: Publication date: Available online 6 August 2014
      Source:European Journal of Medical Genetics
      Author(s): Stéphan Kemeny , Céline Pebrel-Richard , Eléonore Eymard-Pierre , Mathilde Gay-Bellile , Laetitia Gouas , Carole Goumy , Andreï Tchirkov , Christine Francannet , Philippe Vago
      High proportion of disease-associated copy number variant maps to chromosome 17. Genomic studies have provided an insight into its complex genomic structure such as relative abundance of segmental duplication and intercepted repetitive elements. 17q21.31, 17q11.2 and 17q12 loci are well known on this chromosome and are associated with microdeletion and microduplication syndrome. No syndrome associated with 17q21.33 locus have been described. We report clinical, cytogenetic and molecular investigations of a 13 years-old girl admitted for evaluation of microcephaly, scoliosis, skeletal defects and learning difficulties. We carried out detailed analysis of the clinical phenotype of this patient and investigated the genetic basis using Agilent 180K Array Comparative Genomic Hybridization. We identified a ∼ 0.9 Mb de novo microduplication on chromosome 17q21.33. Four genes, COL1A1, SGCA, PPP1R9B and CHAD located within the duplicated region are possible candidates for clinical features present in our patients. Gene expression studies by real-time RT-PCR assay only showed an overexpression of SGCA (P<0.01), a component of the dystrophin glycoprotein complex. Defect of SGCA was previously shown to lead to severe childhood autosomal recessive muscular dystrophy (LGMD2D) which result in progressive muscle weakness and can also be associated with hyperlordosis or scoliosis. Further cases with similar duplications are expected to be diagnosed. This will contribute to the delineation of this potential new microduplication syndrome and to improve genetic counseling.


      PubDate: 2014-08-08T01:27:04Z
       
  • Clinical characterization, genetic mapping and whole-genome sequence
           analysis of a novel autosomal recessive intellectual disability syndrome
    • Abstract: Publication date: Available online 29 July 2014
      Source:European Journal of Medical Genetics
      Author(s): Eevi Kaasinen , Elisa Rahikkala , Peppi Koivunen , Sirpa Miettinen , Mirjam M.C. Wamelink , Mervi Aavikko , Kimmo Palin , Johanna Myllyharju , Jukka S. Moilanen , Leila Pajunen , Auli Karhu , Lauri A. Aaltonen
      We identified six patients presenting with a strikingly similar clinical phenotype of profound syndromic intellectual disability of unknown etiology. All patients lived in the same village. Extensive genealogical work revealed that the healthy parents of the patients were all distantly related to a common ancestor from the 17th century, suggesting autosomal recessive inheritance. In addition to intellectual disability, the clinical features included hypotonia, strabismus, difficulty to fix the eyes to an object, planovalgus in the feet, mild contractures in elbow joints, interphalangeal joint hypermobility and coarse facial features that develop gradually during childhood. The clinical phenotype did not fit any known syndrome. Genome-wide SNP genotyping of the patients and genetic mapping revealed the longest shared homozygosity at 3p22.1-3p21.1 encompassing 11.5Mb, with no other credible candidate loci emerging. Single point parametric linkage analysis showed logarithm of the odds score of 11 for the homozygous region, thus identifying a novel intellectual disability predisposition locus. Whole-genome sequencing of one affected individual pinpointed three genes with potentially protein damaging homozygous sequence changes within the predisposition locus: transketolase (TKT), prolyl 4-hydroxylase transmembrane (P4HTM), and ubiquitin specific peptidase 4 (USP4). The changes were found in heterozygous form with 0.3-0.7% allele frequencies in 402 whole-genome sequenced controls from the north-east of Finland. No homozygotes were found in this nor additional control data sets. Our study facilitates clinical and molecular diagnosis of patients with this novel autosomal recessive intellectual disability syndrome. However, further studies are needed to unambiguously identify the underlying genetic defect.


      PubDate: 2014-07-30T00:31:12Z
       
  • Raine syndrome: An overview
    • Abstract: Publication date: Available online 12 July 2014
      Source:European Journal of Medical Genetics
      Author(s): Víctor Faundes , Silvia Castillo-Taucher , Patricio Gonzalez-Hormazabal , Kate Chandler , Andrew Crosby , Barry Chioza
      Raine syndrome (RS) is a bone dysplasia characterised by generalised osteosclerosis with periosteal bone formation, characteristic face, and brain abnormalities [MIM # 259775]. Its prevalence is estimated to be < 1/1,000,000. Although it was originally thought always to be lethal, there have now been six reports of patients surviving into childhood and this phenotype is still being defined. The skeletal dysplasia predominantly affects craniofacial development explaining the severe proptosis, underdeveloped midface, depressed nasal bridge and short nose. The main radiological manifestation is a diffuse, marked osteosclerosis of the base of skull and long bones. Raine syndrome is caused by biallelic mutations in FAM20C, located on chromosome 7p22.3. This gene encodes a Golgi casein kinase, which phosphorylates serine residues of extracellular proteins involved in biomineralisation. Facial appearance and radiological findings allow the clinical diagnosis, and molecular testing of FAM20C can confirm this. Desmosterolosis and congenital cytomegalovirus infection may resemble Raine syndrome. If Raine syndrome is suspected prenatally the newborn should be admitted at a neonatal intensive care unit as significant respiratory distress is often present immediately after birth. We present here a review of the pertinent literature in clinical manifestations, molecular background, diagnosis and management.


      PubDate: 2014-07-27T00:25:03Z
       
  • Genetics of common malformations
    • Abstract: Publication date: Available online 10 June 2014
      Source:European Journal of Medical Genetics
      Author(s): John M. Graham Jr. , Raoul C. Hennekam
      Advanced technology has recently allowed us to study rare Mendelian disorders in an unprecedented manner. The same technology should allow us also to study more common malformations. Many of these are not caused by a variant in a single Mendelian gene but by interplay between series of genetic variants and exogenous influences. Likely the site from which the DNA is derived is of great importance in studying malformations as mosaicism may be much more common than earlier anticipated. Factors other than simple variants in our genomic DNA should be considered in the studies as well. Not only is recognition of someone's liability to disease important, but also determining exogenous factors involved in malformations should receive more attention as it may allow us decrease the burden of malformations in humans.


      PubDate: 2014-07-27T00:25:03Z
       
  • 15q26.1 microdeletion encompassing only CHD2 and RGMA in two adults with
           moderate intellectual disability, epilepsy and truncal obesity
    • Abstract: Publication date: Available online 13 June 2014
      Source:European Journal of Medical Genetics
      Author(s): Carolina Courage , Gunnar Houge , Sabina Gallati , Jack Schjelderup , Claudine Rieubland
      We report two patients with microdeletions in chromosomal subdomain 15q26.1 encompassing only two genes, CHD2 and RGMA. Both patients present a distinct phenotype with intellectual disability, epilepsy, behavioral issues, truncal obesity, scoliosis and facial dysmorphism. CHD2 haploinsufficiency is known to cause intellectual disability and epilepsy, RGMA haploinsufficiency might explain truncal obesity with onset around puberty observed in our two patients.


      PubDate: 2014-07-27T00:25:03Z
       
  • Infantile hydrocephalus: A review of epidemiology, classification and
           causes
    • Abstract: Publication date: Available online 13 June 2014
      Source:European Journal of Medical Genetics
      Author(s): Hannah M. Tully , William B. Dobyns
      Hydrocephalus is a common but complex condition caused by physical or functional obstruction of CSF flow that leads to progressive ventricular dilatation. Though hydrocephalus was recently estimated to affect 1.1 in 1000 infants, there have been few systematic assessments of the causes of hydrocephalus in this age group, which makes it a challenging condition to approach as a scientist or as a clinician. Here, we review contemporary literature on the epidemiology, classification and pathogenesis of infantile hydrocephalus. We describe the major environmental and genetic causes of hydrocephalus, with the goal of providing a framework to assess infants with hydrocephalus and guide future research.


      PubDate: 2014-07-27T00:25:03Z
       
  • Clinical and etiological heterogeneity in patients with tracheo-esophageal
           malformations and associated anomalies
    • Abstract: Publication date: Available online 12 June 2014
      Source:European Journal of Medical Genetics
      Author(s): Erwin Brosens , Mirjam Ploeg , Yolande van Bever , Anna E. Koopmans , Hanneke IJsselstijn , Robbert J. Rottier , Rene Wijnen , Dick Tibboel , Annelies de Klein
      Esophageal Atresia (EA) is a severe developmental defect of the foregut that presents with or without a Tracheo-Esophageal Fistula (TEF). The prevalence of EA/TEF over time and around the world has been relatively stable. EA/TEF is manifested in a broad spectrum of anomalies: in some patients it manifests as an isolated atresia or fistula, but in over half it affects several organ systems. While the associated malformations are often those of the VACTERL spectrum (Vertebral, Anorectal, Cardiac, Tracheo-Esophageal, Renal and Limb), many patients are affected by other malformations, such as microcephaly, micrognathia, pyloric stenosis, duodenal atresia, a single umbilical artery, and anomalies of the genitourinary, respiratory and gastrointestinal systems. Though EA/TEF is a genetically heterogeneous condition, recurrent genes and loci are sometimes affected. Tracheo-Esophageal (TE) defects are in fact a variable feature in several known single gene disorders and in patients with specific recurrent Copy Number Variations and structural chromosomal aberrations. At present, a causal genetic aberration can be identified in 11–12% of patients. In most, EA/TEF is a sporadic finding; the familial recurrence rate is low (1%). As this suggests that epigenetic and environmental factors also contribute to the disease, non-syndromic EA/TEF is generally believed to be a multifactorial condition. Several population-based studies and case reports describe a wide range of associated risks, including age, diabetes, drug use, herbicides, smoking and fetal alcohol exposure. The phenotypical and genetic heterogeneity seen in EA/TEF patients indicates not one underlying cause, but several. Unraveling the complex multifactorial and heterogeneous etiology of EA/TEF and associated features will require large cohorts of patients. Combined statistical analysis of component findings, genome sequencing, and genome wide association studies will elucidate new causal genetic defects and predisposing loci in the etiology within specific sub-populations. Improved knowledge of environmental risk factors, genetic predisposition and causal genetic syndromes may improve prediction and parental counseling, and prevent co-morbidity.


      PubDate: 2014-07-27T00:25:03Z
       
  • Etiopathogenesis of equinovarus foot malformations
    • Abstract: Publication date: Available online 13 June 2014
      Source:European Journal of Medical Genetics
      Author(s): Carlos A. Bacino , Jacqueline T. Hecht
      Congenital talipes equinovarus (CTEV) is the most common musculoskeletal birth defect affecting approximately 1/700–1/1000 of liveborns. Even though extensive epidemiological and genetic studies have been carried out to address its causes, the precise mechanisms leading to this common birth defect remain elusive. CTEV is a multifactorial disorder, hence the combination of genetic and environmental factors are known contributors to this developmental abnormality. So far a handful of genes involved in limb patterning like PITX1, HOXA, HOXD, TBX4, and RBM10, as well as genes involved in muscle contraction, have been identified as possible players. Among many environmental factors investigated, maternal smoking seems to hold the strongest consistent association with this disorder. This article will review and discuss some of the most common genetic and environmental factors associated with the etiopathogenesis of CTEV.


      PubDate: 2014-07-27T00:25:03Z
       
  • Homozygous loss-of-function mutation in ALMS1 causes the lethal disorder
           mitogenic cardiomyopathy in two siblings
    • Abstract: Publication date: Available online 24 June 2014
      Source:European Journal of Medical Genetics
      Author(s): Jacoba J. Louw , Anniek Corveleyn , Yaojuan Jia , Sajid Iqbal , Derize Boshoff , Marc Gewillig , Hilde Peeters , Philippe Moerman , Koenraad Devriendt
      Background Two siblings from consanguineous parents of Turkish descent presented with isolated dilated cardiomyopathy, leading to early death in infancy. The diagnosis of mitogenic cardiomyopathy was made histologically. Methods and results Linkage analysis combined with exome sequencing identified a homozygous deleterious mutation in the ALMS1 gene as the cause of this phenotype. Conclusions Alström syndrome is characterized by a typically transient dilating cardiomyopathy in infancy, suggesting that mitogenic cardiomyopathy represents the extreme phenotype, resulting in demise before the other clinical symptoms become evident. This observation further illustrates the role of ALMS1 and cell cycle regulation.


      PubDate: 2014-07-27T00:25:03Z
       
  • Biallelic mutations at PPARG cause a congenital, generalized lipodystrophy
           similar to the Berardinelli–Seip syndrome
    • Abstract: Publication date: Available online 28 June 2014
      Source:European Journal of Medical Genetics
      Author(s): D.A. Dyment , W.T. Gibson , L. Huang , H. Bassyouni , R.A. Hegele , A.M. Innes
      We present an individual with a generalized and infantile onset lipodystrophy who later developed hypertriglyceridemia, pancreatitis, refractory diabetes, irregular menses and renal failure. She showed the hallmark features of a congenital, generalized lipodystrophy (CGL). Sequencing PPARG identified two pathogenic mutations; c.413_416delAATG; p.Glu138ValfsX168 and c.490C>T; p.R164W. The phenotype and presence of two mutations suggests that biallelic mutations at PPARG cause a CGL similar to that observed with biallelic AGPAT2 or BSCL2 mutations.


      PubDate: 2014-07-27T00:25:03Z
       
  • The early detection of Salla disease through second-tier tests in newborn
           screening: How to face incidental findings
    • Abstract: Publication date: Available online 30 June 2014
      Source:European Journal of Medical Genetics
      Author(s): María L. Couce , Judit Macías-Vidal , Daisy E. Castiñeiras , María D. Bóveda , José M. Fraga , Ana Fernández-Marmiesse , María J. Coll
      We describe here a 34 months child, practically asymptomatic which presented with high levels of free sialic acid in urine by biochemical detection in second-tier tests newborn screening and with two disease causing mutations in SLC17A5 gene. SLC17A5 mutation analysis showed p.Tyr306* previously decribed and the novel mutation p.Leu167Pro. This early onset diagnosis allowed us to perform a fast and accurate genetic counseling to the family, helped to better understanding the natural history of this rare disease and probably it could promote cost reduction in future diagnostic tests in the hypothetic case of starting symptoms without diagnosis established. Moreover, an early diagnosis could save family from a long period of time until achieving a definitive diagnostic and to develop an early symptomatic and supportive management of patient to attenuate, as much as possible, disease complications. But, above all, this case illustrates the huge ethical dilemma which arises from any secondary finding (second tier) in newborn screening.


      PubDate: 2014-07-27T00:25:03Z
       
  • Genetics of gastrointestinal atresias
    • Abstract: Publication date: Available online 11 July 2014
      Source:European Journal of Medical Genetics
      Author(s): Jacopo Celli
      Gastrointestinal atresias are a common and serious feature within the spectrum of gastrointestinal malformations. Atresias tend to be lethal, although, now-days surgery and appropriate care can restore function to the affected organs. In spite of their frequency, their life threatening condition and report history gastrointestinal atresias' etiology remains mostly unclarified. Gastrointestinal atresias can occur as sporadic but they are more commonly seen in association with other anomalies. For the syndromic cases there is mounting evidence of a strong genetic component. Sporadic cases are generally thought to originate from mechanical or vascular incidents in utero, especially for the atresias of the lower intestinal tract. However, recent data show that a genetic component may be present also in these cases. Embryological and genetic studies are starting to uncover the mechanism of gastrointestinal development and their genetic components. Here we present an overview of the current knowledge of gastrointestinal atresias, their syndromic forms and the genetic pathways involved in gastrointestinal malformation.


      PubDate: 2014-07-27T00:25:03Z
       
  • 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
       
  • 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
       
  • 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
       
  • 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
       
  • 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
       
 
 
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