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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]
  • 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
       
  • 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
       
  • 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
       
  • 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
       
  • 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
       
  • 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
       
  • 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
       
  • 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
       
  • 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
       
  • 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
       
 
 
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