for Journals by Title or ISSN
for Articles by Keywords
help

Publisher: Elsevier   (Total: 3043 journals)

 A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  

We no longer collect new content from this publisher because the publisher has forbidden systematic access to its RSS feeds.
Journal Cover European Journal of Medical Genetics
  [SJR: 0.934]   [H-I: 40]   [6 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1769-7212
   Published by Elsevier Homepage  [3043 journals]
  • BRCA1/2 missense mutations and the value of in-silico analyses
    • Abstract: Publication date: Available online 12 August 2017
      Source:European Journal of Medical Genetics
      Author(s): Carolin E. Sadowski, Daniela Kohlstedt, Cornelia Meisel, Katja Keller, Kerstin Becker, Luisa Mackenroth, Andreas Rump, Evelin Schröck, Pauline Wimberger, Karin Kast
      Introduction The clinical implications of genetic variants in BRCA1/2 in healthy and affected individuals are considerable. Variant interpretation, however, is especially challenging for missense variants. The majority of them are classified as variants of unknown clinical significance (VUS). Computational (in-silico) predictive programs are easy to access, but represent only one tool out of a wide range of complemental approaches to classify VUS. With this single-center study, we aimed to evaluate the impact of in-silico analyses in a spectrum of different BRCA1/2 missense variants. Methods We conducted mutation analysis of BRCA1/2 in 523 index patients with suspected hereditary breast and ovarian cancer (HBOC). Classification of the genetic variants was performed according to the German Consortium (GC)-HBOC database. Additionally, all missense variants were classified by the following three in-silico prediction tools: SIFT, Mutation Taster (MT2) and PolyPhen2 (PPH2). Results Overall 201 different variants, 68 of which constituted missense variants were ranked as pathogenic, neutral, or unknown. The classification of missense variants by in-silico tools resulted in a higher amount of pathogenic mutations (25% vs. 13.2%) compared to the GC-HBOC-classification. Altogether, more than fifty percent (38/68, 55.9%) of missense variants were ranked differently. Sensitivity of in-silico-tools for mutation prediction was 88.9% (PPH2), 100% (SIFT) and 100% (MT2). Conclusion We found a relevant discrepancy in variant classification by using in-silico prediction tools, resulting in potential overestimation and/or underestimation of cancer risk. More reliable, notably gene-specific, prediction tools and functional tests are needed to improve clinical counseling.

      PubDate: 2017-08-15T17:24:44Z
       
  • Impairment of different protein domains causes variable clinical
           presentation within Pitt-Hopkins syndrome and suggests intragenic
           molecular syndromology of TCF4
    • Abstract: Publication date: Available online 12 August 2017
      Source:European Journal of Medical Genetics
      Author(s): Maria Francesca Bedeschi, Giuseppe Marangi, Maria Rosaria Calvello, Stefania Ricciardi, Francesca Pia Chiara Leone, Marco Baccarin, Silvana Guerneri, Daniela Orteschi, Marina Murdolo, Serena Lattante, Silvia Frangella, Beth Keena, Margaret H. Harr, Elaine Zackai, Marcella Zollino
      Pitt-Hopkins syndrome is a neurodevelopmental disorder characterized by severe intellectual disability and a distinctive facial gestalt. It is caused by haploinsufficiency of the TCF4 gene. The TCF4 protein has different functional domains, with the NLS (nuclear localization signal) domain coded by exons 7–8 and the bHLH (basic Helix-Loop-Helix) domain coded by exon 18. Several alternatively spliced TCF4 variants have been described, allowing for translation of variable protein isoforms. Typical PTHS patients have impairment of at least the bHLH domain. To which extent impairment of the remaining domains contributes to the final phenotype is not clear. There is recent evidence that certain loss-of-function variants disrupting TCF4 are associated with mild ID, but not with typical PTHS. We describe a frameshift-causing partial gene deletion encompassing exons 4–6 of TCF4 in an adult patient with mild ID and nonspecific facial dysmorphisms but without the typical features of PTHS, and a c.520C > T nonsense variant within exon 8 in a child presenting with a severe phenotype largely mimicking PTHS, but lacking the typical facial dysmorphism. Investigation on mRNA, along with literature review, led us to suggest a preliminary phenotypic map of loss-of-function variants affecting TCF4. An intragenic phenotypic map of loss-of-function variants in TCF4 is suggested here for the first time: variants within exons 1–4 and exons 4–6 give rise to a recurrent phenotype with mild ID not in the spectrum of Pitt-Hopkins syndrome (biallelic preservation of both the NLS and bHLH domains); variants within exons 7–8 cause a severe phenotype resembling PTHS but in absence of the typical facial dysmorphism (impairment limited to the NLS domain); variants within exons 9–19 cause typical Pitt-Hopkins syndrome (impairment of at least the bHLH domain). Understanding the TCF4 molecular syndromology can allow for proper nosology in the current era of whole genomic investigations.

      PubDate: 2017-08-15T17:24:44Z
       
  • Reducing diagnostic turnaround times of exome sequencing for families
           requiring timely diagnoses
    • Abstract: Publication date: Available online 12 August 2017
      Source:European Journal of Medical Genetics
      Author(s): Aurélie Bourchany, Christel Thauvin-Robinet, Daphné Lehalle, Ange-Line Bruel, Alice Masurel-Paulet, Nolwenn Jean, Sophie Nambot, Marjorie Willems, Laetitia Lambert, Salima El Chehadeh-Djebbar, Elise Schaefer, Aurélia Jaquette, Judith St-Onge, Charlotte Poe, Thibaud Jouan, Martin Chevarin, Patrick Callier, Anne-Laure Mosca-Boidron, Nicole Laurent, Mathilde Lefebvre, Frédéric Huet, Nada Houcinat, Sébastien Moutton, Christophe Philippe, Frédéric Tran-Mau-Them, Antonio Vitobello, Paul Kuentz, Yannis Duffourd, Jean-Baptiste Rivière, Julien Thevenon, Laurence Faivre
      Background and objective Whole-exome sequencing (WES) has now entered medical practice with powerful applications in the diagnosis of rare Mendelian disorders. Although the usefulness and cost-effectiveness of WES have been widely demonstrated, it is essential to reduce the diagnostic turnaround time to make WES a first-line procedure. Since 2011, the automation of laboratory procedures and advances in sequencing chemistry have made it possible to carry out diagnostic whole genome sequencing from the blood sample to molecular diagnosis of suspected genetic disorders within 50 h. Taking advantage of these advances, the main objective of the study was to improve turnaround times for sequencing results. Methods WES was proposed to 29 patients with severe undiagnosed disorders with developmental abnormalities and faced with medical situations requiring rapid diagnosis. Each family gave consent. The extracted DNA was sequenced on a NextSeq500 (Illumina) instrument. Data were analyzed following standard procedures. Variants were interpreted using in-house software. Each rare variant affecting protein sequences with clinical relevance was tested for familial segregation. Results The diagnostic rate was 45% (13/29), with a mean turnaround time of 40 days from reception of the specimen to delivery of results to the referring physician. Besides permitting genetic counseling, the rapid diagnosis for positive families led to two pre-natal diagnoses and two inclusions in clinical trials. Conclusions This pilot study demonstrated the feasibility of rapid diagnostic WES in our primary genetics center. It reduced the diagnostic odyssey and helped provide support to families.

      PubDate: 2017-08-15T17:24:44Z
       
  • A novel mutation in SMOC1 and variable phenotypic expression in two
           patients with Waardenburg anophthalmia syndrome
    • Abstract: Publication date: Available online 12 August 2017
      Source:European Journal of Medical Genetics
      Author(s): Javad Jamshidi, Shokoufeh Abdollahi, Hamid Ghaedi, Elham Alehabib, Abbas Tafakhori, Somayeh Alinaghi, Marjan Chapi, Amir Hossein Johari, Hossein Darvish
      Waardenburg anophthalmia syndrome (WAS) is a rare disorder that mostly affects the eyes and distal limbs. In the current study we reported two Iranian patients with WAS. The first case was a 26-year-old girl with unilateral anophthalmia, bilateral camptodactyly and clinodactyly in her hands, oligodactly in her left foot and syndactyly of the second to fifth toes in her right foot. She also had severe hearing loss in both ears. The second case was a 12-year-old boy with bilateral anophthalmia, camptodactyly in his right hand, oligodactyly in his foot, clubfoot, and cryptorchidism. Both patients were mentally normal. To detect the causative mutation all exons and exon-intron boundaries of SMOC1 gene were sequenced in patients and other normal family members. We found a homozygous missense mutation (NM_001034852.2(SMOC1):c.367T > C) in exon 3 of SMOC1 gene in both patients. As the mutation segregated with the disease in the family, it should be the causative mutation. Our study extended the mutation spectrum of SMOC1 gene related to WAS.

      PubDate: 2017-08-15T17:24:44Z
       
  • Response to “in silico prediction is insufficient to assess
           pathogenicity of mtDNA variants”
    • Abstract: Publication date: Available online 12 August 2017
      Source:European Journal of Medical Genetics
      Author(s): Mafalda Bacalhau, Maria J. Santos, Manuela Grazina, João Pratas, Marta Simões, Cândida Mendes, Carolina Ribeiro, Luisa Diogo, Maria Carmo Macário


      PubDate: 2017-08-15T17:24:44Z
       
  • Comment to the manuscript by Bacalhau et al. On “in silico prediction is
           insufficient to assess pathogenicity of mtDNA variants”
    • Abstract: Publication date: Available online 12 August 2017
      Source:European Journal of Medical Genetics
      Author(s): Josef Finsterer, Sinda Zarrouk-Mahjoub


      PubDate: 2017-08-15T17:24:44Z
       
  • Prenatal diagnosis of complex phenotype in a 13-week-old fetus with an
           
    • Abstract: Publication date: Available online 12 August 2017
      Source:European Journal of Medical Genetics
      Author(s): Feodora Stipoljev, Danka Miric-Tesanic, Tomislav Hafner, Maja Barbalic, Monika Logara, Ruzica Lasan-Trcic, Ana Vicic, Romana Gjergja-Juraski
      We report the first trimester three-dimensional ultrasonographic findings in a 13-week-old fetus with complex phenotype and a de novo 4.7 Mb multigene deletion encompassing chromosome region 20q13.13-q13.2 detected by chromosomal microarray. Fetal sonography detected radial-ray anomalies in the form of bilateral absence of thumbs and the left club hand deformity. The presence of single atrioventricular canal instead of the atrial septal defect typical for Holt-Oram syndrome pointed us to rather suspect the SALL4 related diseases. Central nervous system anomaly in the form of enlarged lateral brain ventricles with choroid plexus shifted backwards was not previously reported as a part of SALL4 related disorders. The pregnancy was terminated at 14 + 3 weeks of pregnancy and the autopsy confirmed ultrasonographic findings. Deleted region included 38 genes, where only SALL4, ADNP and KCNB1 heterozygote pathogenic variants were described to because of syndromic forms. Radial ray anomalies are common part of clinical picture of SALL4 related disorders. Despite the lack of prenatally described cases, we hypothesized that maldevelopment of lateral brain ventriculomegaly could be very early sonographic sign of disturbed ADNP expression causing Helsmoortel-Van der Aa syndrome, but in some extent also of KCNB1 related early-onset epileptic encephalopathy. Furthermore, the possible dosage-dependent influence of recessive genes located in this region cannot be also excluded. The use of genome-wide technologies enables the detection of subtle chromosomal imbalances and more precise familial genetic counseling regarding actual and future pregnancies.

      PubDate: 2017-08-15T17:24:44Z
       
  • Novel compound heterozygous mutations identified by whole exome sequencing
           in a Japanese patient with geroderma osteodysplastica
    • Abstract: Publication date: Available online 12 August 2017
      Source:European Journal of Medical Genetics
      Author(s): Ryojun Takeda, Masaki Takagi, Hiroyuki Shinohara, Hiroshi Futagawa, Satoshi Narumi, Tomonobu Hasegawa, Gen Nishimura, Hiroshi Yoshihashi
      Geroderma osteodysplastica (GO) is a subtype of cutis laxa syndrome characterized by congenital wrinkly skin, a prematurely aged face, extremely short stature, and osteoporosis leading to recurrent fractures. GO exhibits an autosomal recessive inheritance pattern and is caused by loss-of-function mutations in GORAB, which encodes a protein important for Golgi-related transport. Using whole exome sequencing, we identified novel compound heterozygous nonsense mutations in the GORAB in a GO patient. The patient was a 14-year-old Japanese boy. Wrinkled skin and joint laxity were present at birth. At 1 year of age, he was clinically diagnosed with cutis laxa syndrome based on recurrent long bone fractures and clinical features, including wrinkled skin, joint laxity, and a distinctive face. He did not show retarded gross motor and cognitive development. At 11 years of age, he was treated with oral bisphosphonate and vitamin D owing to recurrent multiple spontaneous fractures of the vertebral and extremity bones associated with a low bone mineral density (BMD). Bisphosphonate treatment improved his BMD and fracture rate. Whole exome sequencing revealed two novel compound heterozygous nonsense mutations in the GORAB gene (p.Arg60* and p.Gln124*), and the diagnosis of GO was established. GO is a rare connective tissue disorder. Approximately 60 cases have been described to date, and this is the first report of a patient from Japan. Few studies have reported the effects of bisphosphonate treatment in GO patients with recurrent spontaneous fractures. Based on this case study, we hypothesize that oral bisphosphonate and vitamin D are effective and safe treatment options for the management of recurrent fractures in GO patients. It is important to establish a precise diagnosis of GO to prevent recurrent fractures and optimize treatment plans.

      PubDate: 2017-08-15T17:24:44Z
       
  • A comparison of splicing assays to detect an intronic variant of the OCRL
           gene in Lowe syndrome
    • Abstract: Publication date: Available online 9 August 2017
      Source:European Journal of Medical Genetics
      Author(s): Keita Nakanishi, Kandai Nozu, Ryugo Hiramoto, Shogo Minamikawa, Tomohiko Yamamura, Junya Fujimura, Tomoko Horinouchi, Takeshi Ninchoji, Hiroshi Kaito, Naoya Morisada, Shingo Ishimori, Koichi Nakanishi, Ichiro Morioka, Hiroyuki Awano, Masafumi Matsuo, Kazumoto Iijima
      Lowe syndrome is an X-linked inherited disorder diagnosed by congenital cataracts, intellectual impairment, and renal tubular dysfunction. It is caused by pathogenic variants of the oculocerebrorenal syndrome of Lowe gene (OCRL), of which more than 250 have been reported so far. Around 30 of these variants are intronic nucleotide changes; however, to show the pathogenicity of these variants is usually laborious. In this report, we conducted genetic testing of a patient clinically diagnosed with Lowe syndrome to detect the presence of OCRL variants. We analyzed variant transcript expression in peripheral blood leukocytes and using a minigene construct in addition to in silico analysis. We detected a 9 base pair intronic insertion between OCRL exon 10 and exon 11 derived from the alteration of the splicing acceptor site in intron 10 caused by the intronic splicing variant NM_000276.3: c.940-11G>A (p.Lys313_Val314insAsnSer*). The findings obtained from transcript analysis of peripheral blood leukocytes and the minigene construct assay were identical to those of in silico analysis. All assays detected the same transcript abnormality and were reliable in revealing the pathogenicity of the intronic variant. The in vitro assay can also be used to clarify the complicated splicing mechanisms in inherited kidney diseases.

      PubDate: 2017-08-15T17:24:44Z
       
  • A novel mutation in CDK5RAP2 gene causes primary microcephaly with speech
           impairment and sparse eyebrows in a consanguineous Pakistani family
    • Abstract: Publication date: Available online 2 August 2017
      Source:European Journal of Medical Genetics
      Author(s): Uzma Abdullah, Muhammad Farooq, Yuan Mang, Syeda Marriam Bakhtiar, Ambrin Fatima, Lars Hansen, Klaus Wilbrandt Kjaer, Lars Allan Larsen, Niels Tommerup, Shahid Mahmood Baig
      The CDK5RAP2 gene encodes a centrosomal protein, highly expressed in fetal brain and essentially indispensable for its normal development, as biallelic mutations lead to primary microcephaly (MCPH). Despite being known as MCPH linked gene for more than a decade, the phenotypic spectrum of CDK5RAP2 mutations is still under explored as only eleven families have been reported worldwide. Here, we analyzed a consanguineous Pakistani MCPH family, characterized by moderate to severe intellectual disability, speech impairment, moderately short stature and sparse eyebrows. Whole exome sequencing of the proband identified a 2bp duplication in exon 34 of CDK5RAP2 that causes frame-shift, leading to a premature stop codon. The resultant transcript is resistant to nonsense mediated decay, suggesting that the mutation leads to a truncated protein lacking C-terminal domains; CDK5R1, and Cnn motif 2 (CM2), required for its localization to the centrosome and the Golgi Apparatus. The clinical variability observed in the family highlights the importance of further detailed clinical description of patients with CDK5RAP2 mutations.

      PubDate: 2017-08-05T15:40:12Z
       
  • Letter regarding the article: “Multiple HABP2 variants in familial
           papillary thyroid carcinoma: Contribution of a group of
           “thyroid-checked” controls” by Kern et al.
    • Abstract: Publication date: Available online 2 August 2017
      Source:European Journal of Medical Genetics
      Author(s): Carla Colombo, Laura Fugazzola, Marina Muzza, Maria Carla Proverbio, Valentina Cirello
      This Journal recently published a study (Kern et al., 2017) reporting the genetic analysis of the whole HABP2 gene in 11 independent kindreds with familial non medullary thyroid cancer (FNMTC). The
      Authors showed that a new variant (p.R122W) displayed a minor allele frequency (MAF) significantly higher in FNMTC patients than in controls (7.5 vs 0.73%, p = 0.016) and cosegregated with thyroid cancer in one kindred, thus suggesting the need for the evaluation of its possible pathogenicity in other series. We thus analyzed this new HABP2 p.R122W variant in our wide series of 32 unrelated FNMTC Italian kindreds. The variant was not found in any of the 72 affected and 12 not affected family members. In conclusion, the HABP2R122W was not found in our wide series and it is thus unlikely to be causal to FNMTC. We therefore suggest that careful replication studies should be performed when assessing the possible association between FNMTC risk and any HABP2 variant.

      PubDate: 2017-08-05T15:40:12Z
       
  • Novel mutations in SERAC1 gene in two Indian patients presenting with
           dystonia and intellectual disability.
    • Abstract: Publication date: Available online 1 August 2017
      Source:European Journal of Medical Genetics
      Author(s): Radha Rama Devi A, Lokesh Lingappa
      In this study we present the first two cases from India of a rare inborn error of metabolism manifesting as dystonia and 3-methylglutaconic aciduria and a Leigh like lesions in the brain MRI associated with SERAC1 gene mutation, a phenotype characteristic of MEGDEL syndrome. A four base pair duplication in exon 15 i.e.NM_032861.3 (SERAC1) c. 1643_1646 dup ATCT (p.(Leu550SerfsX19)) and another with a homozygous missense variation in exon 15 i.e. NM_032861.3 (SERAC1) c.1709 G > A (p.(Gly526Glu)) were detected and both were novel mutations. Hepatopathy was observed in the neonatal period with lactic acidosis in one child and at the age of 5yrs in the other. These cases add to the existing number of patients identified till today and additional mutations in the SERAC1 gene.

      PubDate: 2017-08-05T15:40:12Z
       
  • A de novo mosaic mutation in SPAST with two novel alternative alleles and
           chromosomal copy number variant in a boy with spastic paraplegia and
           autism spectrum disorder
    • Abstract: Publication date: Available online 1 August 2017
      Source:European Journal of Medical Genetics
      Author(s): A.M. Matthews, M. Tarailo-Graovac, E.M. Price, I. Blydt-Hansen, A. Ghani, B.I. Drögemöller, W.P. Robinson, C.J. Ross, W.W. Wasserman, H. Siden, C.D. van Karnebeek
      Here we report a 12 year old male with an extreme presentation of spastic paraplegia along with autism and dysmorphisms. Whole exome sequencing identified a predicted pathogenic pair of missense variants in SPAST at the same chromosomal location, each with a different alternative allele, while a chromosome microarray identified a 1.73 Mb paternally inherited copy gain of 1q21.1q21.2 resulting in a blended phenotype of both Spastic paraplegia 4 and 1q21.1 microduplication syndrome. We believe that the extreme phenotype observed is likely caused by the presence of cells which contain only mutant SPAST, but that the viability of the patient is possible due mosaicism of mutant alleles observed in different proportions across tissues.

      PubDate: 2017-08-05T15:40:12Z
       
  • Reporting practices for variants of uncertain significance from next
           generation sequencing technologies
    • Abstract: Publication date: Available online 1 August 2017
      Source:European Journal of Medical Genetics
      Author(s): Danya F. Vears, Karine Sénécal, Pascal Borry
      The nature of next generation sequencing technologies (NGS) results in the generation of large amounts of data and the identification of numerous variants, for some of which the clinical significance may be difficult to ascertain based on our current knowledge. These Variants of Uncertain Significance (VUS) may be identified in genes in which the function is known or unknown and which may or may not be related to the original rationale for sequencing the patient. Little is known about whether laboratories report VUS to clinicians and current guidelines issued by some of the most notable professional bodies do not provide specific recommendations on this point. To address this, 26 interviews were conducted with 27 laboratory personnel, representing 24 laboratories in Europe (12), Canada (5) and Australasia (7) in order to explore their reporting practices. Participants highlighted that the classification of variants is a real challenge despite the presence of classification guidelines. We identified variation in the reporting practices of VUS across the laboratories within the study. While some laboratories limit their reporting to variants that are pathogenic and thought to be causative of the phenotype, more commonly laboratories report VUS when they are identified in genes related to the clinical question. Some laboratories will also report VUS in candidate genes. VUS that are secondary findings are generally not reported. While it is unclear whether uniformity in reporting is desirable, exploring the perspectives of laboratory personnel undertaking these analyses are critical to ensure the feasibility of any future reporting recommendations.

      PubDate: 2017-08-05T15:40:12Z
       
  • Exome sequence identified a c.320A > G ALG13 variant in a female with
           infantile epileptic encephalopathy with normal glycosylation and random X
           inactivation: Review of the literature
    • Abstract: Publication date: Available online 1 August 2017
      Source:European Journal of Medical Genetics
      Author(s): Sana Hamici, Fatma Bastaki, Mohamed Khalifa
      Congenital Disorders of Glycosylation (CDG) are new and rapidly expanding neurometabolic disorders with multisystem involvements, broad phenotypic manifestations, and variable severity. The majority results from a defect of one of the steps involved with protein or lipid N-glycosylation pathway. Almost all are inherited in autosomal recessive patterns with a few exceptions such as the X-linked ALG13. Mutations of ALG13 are reported, so far in only 10 patients, all were ascertained through exome/genome sequencing. Specifically, the ALG13 c.320A > G (p.Asn107Ser) variant was reported only in females and in all were de novo mutations. These findings may suggest an X-linked dominant inheritance of this mutation with embryonic male lethality. These patients presented with severe infantile epileptic encephalopathy, global developmental delay, and multisystem abnormalities. Only two of these females had glycosylation studies done, and both showed normal pattern of glycosylated serum transferrin isoforms, and none had their X-chromosome inactivation patterns studied. Here, we report on another female patient who is heterozygous for the same ALG13 c.320A > G (p.Asn107Ser) variant. She presented with infantile spasms, epileptic encephalopathy, hypsarrhythmia, hypotonia, developmental delay, intellectual disability, abnormal coagulation profile, feeding problems, hypotonia, and dysmorphic features. The diagnosis of CGD was suspected clinically, but glycosylation studies were done twice and showed normal patterns on both occasions. Her X-inactivation study was also done and, surprisingly, showed a random pattern of X-inactivation, with no evidence of skewness.

      PubDate: 2017-08-05T15:40:12Z
       
  • Ehlers Danlos syndrome, kyphoscoliotic type due to Lysyl Hydroxylase 1
           deficiency in two children without congenital or early onset
           kyphoscoliosis
    • Abstract: Publication date: Available online 27 July 2017
      Source:European Journal of Medical Genetics
      Author(s): Fleur S. van Dijk, Grazia M.S. Mancini, Alessandra Maugeri, Jan M. Cobben
      We report two children with Ehlers Danlos, kyphoscoliotic type confirmed by Lysyl Hydroxylase 1 deficiency due to bi-allelic PLOD1 mutations (kEDS-PLOD1) who were initially thought to have either a diagnosis of classical EDS (cEDS) or a neuromuscular disorder due to absence of (congenital) scoliosis. As the two patients reported here illustrate, patients with kEDS-PLOD1 do not always have a kyphoscoliosis present at birth or in the first year of life, neither do they necessarily develop kyphoscoliosis later in infancy. Using the past criteria for kEDS there was considerable overlap with the clinical diagnostic criteria for EDS classical type. In the patients reported here without (kypho) scoliosis this has delayed the diagnosis, which is unfortunate as the diagnosis of kEDS-PLOD1 results in a different recurrence risk and has management consequences. Interestingly, the new criteria for kEDS would not have prevented this diagnostic delay as congenital or early onset kyphoscoliosis (progressive or non-progressive) is deemed obligatory for the diagnosis of kEDS. Being aware of the limitations of clinical diagnostic criteria, we recommend that (i) in patients without a positive family history nor identified COL5A1/2 mutations, lysyl hydroxylase deficiency or biallelic PLOD1 mutations should be excluded before the diagnosis classical EDS can be made and (ii) PLOD1 and COL5A1/2 should be included in the same Next Generation Sequencing (NGS) gene panel.

      PubDate: 2017-08-05T15:40:12Z
       
  • Confirmation that mutations in DDX59 cause an autosomal recessive form of
           oral-facial-digital syndrome: Further delineation of the DDX59 phenotype
           in two new families
    • Abstract: Publication date: Available online 12 July 2017
      Source:European Journal of Medical Genetics
      Author(s): Sara Faily, Rahat Perveen, Jill Urquhart, Kate Chandler, Jill Clayton-Smith
      We report three probands from two unrelated consanguineous families of South Asian origin who all carry the same rare novel homozygous variant within the dead box helicase gene DDX59 in association with features of oral-facial-digital syndrome (OFDS). DDX59 variants have been reported previously in an unclassified, autosomal recessive form of OFDS; clinically associated with features including tongue lobulation, cleft palate, frontal bossing, hypertelorism and postaxial polydactyly. All three probands had lobulated tongues with tongue hamartomas, abnormal tongue tip, developmental delay and microcephaly, with just one proband demonstrating polydactlyly. The novel DDX59 variant was identified through autozygosity studies followed by sequencing of homozygous regions identified. It affects a stop codon, extending the protein product and is therefore predicted to be pathogenic. It is only the third reported DDX59 mutation associated with OFDS reported so far.

      PubDate: 2017-07-21T11:22:27Z
       
  • Homozygous c.359del variant in MGME1 is associated with early onset
           cerebellar ataxia
    • Abstract: Publication date: Available online 12 July 2017
      Source:European Journal of Medical Genetics
      Author(s): Malavika Hebbar, Katta M. Girisha, Anshika Srivastava, Stephanie Bielas, Anju Shukla
      We ascertained a child with early onset cerebellar ataxia and identified a novel frameshift deletion, c.359del [p. (Pro120Leufs*2), NM_052865.2] in exon 2 of MGME1 (mitochondrial genome maintenance exonuclease 1) by exome sequencing. Variations in MGME1 have been reported to cause mitochondrial DNA (mtDNA) depletion syndrome 11 (MIM #615084) in an earlier work. The phenotype included progressive external ophthalmoplegia, emaciation, respiratory failure and late onset progressive ataxia. However, the child presented here has early onset progressive ataxia, speech delay, microcephaly, cerebellar atrophy and fundus albipunctatus. This is the second report of a mutation in MGME1 and describes a more severe phenotype.

      PubDate: 2017-07-21T11:22:27Z
       
  • Microcephaly with simplified gyral pattern, epilepsy and permanent
           neonatal diabetes syndrome (MEDS). A new patient and review of the
           literature
    • Abstract: Publication date: Available online 12 July 2017
      Source:European Journal of Medical Genetics
      Author(s): Irene Valenzuela, Susana Boronat, Elena Martínez-Sáez, María Clemente, Ángel Sánchez-Montañez, Francina Munell, Antonio Carrascosa, Alfons Macaya
      Microcephaly with simplified gyration, epilepsy and permanent neonatal diabetes syndrome (MEDS) is a recently described, autosomal recessive-inherited syndrome. We report the case of an infant presenting with lethargy at age five weeks and clinical findings of persistent hyperglycaemia and microcephaly with simplified gyration, suggestive of MEDS. The diagnosis was confirmed by the detection of a known c.233 T > C mutation in the IER3IP1 gene. Only eight cases of MEDS have been reported in the literature. We reviewed these with the aim of better delineating their clinical manifestations, which should allow earlier and more accurate diagnosis and genetic counseling.

      PubDate: 2017-07-21T11:22:27Z
       
  • Early manifestations of epileptic encephalopathy, brain atrophy, and
           elevation of serum neuron specific enolase in a boy with beta-propeller
           protein-associated neurodegeneration
    • Abstract: Publication date: Available online 12 July 2017
      Source:European Journal of Medical Genetics
      Author(s): Kyoko Takano, Kazuya Goto, Mitsuo Motobayashi, Keiko Wakui, Rie Kawamura, Tomomi Yamaguchi, Yoshimitsu Fukushima, Tomoki Kosho
      Mutations in WDR45 are responsible for beta-propeller protein-associated neurodegeneration (BPAN), which is an X-linked form of neurodegeneration with brain iron accumulation. BPAN mainly affects females and is characterized by seizures and developmental delay or intellectual disability until adolescence or early adulthood, followed by severe dystonia, parkinsonism, and progressive dementia. However, rare male patients have recently been reported with hemizygous germline mutations in WDR45 and severe clinical manifestations, such as epileptic encephalopathies. We report here a 4-year-old boy presenting with profound developmental delay, non-syndromic epileptic encephalopathy, and early brain atrophy. The level of serum neuron specific enolase (NSE) was elevated, but the level of serum phosphorylated neurofilament heavy chain was not detectable. Targeted next-generation sequencing identified a de novo hemizygous splice donor site mutation, c.830+1G > A in WDR45, which resulted in a splicing defect evidenced by reverse transcriptase-PCR. Mutations in WDR45 should be considered as a cause for epileptic encephalopathies in males with profound developmental delay and brain atrophy. Furthermore, elevation of serum NSE may contribute to early diagnosis of BPAN.

      PubDate: 2017-07-21T11:22:27Z
       
  • Letter regarding the article: “A novel missense variant (Gln220Arg) of
           GNB4 encoding guanine nucleotide-binding protein, subunit beta-4 in a
           Japanese family with autosomal dominant motor and sensory neuropathy”
    • Abstract: Publication date: Available online 10 July 2017
      Source:European Journal of Medical Genetics
      Author(s): José Berciano, Antonio García


      PubDate: 2017-07-21T11:22:27Z
       
  • Response to the Letter to the Editor by Berciano J & García A
    • Abstract: Publication date: Available online 8 July 2017
      Source:European Journal of Medical Genetics
      Author(s): Shiroh Miura, Hiroki Shibata


      PubDate: 2017-07-10T09:50:04Z
       
  • SMD Kozlowski type caused by p.Arg594His substitution in TRPV4 reveals
           abnormal ossification and notochordal remnants in discs and vertebrae
    • Abstract: Publication date: Available online 4 July 2017
      Source:European Journal of Medical Genetics
      Author(s): Tadeusz Bieganski, Peter Beighton, Maciej Lukaszewski, Krzysztof Bik, Lukasz Kuszel, Ewa Wasilewska, Kazimierz Kozlowski, Malwina Czarny-Ratajczak
      Spondylometaphyseal dysplasia Kozlowski type (SMDK) is a monogenic disorder within the TRPV4 dysplasia spectrum and has characteristic spinal and metaphyseal involvement. We report skeletal MR imaging in a two-year-old patient who manifested typical clinical and radiographic features of SMDK. The diagnosis was confirmed by molecular analysis which revealed a mutation NM_021625.4:c.1781G > A - p.(Arg594His) in exon 11 of the TRPV4 gene. We have documented abnormalities in endochondral formation of the long and short tubular bones as well as round bones of the wrists and feet. The vertebral bodies had increased thickness of hyaline cartilage which enveloped ossification centers. The vertebrae and discs also had abnormalities in size, shape and structure. These anomalies were most likely the consequence of notochordal remnants presence within the intervertebral discs and in the vertebral bodies. The advantages of MR imaging in bone dysplasias caused by TRPV4 mutations are emphasized in this article.

      PubDate: 2017-07-10T09:50:04Z
       
  • First de novo ANK3 nonsense mutation in a boy with intellectual
           disability, speech impairment and autistic features
    • Abstract: Publication date: Available online 4 July 2017
      Source:European Journal of Medical Genetics
      Author(s): Katja Kloth, Jonas Denecke, Maja Hempel, Jessika Johannsen, Tim M. Strom, Christian Kubisch, Davor Lessel
      Ankyrin-G, encoded by ANK3, plays an important role in neurodevelopment and neuronal function. There are multiple isoforms of Ankyrin-G resulting in differential tissue expression and function. Heterozygous missense mutations in ANK3 have been associated with autism spectrum disorder. Further, in three siblings a homozygous frameshift mutation affecting only the longest isoform and a patient with a balanced translocation disrupting all isoforms were documented. The latter four patients were affected by a variable degree of intellectual disability, attention deficit hyperactivity disorder and autism. Here, we report on a boy with speech impairment, intellectual disability, autistic features, macrocephaly, macrosomia, chronic hunger and an altered sleeping pattern. By trio-whole-exome sequencing, we identified the first de novo nonsense mutation affecting all ANK3 transcripts. Thus, our data expand the phenotype of ANK3-associated diseases and suggest an isoform-based, phenotypic continuum between dominant and recessive ANK3-associated pathologies.

      PubDate: 2017-07-10T09:50:04Z
       
  • The first patient with sporadic X-linked intellectual disability with de
           novo ZDHHC9 mutation identified by targeted next-generation sequencing
    • Abstract: Publication date: Available online 4 July 2017
      Source:European Journal of Medical Genetics
      Author(s): Ji Yoon Han, In Goo Lee, Soyoung Shin, Myungshin Kim, Ja Hyun Jang, Joonhong Park
      X-linked intellectual disability (XLID) is a genetically heterogeneous disorder involving more than 100 genes known to date. Here, we describe a Korean male infant with global developmental delay. He had neither facial dysmorphism nor skeletal abnormalities. Bayley scale of infant and toddler development third edition (Bayley-III) measured at age of 2 years revealed marked global developmental delays without Marfanoid habitus, structural brain abnormalities, or epilepsy. The patient's cognitive, motor, and language developmental ages were 8–9 months, 12 months, and 9 months, respectively. Targeted next-generation sequencing revealed a de novo mutation [NM_001008222.2(ZDHHC9): c.286C > T (p.(Arg96Trp))] in the affected patient. This mutation has been reported previously in a family XLID with Marfanoid features. Sanger sequencing analysis of the proband and his parents revealed that the missense mutation was present in the proband only (absent in his parents). This indicates that the mutation is de novo in origin. To the best of our knowledge, this is the first report describing sporadic XLID with de novo ZDHHC9 mutation identified by targeted next-generation sequencing.

      PubDate: 2017-07-10T09:50:04Z
       
  • Pierpont syndrome associated with the p.Tyr446Cys missense mutation in
           TBL1XR1
    • Abstract: Publication date: Available online 4 July 2017
      Source:European Journal of Medical Genetics
      Author(s): Anne Slavotinek, Heather Pua, Ugur Hodoglugil, Jude Abadie, Joseph Shieh, Jessica Van Ziffle, Mark Kvale, Hane Lee, Pui-Yan Kwok, Neil Risch, Marta Sabbadini
      We present a 7-year old male with severe delays, hypotonia and dysmorphic features who had striking, deep palmar and plantar creases and pillowing of the soft tissues of the palms and soles. His facial features included a high anterior hairline, small eyes with narrowed palpebral fissures, a bulbous nasal tip with a short columella, and a large mouth with a thin upper vermilion, and small chin. He had a submucous cleft palate, bilateral cryptorchidism and hydronephrosis. Cranial imaging demonstrated an Arnold Chiari malformation that was also present in his maternal uncle by report. Exome sequencing revealed a de novo heterozygous sequence variant, p.Tyr446Cys, in TBL1XR1 that has previously been reported in six patients with Pierpont syndrome. This sequence variant occurs in the carboxy-terminal, WD40 domain of the protein. As TBL1XR1 is a critical component of the NCoR/SMRT co-repressor complex and the WD40 repeats are hypothesized to interact with histone H2B and H4, the mutation may impact protein interactions necessary for stabilizing the complex with chromatin. De novo missense and frameshift mutations and deletions involving TBL1XR1 have been described in patients with intellectual disability and autism, but without any of the dysmorphic findings or malformations associated with Pierpont syndrome, implying a mutation-specific mechanism for the pathogenicity of p.Tyr446Cys. Our case is the first individual with this mutation to have a submucous cleft palate and hydronephrosis, although his severe delays, hypotonia, dysmorphic findings and emerging scoliosis appear consistent with previous reports. His distinctive facial and digital features are further evidence that p.Tyr446Cys results in a clinically recognizable, syndromic form of intellectual disability in contrast to other TBL1XR1 mutations.

      PubDate: 2017-07-10T09:50:04Z
       
  • Testicular Adrenal Rest Tumor (TART) in congenital adrenal hyperplasia
    • Abstract: Publication date: Available online 1 July 2017
      Source:European Journal of Medical Genetics
      Author(s): Hatice Ozisik, Banu Sarer Yurekli, Ilgin Yildirim Simsir, Ilker Altun, Utku Soyaltın, Ezgi Guler, Huseyin Onay, Banu Sarsik, Fusun Saygili
      Congenital adrenal hyperplasia is one of the most common autosomal recessive genetic disorders. Testicular adrenal tumors are significant complications of congenital adrenal hyperplasia. We would like to present two patients of testicular adrenal rest tumors. Patient 1 24 year-old male, he was diagnosed with congenital adrenal hyperplasia at the age of 8 due to precocious puberty. He received hydro-cortisone treatment until the age of 18. Testicular mass had been detected and right radical orchiectomy had been applied 6 months ago and reported as testicular adrenal rest tumor. In scrotal ultrasound, a mixed type mass lesion (6 × 4x3 cm) covering a large part of left testis was observed. The imaging findings were consistent with adrenal rest tumor. The patient took adrenocorticotropic hormone supressive therapy with dexamethasone 0.75 mg once a day. Patient 2, 38 year-old male, he had been followed-up as adrenal insufficiency for 35 years. He underwent right orchiectomy operation due to the testicular mass in 2010 and the pathological examination revealed Leydig cell tumor. In scrotal ultrasound, small multifocal lesions were detected on the left testis and resection was done. It was reported as testicular adrenal rest tumor. He is being followed-up with glucocorticoid treatment according to androgen and adrenocorticotropic hormone levels. Early diagnosis of testicular adrenal rest tumor is significant in preventing irreversible testicular damage and infertility. In the differential diagnosis, we should keep in mind that testicular adrenal rest tumor can mimic other testicular tumors such as primary germ cell tumors.

      PubDate: 2017-07-01T07:18:11Z
       
  • Genotype-phenotype evaluation of MED13L defects in the light of a novel
           truncating and a recurrent missense mutation
    • Abstract: Publication date: Available online 21 June 2017
      Source:European Journal of Medical Genetics
      Author(s): Reza Asadollahi, Markus Zweier, Laura Gogoll, Raphael Schiffmann, Heinrich Sticht, Katharina Steindl, Anita Rauch
      A decade after the designation of MED13L as a gene and its link to intellectual disability (ID) and dextro-looped transposition of great arteries in 2003, we previously described a recognizable syndrome due to MED13L haploinsufficiency. Subsequent reports of 22 further patients diagnosed by genome-wide testing further delineated the syndrome with expansion of the phenotypic spectrum and showed reduced penetrance for congenital heart defects. We now report two novel patients identified by whole exome sequencing, one with a de novo MED13L truncating mutation and the other with a de novo missense mutation. The first patient indicates some facial resemblance to Kleefstra syndrome as a novel differential diagnosis, and the second patient shows, for the first time, recurrence of a MED13L missense mutation (p.(Asp860Gly)). Notably, our in silico modelling predicted this missense mutation to decrease the stability of an alpha-helix and thereby affecting the MED13L secondary structure, while the majority of published missense mutations remain variants of uncertain significance. Review of the reported patients with MED13L haploinsufficiency indicates moderate to severe ID and facial anomalies in all patients, as well as severe speech delay and muscular hypotonia in the majority. Further common signs include abnormal MRI findings of myelination defects and abnormal corpus callosum, ataxia and coordination problems, autistic features, seizures/abnormal EEG, or congenital heart defects, present in about 20–50% of the patients. With reference to facial anomalies, the majority of patients were reported to show broad/prominent forehead, low set ears, bitemporal narrowing, upslanting palpebral fissures, depressed/flat nasal bridge, bulbous nose, and abnormal chin, but macroglossia and horizontal eyebrows were also observed in ∼30%. The latter are especially important in the differential diagnosis of 1p36 deletion and Kleefstra syndromes, while the more common facial gestalt shows some resemblance to 22q11.2 deletion syndrome. Despite the fact that MED13L was found to be one of the most common ID genes in the Deciphering Developmental Disorders Study, further detailed patient descriptions are needed to explore the full clinical spectrum, potential genotype-phenotype correlations, as well as the role of missense mutations and potential mutational hotspots along the gene.

      PubDate: 2017-06-22T04:02:17Z
       
  • High-throughput sequencing of the entire genomic regions of CCM1/KRIT1,
           CCM2 and CCM3/PDCD10 to search for pathogenic deep-intronic splice
           mutations in cerebral cavernous malformations
    • Abstract: Publication date: Available online 20 June 2017
      Source:European Journal of Medical Genetics
      Author(s): Matthias Rath, Sönke E. Jenssen, Konrad Schwefel, Stefanie Spiegler, Dana Kleimeier, Christian Sperling, Lars Kaderali, Ute Felbor
      Cerebral cavernous malformations (CCM) are vascular lesions of the central nervous system that can cause headaches, seizures and hemorrhagic stroke. Disease-associated mutations have been identified in three genes: CCM1/KRIT1, CCM2 and CCM3/PDCD10. The precise proportion of deep-intronic variants in these genes and their clinical relevance is yet unknown. Here, a long-range PCR (LR-PCR) approach for target enrichment of the entire genomic regions of the three genes was combined with next generation sequencing (NGS) to screen for coding and non-coding variants. NGS detected all six CCM1/KRIT1, two CCM2 and four CCM3/PDCD10 mutations that had previously been identified by Sanger sequencing. Two of the pathogenic variants presented here are novel. Additionally, 20 stringently selected CCM index cases that had remained mutation-negative after conventional sequencing and exclusion of copy number variations were screened for deep-intronic mutations. The combination of bioinformatics filtering and transcript analyses did not reveal any deep-intronic splice mutations in these cases. Our results demonstrate that target enrichment by LR-PCR combined with NGS can be used for a comprehensive analysis of the entire genomic regions of the CCM genes in a research context. However, its clinical utility is limited as deep-intronic splice mutations in CCM1/KRIT1, CCM2 and CCM3/PDCD10 seem to be rather rare.

      PubDate: 2017-06-22T04:02:17Z
       
  • NGS panel analysis in 24 ectopia lentis patients; a clinically relevant
           test with a high diagnostic yield
    • Abstract: Publication date: Available online 19 June 2017
      Source:European Journal of Medical Genetics
      Author(s): E. Overwater, K. Floor, D. van Beek, K. de Boer, T. van Dijk, Y. Hilhorst-Hofstee, A.J.M. Hoogeboom, K.J. van Kaam, J.M. van de Kamp, M. Kempers, I.P.C. Krapels, H.Y. Kroes, B. Loeys, S. Salemink, C.T.R.M. Stumpel, V.J.M. Verhoeven, E. Wijnands-van den Berg, J.M. Cobben, J.P. van Tintelen, M.M. Weiss, A.C. Houweling, A. Maugeri
      Background Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. Objective The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL. Methods A NGS gene panel was analysed in 24 patients with EL. Results A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected. Conclusion The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition.

      PubDate: 2017-06-22T04:02:17Z
       
  • Digenic inheritance of mutations in the cardiac troponin (TNNT2) and
           cardiac beta myosin heavy chain (MYH7) as the cause of severe dilated
           cardiomyopathy
    • Abstract: Publication date: Available online 19 June 2017
      Source:European Journal of Medical Genetics
      Author(s): Evmorfia Petropoulou, Mohammadhossein Soltani, Ali Dehghani Firoozabadi, Seyedeh Mahdieh Namayandeh, Jade Crockford, Reza Maroofian, Yalda Jamshidi
      Familial dilated cardiomyopathy (DCM) is characterized by ventricular dilation and depressed myocardial performance. It is a genetically heterogeneous disorder associated with mutations in over 60 genes. We carried out whole exome sequencing in combination with cardiomyopathy-related gene-filtering on two affected family members to identify the possible causative mutation in a consanguineous Iranian family with DCM. Two novel variants in cardiomyopathy-related genes were identified: c.247 A > C; p.N83H in the Troponin T Type 2 gene (TNNT2) and c.2863G > A; p.D955N in the Myosin Heavy Polypeptide 7 gene (MYH7). Sanger sequencing and co-segregation analysis in the remaining family members supported the coexistence of these digenic mutations in affected members of the family. Carriers of either variant alone were asymptomatic. In summary, we find that digenic inheritance of two novel variants in DCM related genes is associated with a severe form of DCM. Exome sequencing has been shown to be very useful in identifying pathogenic mutations in cardiomyopathy families, and this report emphasizes the importance of comprehensive screening of DCM related genes, even after the identification of a single disease-causing mutation.

      PubDate: 2017-06-22T04:02:17Z
       
  • A novel missense variant (Gln220Arg) of GNB4 encoding guanine
           nucleotide-binding protein, subunit beta-4 in a Japanese family with
           autosomal dominant motor and sensory neuropathy
    • Abstract: Publication date: Available online 19 June 2017
      Source:European Journal of Medical Genetics
      Author(s): Shiroh Miura, Takuya Morikawa, Ryuta Fujioka, Kazuhito Noda, Kengo Kosaka, Takayuki Taniwaki, Hiroki Shibata
      Dominant intermediate Charcot–Marie–Tooth disease F (CMTDIF) is an autosomal dominant hereditary form of Charcot–Marie–Tooth disease (CMT) caused by variations in the guanine nucleotide-binding protein, subunit beta-4 gene (GNB4). We examined two Japanese familial cases with CMT. Case 1 was a 49-year-old male whose chief complaint was slowly progressive gait disturbance and limb dysesthesia that appeared at the age of 47. On neurological examination, he showed hyporeflexia or areflexia, distal limb muscle weakness, and distal sensory impairment with lower dominancy. Nerve conduction studies demonstrated demyelinating sensorimotor neuropathy with reduced action potentials in the lower limbs. Case 2 was an 80-year-old man, Case 1's father, who reported difficulty in riding a bicycle at the age of 76. On neurological examination, he showed areflexia in the upper and lower limbs. Distal sensory impairment in the lower limbs was also observed. Nerve conduction studies revealed mainly axonal involvement. Exome sequencing identified a novel heterozygous nonsynonymous variant (NM_021629.3:c.659T > C [p.Gln220Arg]) in GNB4 exon 8, which is known to be responsible for CMT. Sanger sequencing confirmed that both patients are heterozygous for the variation, which causes an amino acid substitution, Gln220Arg, in the highly conserved region of the WD40 domain of GNB4. The frequency of this variant in the Exome Aggregation Consortium Database was 0.000008247, and we confirmed its absence in 502 Japanese control subjects. We conclude that this novel GNB4 variant is causative for CMTDIF in these patients, who represent the first record of the disease in the Japanese population.

      PubDate: 2017-06-22T04:02:17Z
       
  • Familial epilepsy with anterior polymicrogyria as a presentation of
           COL18A1 mutations
    • Abstract: Publication date: Available online 8 June 2017
      Source:European Journal of Medical Genetics
      Author(s): Mark A. Corbett, Samantha J. Turner, Alison Gardner, Jeremy Silver, Jim Stankovich, Richard J. Leventer, Christopher P. Derry, Renée Carroll, Thuong Ha, Ingrid E. Scheffer, Melanie Bahlo, Graeme D. Jackson, David A. Mackey, Samuel F. Berkovic, Jozef Gecz
      Knobloch syndrome [OMIM: (KNO1) #267750] is a rare and clinically heterogeneous autosomal recessive disorder caused by mutations in COL18A1. Knobloch syndrome is characterised by abnormalities of the eye and occipital skull defects however the full phenotypic spectrum is yet to be defined. This report describes a family of four affected sisters with polymicrogyria, refractory seizures, and intellectual impairment of varying severity with a Lennox-Gastaut phenotype, and complex eye abnormalities where a syndromic diagnosis was not initially made. Whole exome sequencing of two affected sisters followed by filtering for rare and potentially disease causing variants in all genes identified compound heterozygous variants in NM_030582.3 (COL18A1): c.3690G > A: p.(Trp1230*) and NM_030582.3 (COL18A1): c.4063_4064delCT: p.(Leu1355Valfs*72). The two variants co-segregated with the affected individuals in the family. Identification of COL18A1 mutations in individuals with a Lennox-Gastaut phenotype and anterior polymicrogyria but lacking the classical occipital encephalocele expands the COL18A1 clinical spectrum.

      PubDate: 2017-06-12T01:39:46Z
       
  • Pachydermoperiostosis of the complete type: A novel missense mutation
           c.101T > C in the SLCO2A1 gene
    • Abstract: Publication date: Available online 8 June 2017
      Source:European Journal of Medical Genetics
      Author(s): Wenbin Ma, Shuqin Guo, Yan Li, Zhihong Li
      We report on a rare case of pachydermoperiostosis (PDP) in a 25-year-old male who was admitted to our hospital because of enlargement of fingers and toes. Through examination, we found some typical features on the patient including finger clubbing, periostosis, pachydermia, and cutis verticis gyrata (CVG). But laboratory tests were almost within normal ranges, which ruled out rheumatic arthritis, osteopulmonary arthropathy, thyroid acropathy, and acromegaly. Then, we diagnosed this case as PDP, which was confirmed by gene sequencing. The pathogenesis is concerned with abnormal rise of the level of PGE2 that results from the solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene defect. Meanwhile, we found a novel missense mutation c.101T > C of the SLCO2A1 gene in the patient with PDP.

      PubDate: 2017-06-12T01:39:46Z
       
  • Postzygotic telomere capture causes segmental UPD, duplication and
           deletion of chromosome 8p in a patient with intellectual disability and
           obesity
    • Abstract: Publication date: Available online 8 June 2017
      Source:European Journal of Medical Genetics
      Author(s): Jeroen Knijnenburg, Madiek E.W. Uytdewilligen, Daniella A.C.M. van Hassel, Rianne Oostenbrink, Bert H.J. Eussen, Annelies de Klein, Alice S. Brooks, Laura J.C.M. van Zutven
      Using SNP array and FISH analysis, a patient with moderate intellectual disability and obesity was found to harbour an atypical 1.6 Mb inverted duplication on 8p23.1, directly flanked by a distally located interstitial deletion of 2.3 Mb and a terminal segmental uniparental disomy. The duplicated and deleted regions lie exactly between the two segmental duplication regions. These segmental duplications on chromosome 8p23.1 are known to be involved in chromosomal rearrangements because of mutual homology and homology to other genomic regions. Genomic instability mediated by these segmental duplications is generally caused by non-allelic homologous recombination, resulting in deletions, reciprocal duplications, inversions and translocations. Additional analysis of the parental origin of the fragments of this atypical inverted duplication/interstitial deletion shows paternal contribution in the maternal derivate chromosome 8. Combined with the finding that the normal chromosome 8 carries an inversion in 8p23.1 we hypothesize that a double strand break in 8p23.1 of the maternal chromosome was postzygotically repaired with the paternal inverted copy resulting in a duplication, deletion and segmental uniparental disomy, with no particular mediation of the 8p23.1 segmental duplication regions in recombination.

      PubDate: 2017-06-12T01:39:46Z
       
  • Recurrent elevated liver transaminases and acute liver failure in two
           siblings with novel bi-allelic mutations of NBAS
    • Abstract: Publication date: Available online 30 May 2017
      Source:European Journal of Medical Genetics
      Author(s): Frederico S. Regateiro, Serkan Belkaya, Nélson Neves, Sandra Ferreira, Paula Silvestre, Sónia Lemos, Margarida Venâncio, Jean-Laurent Casanova, Isabel Gonçalves, Emmanuelle Jouanguy, Luísa Diogo
      Background Acute liver failure (ALF) in children can be life-threatening. Although many causes are known, ALF remains unexplained in about half of the cases. Recently, bi-allelic mutations in NBAS were reported to underlie recurrent episodes of elevated liver transaminases (ELT) and ALF in the context of diverse extrahepatic phenotypes. Results We here describe two sisters, born to non-consanguineous Portuguese parents, who had short stature and presented with recurrent episodes of severe ELT triggered by febrile respiratory viral infections from early childhood. Patient 1 presented mild facial dysmorphism and died during the second ELT crisis at 3–11/12 years of age. Patient 2, currently 9 years old, had multiple episodes of ELT (>30), twice with ALF, often accompanied by extensive urticaria and facial angioedema. Whole-exome and Sanger sequencing revealed that both patients carried previously undescribed compound heterozygous mutations of NBAS (NM_015909.3): c.680A > C (p.His227Pro), affecting an evolutionarily conserved residue, and c.1749G > A (p.Trp583*), causing a premature stop codon. Both mutations are predicted to be highly damaging. The parents and two younger siblings are healthy and heterozygous for one or another mutant allele. Discussion This multiplex kindred with autosomal recessive NBAS deficiency expands the genotypic and phenotypic spectrum of this recently described clinical syndrome. Novel analytical and histological abnormalities here reported might contribute to a better understanding of the disease pathophysiology.

      PubDate: 2017-06-02T00:11:35Z
       
  • Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly
           syndrome with oro-facial and skeletal symptoms
    • Abstract: Publication date: Available online 27 May 2017
      Source:European Journal of Medical Genetics
      Author(s): Muhammad Afzal, Qamar Zaman, Uwe Kornak, Stefan Mundlos, Sajid Malik, Ricarda Flöttmann
      Cenani-Lenz syndactyly syndrome (CLSS; MIM-212780) is a rare autosomal recessive limb malformation characterized by complete osseous fusion of all fingers and toes, disorganization of phalangeal elements and severe shortening of the radius and ulna. It is occasionally associated with renal hypoplasia, oro-facial defects, scoliosis of the thoracic spine, hearing loss, and genital anomalies. Here we describe a consanguineous Pakistani kindred with a severe form of CLSS characterized by complete syndactyly and disorganization of fingers, oligo-syndactyly of toes, shortening of limbs, frontal bossing, and hypoplasia/agenesis of left kidney. The affected individuals were additionally presented with short stature, cleft-lip and hypoplastic shoulder joint with restricted upper limb movement. A novel splice variant in LRP4 (c.316+1G > A) segregated with the phenotype in a five generations family. The mutation is predicted to add 29 non-native amino acids with a premature termination, resulting in approximately 90% length reduction of the wild-type transcript. These findings not only further expand the phenotypic variability of CLSS but also indicate that early truncated and loss-of-function mutations in LRP4 lead to a more severe CLSS phenotype.

      PubDate: 2017-05-27T23:31:33Z
       
  • A novel deletion of SNURF/SNRPN exon 1 in a patient with Prader-Willi-like
           phenotype
    • Abstract: Publication date: Available online 26 May 2017
      Source:European Journal of Medical Genetics
      Author(s): Yang Cao, Susan S. AlHumaidi, Eissa A. Faqeih, Beth A. Pitel, Patrick Lundquist, Umut Aypar
      Here we report the smallest deletion involving SNURF/SNRPN that causes major symptoms of Prader-Willi syndrome (PWS), including hypotonia, dysmorphic features, intellectual disability, and obesity. A female patient with the aforementioned and additional features was referred to the Mayo Clinic Cytogenetics laboratory for genetic testing. Chromosomal microarray analysis and subsequent Sanger sequencing identified a de novo 6.4 kb deletion at 15q11.2, containing exon 1 of the SNURF gene and exon 1 of the shortest isoform of the SNRPN gene. SNURF/SNRPN exon 1, which is methylated on the silent maternal allele, is associated with acetylated histones on the expressed paternal allele. This region also overlaps with the PWS-imprinting center (IC). Subsequent molecular methylation analysis was performed using methylation-specific MLPA (MS-MLPA), which characterized that the deletion of SNURF/SNRPN exon 1 was paternal in origin, consistent with the PWS-like phenotype. Since SNURF/SNRPN gene and the PWS-IC are known to regulate snoRNAs, it is likely that the PWS-like phenotype observed in patients with paternal SNURF/SNRPN deletion is due to the disrupted expression of SNORD116 snoRNAs.

      PubDate: 2017-05-27T23:31:33Z
       
  • Novel missense loss-of-function mutations of WNT1 in an autosomal
           recessive Osteogenesis imperfecta patient
    • Abstract: Publication date: Available online 17 May 2017
      Source:European Journal of Medical Genetics
      Author(s): Joon Yeon Won, Woo Young Jang, Hye-Ran Lee, Seon Young Park, Woo-Young Kim, Jong Hoon Park, Yonghwan Kim, Tae-Joon Cho
      Osteogenesis imperfecta (OI) is a heritable skeletal disorder characterized by bone fragility and low bone mass. Recently, loss-of-function mutations of WNT1 have been reported to be causative in OI or osteoporosis. We report an OI patient with novel compound heterozygous WNT1 missense mutations, p.Glu123Asp and p.Cys153Gly. Both mutations are found in the exon 3, and the p.Glu123Asp is the most proximal N-terminus missense mutation among the reported WNT1 missense mutations in OI patients. In vitro functional analysis reveals that while expression of wildtype WNT1 stimulates canonical WNT1-mediated β-catenin signaling, that of individual WNT1 mutant fails to do so, indicative of the pathogenic nature of the WNT1 variants. Although the pathogenic mechanism of WNT1 defects in OI has yet to be uncovered, these findings further contribute to the implications and importance of functional relevance of WNT1 in skeletal disorders.

      PubDate: 2017-05-17T20:35:12Z
       
  • A 'joint venture' model of recontacting in clinical genomics: Challenges
           for responsible implementation
    • Abstract: Publication date: Available online 10 May 2017
      Source:European Journal of Medical Genetics
      Author(s): Sandi Dheensa, Daniele Carrieri, Susan Kelly, Angus Clarke, Shane Doheny, Peter Turnpenny, Anneke Lucassen Dphil
      Advances in genomics often lead healthcare professionals (HCPs) to learn new information, e.g., about reinterpreted variants that could have clinical significance for patients seen previously. A question arises of whether HCPs should recontact these former patients. We present some findings interrogating the views of patients with a rare or undiagnosed condition about how such recontacting might be organised ethically and practically. Forty-one interviews with patients were analysed thematically. Participants suggested a 'joint venture' model in which efforts to recontact are shared with HCPs. Some proposed an ICT-approach involving an electronic health record that automatically alerts them to potentially relevant updates. The need for rigorous privacy controls and transparency about who could access their data was emphasised. Importantly, these findings highlight that the lack of clarity about recontacting is a symptom of a wider problem: the lack of necessary infrastructure to pool genomic data responsibly, to aggregate it with other health data, and to enable patients to receive updates. We hope that our findings will instigate a debate about the way responsibilities for recontacting under any joint venture model could be allocated, as well as the limitations and normative implications of using ICT as a solution to this intractable problem. As a first step to delineating responsibilities in the clinical setting, we suggest clinicians should routinely discuss recontacting with patients, including the new information that should trigger a clinician to initiate recontact, as part of the consent process for genetic testing.

      PubDate: 2017-05-12T20:01:25Z
       
  • The congenital great toe malformation of fibrodysplasia ossificans
           progressiva? - A close call
    • Abstract: Publication date: Available online 1 May 2017
      Source:European Journal of Medical Genetics
      Author(s): O. Will Towler, Eileen M. Shore, Meiqi Xu, Abbey Bamford, Ilse Anderson, Robert J. Pignolo, Frederick S. Kaplan
      Background Congenital bilateral hallux valgus with associated absence or fusion of the interphalangeal joint is a classic diagnostic feature of fibrodysplasia ossificans progressiva (FOP), a human genetic disease of extra-skeletal bone formation caused in nearly all cases by a gain-of-function mutation in Activin A Receptor I/Activin-like Kinase 2 (ACVR1/ALK2), which encodes a bone morphogenetic protein (BMP) Type 1 receptor. This toe malformation prompts the suspicion of FOP even before the appearance of extra-skeletal bone. Here we report the case of a four-month-old child who was suspected of having FOP on the basis of a great toe malformation identical to that seen in children with the disease. Methods The patient's genomic DNA of the coding region of ACVR1 was sequenced and analyzed for mutations known to cause FOP and novel mutations. Subsequent comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) analyses were performed to detect mutations elsewhere in the genome. Results Genetic testing exonerated ACVR1 as culpable for the patient's toe malformation. CGH and SNP analyses identified a large intragenic deletion in a different BMP Type 1 receptor gene, BMP Receptor 1B/Activin-like kinase 6 (BMPR1B/ALK6), a gene associated with a variable spectrum of autosomal dominant brachydactyly phenotypes. Conclusions This report illustrates that while toe morphology remains the earliest indicator of FOP, toe morphology alone is not an unequivocal clinical diagnostic feature of FOP, and supports that embryonic development of the great toe is highly sensitive to dysregulated signaling from at least two BMP type I receptors.

      PubDate: 2017-05-02T17:01:02Z
       
  • Fetal costello syndrome with neuromuscular spindles excess and p.Gly12Val
           HRAS mutation
    • Abstract: Publication date: Available online 25 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Chloé Quélin, Philippe Loget, Céline Rozel, Dominique D'Hervé, Mélanie Fradin, Florence Demurger, Sylvie Odent, Laurent Pasquier, Hélène Cavé, Pascale Marcorelles
      Costello syndrome (CS) is a rare multiple congenital disorder caused by activating germline mutations in HRAS gene and is characterized by coarse facial features, severe feeding difficulties, failure to thrive, mild to severe intellectual disability, severe postnatal growth retardation, cardiac abnormalities or cancer predisposition. Phenotypic spectrum associated with HRAS mutations is broad, ranging from attenuated CS phenotype to neonatal and lethal forms with limited genotype-phenotype correlations. Congenital myopathy with neuromuscular spindle excess has been rarely described in the literature. We report a new severe fetal case of CS with distal arthrogryposis due to neuromuscular spindle excess, confirmed by the detection of the p.Gly12Val mutation in HRAS gene. This case emphasizes the fact that HRAS is the only gene responsible for neuromuscular spindle excess, underlines a correlation between p.Gly12Val mutation and severe CS phenotype and points out the importance of a muscle biopsy performed according to the suitable procedure in neuromuscular disorders for any fetal arthrogryposis.

      PubDate: 2017-05-02T17:01:02Z
       
  • Marshall-Smith Syndrome: Novel pathogenic variant and previously
           unreported associations with precocious puberty and aortic root dilatation
           
    • Abstract: Publication date: Available online 24 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Anjali Aggarwal, Joanne Nguyen, Michelle Rivera-Davila, David Rodriguez-Buritica
      Marshall-Smith Syndrome (MRSHSS) is a very rare genetic disorder characterized by failure to thrive and characteristic dysmorphic features associated with accelerated osseous maturation. We present a nine-year-old girl who was diagnosed with MRSHSS based on characteristic clinical features supported by the identification of a novel de novo pathogenic variant in the NFIX gene. The patient also presented with precocious puberty diagnosed at five years of age and had an abnormal GnRH stimulation test indicative of central precocious puberty. Central precocious puberty has not been described in association with MRSHSS previously in the medical literature and broadens our knowledge of the natural history of MRSHSS. The causes of advanced bone age in this syndrome are also reviewed. Additionally, the patient showed progressive dilatation of the aortic root. Although connective tissue abnormalities have been described in association with MRSHSS, aortic root dilatation has not. Understanding the mechanism of comorbidities such as advanced bone age and aortic root dilatation in MRSHSS patients enables future development of anticipatory guidance, preventative care measures, and treatment guidelines.

      PubDate: 2017-04-25T15:25:04Z
       
  • Association of autoimmune thyroiditis and celiac disease with Juvenile
           Polyposis due to 10q23.1q23.31 deletion: Potential role of PI3K/Akt
           pathway dysregulation
    • Abstract: Publication date: Available online 18 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Federica Guaraldi, Giovanni Di Nardo, Luigi Tarani, Luca Bertelli, Francesco Claudio Susca, Rosanna Bagnulo, Nicoletta Resta
      Juvenile Polyposis (JP) is a rare hereditary condition characterized by diffuse hamartomatous gastrointestinal polyposis, associated with a significantly increased risk of neoplastic transformation. Most of the cases are caused by SMAD and BMPR1A mutations, while 10q23 microdeletions, encompassing both PTEN and BMPR1A oncogenes, are extremely rare, typically associated with more aggressive JP, and extraintestinal features overlapping with PTEN Hamartoma Tumor Syndrome. We present the first case of a young female with multiple autoimmune disorders (i.e. thyroiditis and celiac disease), associated with JP, cardiac defects and epilepsy, who carries a de novo heterozygous 10q23.1q23.31 deletion. The dysregulation of the PI3K/Akt pathway is advanced as the putative mechanism connecting autoimmune, malformative and neoplastic disorders. A literature review of clinical manifestation, gene alterations and the treatment of patients with 10q23 deletion is also provided, highlighting the importance of comprehensive, long-term, multi-disciplinary management, aimed at early identification and treatment of both intestinal and extraintestinal disorders.

      PubDate: 2017-04-25T15:25:04Z
       
  • Identification of a novel and functional mutation in the TBX5 gene in a
           patient by screening from 354 patients with isolated ventricular septal
           defect
    • Abstract: Publication date: Available online 18 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Huan-Xin Chen, Xi Zhang, Hai-Tao Hou, Jun Wang, Qin Yang, Xiu-Li Wang, Guo-Wei He
      Ventricular septal defect (VSD) is the most frequently occurring congenital heart disease in newborns. A number of genetic studies have linked TBX5 mutations to cardiac abnormalities. We aimed to identify potential pathogenic mutations in TBX5 and to provide insights into the etiology of sporadic and isolated VSD. Case-control mutational and functional analyses were performed in 354 sporadic patients with isolated VSD and 341 controls. All the coding exons and intron-exon boundaries of TBX5 were first sequenced in a group of VSD patients and controls. Sanger sequencing with high-resolution melting (HRM) curve analysis in new patients and controls was then used to detect TBX5 mutation and frequency. Luciferase activities were measured to identify transcriptional regulation of TBX5 to MYH6 and ANF promoter. A novel heterozygous missense mutations c.40C > A (p.Pro14Thr) was identified in TBX5 gene exon-2, resulting proline to threonine substitution. TBX5 containing mutation reduced transcriptional activities of the MYH6 promoter but enhanced transcriptional activities of the ANF promoter, compared with the wild type. This novel heterozygous missense mutation in TBX5 gene exon-2 that causes significant changes of the activity of TBX5 is therefore highly possible to be the cause of the defect in the VSD patients.

      PubDate: 2017-04-25T15:25:04Z
       
  • Novel homozygous FANCL mutation and somatic heterozygous SETBP1 mutation
           in a Chinese girl with Fanconi Anemia
    • Abstract: Publication date: Available online 15 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Weiqing Wu, Yang Liu, Qinghua Zhou, Qin Wang, Fuwei Luo, Zhiyong Xu, Qian Geng, Peining Li, Hui Z. Zhang, Jiansheng Xie
      Fanconi Anemia (FA) is a rare genetically heterogeneous disorder with 17 known complement groups caused by mutations in different genes. FA complementation group L (FA-L, OMIM #608111) occurred in 0.2% of all FA and only eight mutant variants in the FANCL gene were documented. Phenotype and genotype correlation in FANCL associated FA is still obscure. Here we describe a Chinese girl with FA-L caused by a novel homozygous mutation c.822_823insCTTTCAGG (p.Asp275LeufsX13) in the FANCL gene. The patient's clinical course was typical for FA with progression to bone marrow failure, and death from acute myelomonocytic leukemia (AML-M4) at 9 years of age. Mutation analysis also detected a likely somatic c.2608G > A (p.Gly870Ser) in the SETBP1 gene. Consistent copy number losses of 7q and 18p and gains of 3q and 21q and accumulated non-clonal single cell chromosomal abnormalities were detected in blood leukocytes as her FA progressed. This is the first Chinese FA-L case caused by a novel FANCL mutation. The somatic gene mutation and copy number aberrations could be used to monitor disease progression and the clinical findings provide further information for genotype-phenotype correlation for FA-L.

      PubDate: 2017-04-18T14:50:35Z
       
  • Metatropic dysplasia in third trimester of pregnancy and a novel causative
           variant in the TRPV4 gene
    • Abstract: Publication date: Available online 13 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Sara Bargiacchi, Matteo Della Monica, Roberto Biagiotti, Elena Andreucci, Serena Ciabattoni, Paolo Poggi, Marco Di Maurizio, Claudio Defilippi, Ettore Cariati, Sabrina Giglio
      Prenatal diagnosis of skeletal dysplasias is particularly difficult for many reasons and differentiating these disorders in the prenatal period can be challenging because they are rare and many of the ultrasound findings are not necessarily pathognomonic for a specific disorder. The diagnosis is often made just after birth or exitus. The prenatal diagnosis of osteochondrodysplasias is based predominantly upon fetal ultrasound findings and it focuses substantially on the possible lethality of the disorder, without always being able to find a specific name for the disorder. Metatropic dysplasia is a rare osteochondrodysplasia due to mutations in the TRPV4 gene: TRPV4 is a cation channel, non-selectively permeable to calcium, encoded by a gene on chromosome 12q24.11; it is widely expressed and involved in many different physiological processes through responses to several different stimuli (physical, chemical, and hormonal) in ciliated epithelial cells. The exact incidence of this disorder is not known, however less than a hundred cases have been reported at present, with only two prenatal reports but without any reference to the molecular test. We describe the first report of molecular diagnosis of metatropic dysplasia carried out in prenatal diagnosis: the molecular testing of the TRPV4 (transient receptor potential cation channel, subfamily V, member 4, MIM *605427) gene in our case, in fact, detected a causative variant, confirming the diagnostic suspicion, which was made possible thanks also to the utilization of MRI and CT scan. In our case different imaging methods together with the close cooperation of a multidisciplinary team and test availability, allowed an accurate diagnosis.

      PubDate: 2017-04-18T14:50:35Z
       
  • A case of splenomegaly in CBL syndrome
    • Abstract: Publication date: Available online 13 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Rachel R. Coe, Margaret L. McKinnon, Maja Tarailo-Graovac, Colin J. Ross, Wyeth W. Wasserman, Jan M. Friedman, Paul C. Rogers, Clara D.M. van Karnebeek
      Introduction We present a child with unexplained splenomegaly to highlight this feature as a presenting sign of the RASopathy CBL syndrome and to draw attention to the power and utility of next generation genomic sequencing for providing rapid diagnosis and critical information to guide care in the pediatric clinical setting. Clinical report A 7-year-old boy presented with unexplained splenomegaly, attention deficit hyperactivity disorder, mild learning difficulties, easy bruising, mild thrombocytopenia, and subtle dysmorphic features. Extensive haematological testing including a bone marrow biopsy showed mild megaloblastoid erythropoiesis and borderline fibrosis. There were no haematological cytogenetic anomalies or other haematological pathology to explain the splenomegaly. Metabolic testing and chromosomal microarray were unremarkable. Trio whole-exome sequencing (WES) identified a pathogenic de novo heterozygous germline CBL variant (c.1111T > C, p.Y371H), previously reported to cause CBL syndrome and implicated in development of juvenile myelomonocytic leukemia (JMML). Discussion CBL syndrome (more formally known as “Noonan-syndrome-like disorder with or without juvenile myelomonocytic leukemia”) has overlapping features to Noonan syndrome with significant variability. CBL syndrome and other RASopathy disorders—including Noonan syndrome, neurofibromatosis 1, and Costello syndrome—are important to recognize as these are associated with a cancer-predisposition. CBL syndrome carries a very high risk for JMML, thus accurate diagnosis is of utmost importance. The diagnosis of CBL syndrome in this patient would not have been possible based on clinical features alone. Through WES, a specific genetic diagnosis was made, allowing for an optimized management and surveillance plan, illustrating the power of genomics in clinical practice.

      PubDate: 2017-04-18T14:50:35Z
       
  • Two females with mutations in USP9X highlight the variable expressivity of
           the intellectual disability syndrome
    • Abstract: Publication date: Available online 1 April 2017
      Source:European Journal of Medical Genetics
      Author(s): P.Y.B. Au, L. Huang, S. Broley, L. Gallagher, E. Creede, D. Lahey, S. Ordorica, K. Mina, K.M. Boycott, G. Baynam, D.A. Dyment
      The genetic causes of intellectual disability (ID) are heterogeneous and include both chromosomal and monogenic etiologies. The X-chromosome is known to contain many ID-related genes and males show a marked predominance for intellectual disability. Here we report two females with syndromic intellectual disability. The first individual was relatively mild in her presentation with mild-moderate intellectual disability, hydronephrosis and altered pigmentation along the lines of Blaschko without additional congenital anomalies. A second female presented shortly after birth with dysmorphic facial features, post-axial polydactyly and, on follow-up assessment, demonstrated moderate intellectual disability. Chromosomal studies for Individual 1 identified an X-chromosome deletion due to a de novo pericentric inversion; the inversion breakpoint was associated with deletion of the 5′UTR of the USP9X, a gene which has been implicated in a syndromic intellectual disability affecting females. The second individual had a de novo frameshift mutation detected by whole-exome sequencing that was predicted to be deleterious, NM_001039590.2 (USP9X): c.4104_4105del (p.(Arg1368Serfs*2)). Haploinsufficiency of USP9X in females has been associated with ID and congenital malformations that include heart defects, scoliosis, dental abnormalities, anal atresia, polydactyly, Dandy Walker malformation and hypoplastic corpus callosum. The extent of the congenital malformations observed in Individual 1 was less striking than Individual 2 and other individuals previously reported in the literature, and suggests that USP9X mutations in females can have a wider spectrum of presentation than previously appreciated.

      PubDate: 2017-04-04T13:07:36Z
       
  • The spectrum of infantile myofibromatosis includes both non-penetrance and
           adult recurrence
    • Abstract: Publication date: Available online 9 March 2017
      Source:European Journal of Medical Genetics
      Author(s): Natalia Murray, B. Hanna, Nicole Graf, He Fu, Veronneau Mylène, P.M. Campeau, Anne Ronan
      Infantile myofibromatosis is characterized by benign myofibroblastic tumors within skin, muscle, bone or viscera which have a characteristic staining pattern on immunohistochemistry. The condition typically presents in infancy and the tumors often disappear by the third year of life. Mutations in the PDGFRB gene and NOTCH3 genes have been identified in familial forms of the condition. We present two families with molecularly confirmed germline mutations in the PDGFRB gene, one demonstrating a phenotype ranging from complete non-penetrance to neonatal lethality; and the other illustrating adult recurrence of the tumors.

      PubDate: 2017-03-16T09:13:20Z
       
 
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
 
Home (Search)
Subjects A-Z
Publishers A-Z
Customise
APIs
Your IP address: 54.166.199.43
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-2016