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Journal Cover   European Journal of Medical Genetics
  [SJR: 0.814]   [H-I: 35]   [5 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1769-7212
   Published by Elsevier Homepage  [2800 journals]
  • Five patients with a chromosome 1q21.1 triplication show macrocephaly,
           increased weight and facial similarities
    • Abstract: Publication date: Available online 29 August 2015
      Source:European Journal of Medical Genetics
      Author(s): Anke Van Dijck, Ilse M. Van Der Werf, Edwin Reyniers, Stefaan Scheers, Meron Azage, Kiana Siefkas, Nathalie Van Der AA, Amy Lacroix, Jill Rosenfeld, Bob Argiropoulos, Kellie Davis, A.Micheil Innes, Heather C. Mefford, Geert Mortier, Marije Meuwissen, R.Frank Kooy
      Recurrent rearrangements of chromosome 1q21.1 that occur as a consequence of non-allelic homologous recombination (NAHR) show considerable variability in phenotypic expression and penetrance. Chromosome 1q21.1 deletions (OMIM 612474) have been associated with microcephaly, intellectual disability, autism, schizophrenia, cardiac abnormalities and cataracts. Phenotypic features in individuals with 1q21.1 duplications (OMIM 612475) include macrocephaly, learning difficulties, developmental delay, intellectual disability and mild dysmorphic features. Half of these patients show autistic behavior. For the first time, we describe five patients, including monozygotic twins, with a triplication of the 1q21.1 chromosomal segment. Facial features common to all patients include a high, broad forehead; a flat and broad nasal bridge; long, downslanted palpebral fissures and dysplastic, low-set ears. Likely associated features include macrocephaly and increased weight. We observed that the triplications arose through different mechanisms in the patients: it was de novo in one patient, inherited from a triplication carrier in two cases, while the father of the twins is a 1q21.1 duplication carrier. The de novo triplication contained copies of both maternal alleles, suggesting it was generated by a combination of inter- and intrachromosomal recombination.


      PubDate: 2015-09-01T15:55:56Z
       
  • 7p22.1 microduplication syndrome: clinical and molecular characterization
           of an adult case and review of the literature
    • Abstract: Publication date: Available online 19 August 2015
      Source:European Journal of Medical Genetics
      Author(s): Rossella Caselli, Lucia Ballarati, Aglaia Vignoli, Angela Peron, Maria Paola Recalcati, Ilaria Catusi, Lidia Larizza, Daniela Giardino
      A new 7p22.1 microduplication syndrome characterized by intellectual disability, speech delay and craniofacial dysmorphisms, such as macrocephaly, hypertelorism and ear anomalies, has been outlined by the description of two patients with interstitial microduplications confined to 7p22.1 and the recently defined minimal overlapping 430 kb critical region including five genes. Here we report on the first adult patient aged 35 years with moderate intellectual disability, psychomotor delay, facial dysmorphisms, chryptorchidism and cardiac anomalies, who carries two close microduplications at 7p22.1 of about 900 and 150 kb, respectively. The proximal smaller duplication includes three coding genes and maps outside the minimal described overlapping duplicated region, while the larger one represents the smallest 7p22.1 microduplication reported so far, as it encompasses the entire minimal region with only four additional genes. We compare the phenotype of our patient with that of the few reported cases and discuss on candidate genes in order to enhance the knowledge on genotype-phenotype correlation in 7p22.1 duplication syndrome.


      PubDate: 2015-08-20T13:44:02Z
       
  • Identification of Mutations, Genotype-Phenotype Correlation and Prenatal
           Diagnosis of Maple Syrup Urine Disease in Indian patients
    • Abstract: Publication date: Available online 7 August 2015
      Source:European Journal of Medical Genetics
      Author(s): Deepti Gupta, Sunita Bijarnia-Mahay, Renu Saxena, Sudha Kohli, Ratna Dua-Puri, Jyotsna Verma, E. Thomas, Yosuke Shigematsu, Seiji Yamaguchi, Roumi Deb, Ishwar Chander Verma
      Maple Syrup Urine Disease (MSUD) is caused by mutations in genes BCKDHA, BCKDHB, DBT encoding E1α, E1β, and E2 subunits of enzyme complex, branched-chain alpha-ketoacid dehydrogenase (BCKDH). BCKDH participates in catabolism of branched-chain amino acids (BCAAs) - leucine, isoleucine and valine in the energy production pathway. Deficiency or defect in the enzyme complex causes accumulation of BCAAs and keto-acids leading to toxicity. Twenty-four patients with MSUD were enrolled in the study for molecular characterization and genotype-phenotype correlation. Molecular studies were carried out by sequencing of the 3 genes by Sanger method. Bioinformatics tools were employed to classify novel variations into pathogenic or benign. The predicted effects of novel changes on protein structure were elucidated by 3D modeling. Mutations were detected in 22 of 24 patients (11, 7 and 4 in BCKDHB, BCKDHA and DBT genes, respectively). Twenty mutations including 11 novel mutations were identified. Protein modeling in novel mutations showed alteration of structure and function of these subunits. Mutations, c.1065 delT (BCKDHB gene) and c.939G>C (DBT gene) were noted to be recurrent, identified in 6 of 22 alleles and 5 of 8 alleles, respectively. Two-third patients were of neonatal classical phenotype (16 of 24). BCKDHB gene mutations were present in 10 of these 16 patients. Prenatal diagnoses were performed in 4 families. Consanguinity was noted in 37.5% families. Although no obvious genotype-phenotype correlation could be found in our study, most cases with mutation in BCKDHB gene presented in neonatal period. Large number of novel mutations underlines the heterogeneity and distinctness of gene pool from India.


      PubDate: 2015-08-11T12:16:45Z
       
  • Identification of a novel homozygous SPG7 mutation by whole exome
           sequencing in a Greek family with a complicated form of hereditary spastic
           paraplegia
    • Abstract: Publication date: Available online 7 August 2015
      Source:European Journal of Medical Genetics
      Author(s): Hussein Daoud, Eleni Merkouri Papadima, Bouchra Oulad Amar Bencheikh, Theodora Katsila, Alexandre Dionne-Laporte, Dan Spiegelman, Patrick A. Dion, George P. Patrinos, Sandro Orrù, Guy A. Rouleau
      We report the clinical description and genetic analyses of a Greek family with four individuals affected with a complicated form of hereditary spastic paraplegia (HSP) and a recessive pattern of inheritance. Exome sequencing of all affected individuals led to the identification of a homozygous 25 bp deletion predicted to lead to a frameshift and premature stop codon in the SPG7 gene, encoding paraplegin. This deletion, which is located in the first exon of the SPG7 gene, has not been previously reported and likely lead to the complete absence of the SPG7 protein. Interestingly, this family shows significant phenotypic heterogeneity further highlighting the clinical variability associated with SPG7 mutations. Our findings emphasize the clinical utility of whole exome sequencing for the molecular diagnosis of HSPs.


      PubDate: 2015-08-11T12:16:45Z
       
  • Novel NOG mutation in Japanese patients with stapes ankylosis with broad
           thumbs and toes
    • Abstract: Publication date: Available online 26 July 2015
      Source:European Journal of Medical Genetics
      Author(s): Takashi Ishino, Sachio Takeno, Katsuhiro Hirakawa
      Human noggin (NOG) gene mutation causes multiple bony disorders showing up as stapes ankylosis with broad thumbs and toes (SABTT), proximal symphalangism (SYM1), multiple synostoses syndrome 1 (SYNS1), tarsal-carpal coalition syndrome (TCC) and brachydactyly type B2 (BDB2). These phenotypes are defined as NOG-related syndromes with the same mutation. Some of these syndromes feature stapes ankylosis as one of the several bony symptoms. Here, we report a Japanese family with conductive hearing loss due to congenital stapes ankylosis. This family showed multiple features and was diagnosed with SABTT. We performed analysis of the NOG in the family by direct sequence analysis, and found a novel NOG mutation: c.682 T>G (p.C228G). Our results and a review of previous cases with NOG protein conformation suggest that this mutated NOG protein lead to a change in antagonist activity in BMPs and/or a haploinsufficiency that likely impaired finger 2 structure.


      PubDate: 2015-07-28T20:48:48Z
       
  • NFIX mutations affecting the DNA-binding domain cause a peculiar
           overgrowth syndrome (Malan syndrome): a new patients series
    • Abstract: Publication date: Available online 17 July 2015
      Source:European Journal of Medical Genetics
      Author(s): Fiorella Gurrieri, Maria Luigia Cavaliere, Anita Wischmeijer, Corrado Mammì, Giovanni Neri, Maria Antonietta Pisanti, Giulia Rodella, Carmelo Laganà, Manuela Priolo
      The Nuclear Factor I-X (NFIX) is a member of the nuclear factor I (NFI) protein family and is deleted or mutated in a subset of patients with a peculiar overgrowth condition resembling Sotos Syndrome as well as in patients with Marshall-Smith syndrome. We identified three additional patients with this phenotype each carrying a different new mutation affecting the DNA-binding/dimerization domain of the NFIX protein. The present report further adds weight to the hypothesis that mutations in DNA-binding/dimerization domain are likely to cause haploinsufficiency of the NFIX protein and confirms that NFIX is the second gene that should be tested in individuals with overgrowth conditions resembling Sotos syndrome, previously tested negative for NSD1 mutations. We then propose to consider this overgrowth syndrome (namely Malan syndrome) and Marshall-Smith syndrome NFIX-related diseases.


      PubDate: 2015-07-21T21:40:41Z
       
  • From splitting GLUT1 deficiency syndromes to overlapping phenotypes
    • Abstract: Publication date: Available online 17 July 2015
      Source:European Journal of Medical Genetics
      Author(s): Marie Hully, Sandrine Vuillaumier-Barrot, Christiane Le Bizec, Nathalie Boddaert, Anna Kaminska, Karine Lascelles, Pascale de Lonlay, Claude Cances, Vincent des Portes, Agathe Roubertie, Diane Doummar, Anne LeBihannic, Bertrand Degos, Anne De Saint Martin, Elisabeth Flori, Jean Michel Pedespan, Alice Goldenberg, Catherine Vanhulle, Soumeya Bekri, Anne Roubergue, Bénédicte Heron, Marie-Anne Cournelle, Alice Kuster, Alexis Chenouard, Marie-Noelle Loiseau, Vassili Valayannopoulos, Nicole Chemaly, Cyril Gitiaux, Nathalie Seta, Nadia Bahi-Buisson
      Introduction Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare genetic disorder due to mutations or deletions in SLC2A1, resulting in impaired glucose uptake through the blood brain barrier. The classic phenotype includes pharmacoresistant epilepsy, intellectual deficiency, microcephaly and complex movement disorders, with hypoglycorrhachia, but milder phenotypes have been described (carbohydrate-responsive phenotype, dystonia and ataxia without epilepsy, paroxysmal exertion-induced dystonia). The aim of our study was to provide a comprehensive overview of GLUT1DS in a French cohort. Methods 265 patients were referred to the French national laboratory for molecular screening between July 2006 and January 2012. Mutations in SLC2A1 were detected in 58 patients, with detailed clinical data available in 24, including clinical features with a focus on their epileptic pattern and electroencephalographic findings, biochemical findings and neuroimaging findings. Results 53 point mutations and 5 deletions in SLC2A1 were identified. Most patients (87.5%) exhibited classic phenotype with intellectual deficiency (41.7%), epilepsy (75%) or movement disorder (29%) as initial symptoms at a medium age of 7.5 months, but diagnostic was delayed in most cases (median age at diagnostic 8 years 5 months). Sensitivity to fasting or exertion in combination with those 3 main symptoms were the main differences between mutated and negative patients (p<0.001). Patients with myoclonic seizures (52%) evolved with more severe intellectual deficiency and movement disorders compared with those with Early Onset Absence Epilepsy (38%). Three patients evolved from a classic phenotype during early childhood to a movement disorder predominant phenotype at a late childhood/adulthood. Conclusions Our data confirm that the classic phenotype is the most frequent in GLUT1DS. Myoclonic seizures are a distinctive feature of severe forms. However a great variability among patients and overlapping through life from milder classic phenotype to paroxysmal-prominent- movement-disorder phenotype are possible, thus making it difficult to identify definite genotype-phenotype correlations.


      PubDate: 2015-07-21T21:40:41Z
       
  • Oculo-Auriculo-Vertebral Spectrum: CLINICAL and Molecular Analysis of 51
           Patients
    • Abstract: Publication date: Available online 20 July 2015
      Source:European Journal of Medical Genetics
      Author(s): Ana Beleza-Meireles, Rachel Hart, Jill Clayton-Smith, Renata Oliveira, Cláudia Falcão Reis, Margarida Venâncio, Fabiana Ramos, Joaquim Sá, Lina Ramos, Elizabete Cunha, Luís Miguel Pires, Isabel Marques Carreira, Rachel Scholey, Ronnie Wright, Jill E. Urquhart, Tracy A. Briggs, Bronwyn Kerr, Helen Kingston, Kay Metcalfe, Dian Donnai, William G. Newman, Jorge Manuel Saraiva, May Tassabehji
      Introduction Oculo-auriculo-vertebral spectrum (OAVS OMIM164210) is a craniofacial developmental disorder affecting the development of the structures derived from the 1st and the 2nd branchial arches during embryogenesis, with consequential maxillary, mandibular, and ear abnormalities. The phenotype in OAVS is variable and associated clinical features can involve the cardiac, renal, skeletal, and central nervous systems. Its aetiology is still poorly understood. Methods We have evaluated the clinical phenotypes of 51 previously unpublished patients with OAVS and their parents, and performed comparative genomic hybridization microarray studies to identify potential causative loci. Results Of all 51 patients, 16 (31%) had a family history of OAVS. Most had no relevant pre-natal history and only 5 (10%) cases had a history of environmental exposures that have previously been described as risk factors for OAVS. In 28 (55%) cases, the malformations were unilateral. When the involvement was bilateral, it was asymmetric. Ear abnormalities were present in 47 (92%) patients (unilateral in 24; and bilateral in 23). Hearing loss was common (85%), mostly conductive, but also sensorineural, or a combination of both. Hemifacial microsomia was present in 46 (90%) patients (17 also presented facial nerve palsy). Ocular anomalies were present in 15 (29%) patients. Vertebral anomalies were confirmed in 10 (20%) cases; 50% of those had additional heart, brain and/or other organ abnormalities. Brain abnormalities were present in 5 (10%) patients; developmental delay was more common among these patients. Limb abnormalities were found in 6 (12%) patients, and urogenital anomalies in 5 (10%). Array-CGH analysis identified 22q11 dosage anomalies in 10 out of 22 index cases screened. Discussion In this study we carried out in-depth phenotyping of OAVS in a large, multicentre cohort. Clinical characteristics are in line with those reported previously, however, we observed a higher incidence of hemifacial microsomia and lower incidence of ocular anomalies. Furthermore our data suggests that OAVS patients with vertebral anomalies or congenital heart defects have a higher frequency of additional brain, limb or other malformations. We had a higher rate of familial cases in our cohort in comparison with previous reports, possibly because these cases were referred preferentially to our genetic clinic where family members underwent examination. We propose that familial OAVS cases show phenotypic variability, hence, affected relatives might have been misclassified in previous reports. Moreover, in view of its phenotypic variability, OAVS is potentially a spectrum of conditions, which overlap with other conditions, such as mandibulofacial dysostosis. Array CGH in our cohort identified recurrent dosage anomalies on 22q11, which may contribute to, or increase the risk of OAVS. We hypothesize that although the 22q11 locus may harbour gene(s) or regulatory elements that play a role in the regulation of craniofacial symmetry and 1st and 2nd branchial arch development, OAVS is a heterogeneous condition and many cases have a multifactorial aetiology or are caused by mutations in as yet unidentified gene(s).


      PubDate: 2015-07-21T21:40:41Z
       
  • HCN4 mutation as a molecular explanation on patients with bradycardia and
           non-compaction cardiomyopathy
    • Abstract: Publication date: Available online 21 July 2015
      Source:European Journal of Medical Genetics
      Author(s): Gilles Millat, Alexandre Janin, Olivier de Tauriac, Antoine Roux, Claire Dauphin
      A very recent study suggested that HCN4 mutations could be associated with sinusal bradycardia and myocardial non compaction. A French family with 3 affected sisters presenting the same clinical phenotype (sinus bradycardia in combination with non compaction cardiomyopathy (NCCM)) have benefited both from a systematic cardiovascular exploration and molecular investigations. The molecular analysis, performed by NGS sequencing, led to identify only one likely-disease causing variation: p.Gly482Arg on HCN4 gene. Our results confirm the genetic evidence for the involvement of the HCN4 mutations in the combined bradycardia–NCCM phenotype and illustrates that, in front of this combined clinical phenotype, HCN4 mutations has to be suspected.


      PubDate: 2015-07-21T21:40:41Z
       
  • Screening for GFAP rearrangements in a cohort of Alexander disease and
           undetermined leukoencephalopathy patients
    • Abstract: Publication date: Available online 21 July 2015
      Source:European Journal of Medical Genetics
      Author(s): Marie-Céleste Ferreira, Imen Dorboz, Diana Rodriguez, Odile Boespflug Tanguy
      Alexander disease (AxD), a fatal degenerative leukoencephalopathy, is caused by de novo heterozygous missense mutations in the Glial Fibrillary Acidic Protein (GFAP) gene. The pathological hallmark of the disease is the presence of Rosenthal fibers, cytoplasmic inclusions in astrocytes, composed mainly of GFAP, αB-crystallin and HSP27. To date, several patients with a typical presentation of the disease or displaying characteristic Rosenthal fibers in brain material have been reported with no GFAP mutation. Recently, several studies have demonstrated a correlation between Rosenthal fiber formation and wild-type GFAP overexpression, despite the absence of mutations. We tested the hypothesis that a GFAP gene rearrangement could modulate AxD severity or promote GFAP overexpression and aggregation, resulting in leukoencephalopathy. A QMPSF assay was validated for 11 exonic fragments: 3 in control genes (CFTR, DSCR1, F9) and 8 corresponding to GFAP exons. A total of 97 patients suspected of AxD were analyzed: 28 with a GFAP mutation; 69 with clinical and magnetic resonance imaging criteria compatible with the disease. Neither duplications nor deletions of GFAP were found, suggesting that GFAP coding-region rearrangements may not be involved in AxD or Alexander-related leukoencephalopathies. In addition, 80 patients with undetermined leukodystrophies, and negative for PLP1, GJA12, Sox10 and MCT8 mutations and PLP1 and Lamin B1 rearrangements, were tested. These patients were also negative for GFAP rearrangements. Other hypotheses should be investigated for a molecular diagnosis in patients with undetermined leukoencephalopathy: mutations in GFAP isoforms, splicing sites or regulatory regions, or defaults in genes encoding molecular partners of GFAP.


      PubDate: 2015-07-21T21:40:41Z
       
  • Long term follow up of two independent patients with Schinzel-Giedion
           carrying SETBP1 mutations
    • Abstract: Publication date: Available online 15 July 2015
      Source:European Journal of Medical Genetics
      Author(s): Yvan Herenger, Corinne Stoetzel, Elise Schaefer, Sophie Scheidecker, Marie-Cécile Manière, Valérie Pelletier, Yves Alembik, Dominique Christmann, Jean-Michel Clavert, Joelle Terzic, Michel Fischbach, Anne De Saint Martin, Hélène Dollfus
      Schinzel-Giedion syndrome (SGS, MIM #269150) is a rare syndrome characterized by severe intellectual disability, typical facial gestalt, hypertrichosis and multiple congenital malformations including skeletal, genitourinary, renal and cardiac abnormalities. The prognosis of SGS is very severe and death occurs generally within a few years after birth. In 2002, we reported 2 children with SGS with a follow-up of 3 years. They presented a very similar and particular phenotype associating distinctive facial gestalt, severe developmental delay, megacalycosis, progressive neurodegeneration, alacrimi, corneal hypoesthesia and deafness. Furthermore, temporal bone imaging revealed a tuning-fork malformation of the stapes. In 2010, Hoischen et al. identified in SGS patients pathogenic heterozygous de novo mutations in SETBP1. We sequenced SETBP1 in our patients and found the previoulsy reported c.2608G>A (p.Gly870Ser) mutation in both children. Since 2002, one of our patients died at 6 years old and the other patient is still alive at 15 years old. Such a life expectancy has never been reported so far. We describe herein the follow up of the 2 children during 6 and 15 years respectively. This article gives further evidence of the implication of SETBP1 as the major gene of SGS, and reports the previously unseen natural evolution of the disease in a 15 years old patient.


      PubDate: 2015-07-17T21:38:01Z
       
  • Leukoencephalopathy associated with 11q24 deletion involving the gene
           encoding hepatic and glial cell adhesion molecule in two patients
    • Abstract: Publication date: Available online 17 July 2015
      Source:European Journal of Medical Genetics
      Author(s): Toshiyuki Yamamoto, Shino Shimada, Keiko Shimojima, Noriko Sangu, Shinsuke Ninomiya, Masaya Kubota
      Leukoencephalopathies are heterogeneous entities with white matter abnormalities. Mutations of the gene encoding hepatic and glial cell adhesion molecule (HEPACAM) located on 11q24 are related to one of the leukoencephalopathies: megalencephalic leukoencephalopathy with subcortical cysts type 2 (MLC2). Genomic copy number aberrations were analyzed by microarray comparative hybridization for two patients. One patient who presented with abnormal intensity of the white matter had been previously been diagnosed with the typical genotype and phenotype of Jacobsen syndrome due to an 11q subtelomere deletion, which was further characterized here. In a second patient who exhibited the characteristic finding of leukoencephalopathy, an interstitial deletion of 11q24 was also identified. HEPACAM was involved in both deletions. We therefore suggest that haploinsufficiency of HEPACAM, a gene previously associated with the features of MLC2 and located on the overlapping deletion region between the two patients, might be related to the observed white matter abnormalities.


      PubDate: 2015-07-17T21:38:01Z
       
  • Rare ACTG1 variants in fetal microlissencephaly
    • Abstract: Publication date: Available online 16 July 2015
      Source:European Journal of Medical Genetics
      Author(s): Karine Poirier, Jelena Martinovic, Annie Laquerrière, Mara Cavallin, Catherine Fallet Bianco, Isabelle Desguerre, Stephanie Valence, Jocelyne Grande-Goburghun, Christine Francannet, Jean François Deleuze, Anne Boland, Jamel Chelly, Nadia Bahi-Buisson
      Heterozygous ACTG1 mutations are responsible for Baraitser–Winter cerebrofrontofacial syndrome which cortical malformation is characterized by pachygyria with frontal to occipital gradient of severity. We identified by whole exome sequencing in a cohort of 12 patients with prenatally diagnosed microlissencephaly, 2 foetal cases with missense mutations in the ACTG1 gene and in one case of living patient with typical Baraitser–Winter syndrome. Both foetuses and child exhibited microcephaly and facial dysmorphism consisting of microretrognatism, hypertelorism and low-set ears. Brain malformations included lissencephaly with an immature cortical plate, dysmorphic (2/3) or absent corpus callosum and vermian hypoplasia (2/3) Our results highlight the powerful diagnostic value of exome sequencing for patients with microlissencephaly, that may expand the malformation spectrum of ACTG1-related Baraitser–Winter cerebrofrontofacial syndrome and may suggest that ACTG1 could be added to the list of genes for assessing microlissencephaly.


      PubDate: 2015-07-17T21:38:01Z
       
  • FGFR2 mutation in a patient without typical features of Pfeiffer syndrome
           – The emerging role of combined NGS and phenotype based strategies
    • Abstract: Publication date: August 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 8
      Author(s): Ricarda Flöttmann , Alexej Knaus , Tomasz Zemojtel , Peter N. Robinson , Stefan Mundlos , Denise Horn , Malte Spielmann
      Pfeiffer syndrome (MIM: #101600) is a rare autosomal dominant disorder classically characterized by limb and craniofacial anomalies. It is caused by heterozygous mutations in the fibroblast growth factor receptors types 1 and 2 (FGFR1 and FGFR2). We applied a next generation sequencing (NGS) panel approach comprising all 2877 genes currently known to be causative for one or more Mendelian diseases combined with the phenotype based computational tool PhenIX (Phenotypic Interpretation of eXomes). We report on a patient presenting with multiple anomalies of hands and feet including brachydactyly and symphalangism. No clinical diagnosis could be established based on the clinical findings and testing of several genes associated with brachydactyly and symphalangism failed to identify mutations. Via next generation sequencing (NGS) panel approach we then identified a novel de novo missense FGFR2 mutation affecting an amino acid reported to be mutated in Pfeiffer syndrome. Since our patient shows typical radiological findings of Pfeiffer syndrome in hands and feet but at the same time lacks several characteristic features such as clinical signs of craniosynostosis and prominent eyes we suggest introducing the term “FGFR2 associated phenotypes” for similar cases. Our results highlight the emerging role of combined NGS and phenotype based bioinformatics strategies to establish clinical diagnoses.


      PubDate: 2015-07-14T11:16:47Z
       
  • Progressive brain atrophy in Schinzel–Giedion syndrome with a SETBP1
           mutation
    • Abstract: Publication date: August 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 8
      Author(s): Akihito Takeuchi , Nobuhiko Okamoto , Shoko Fujinaga , Hirosuke Morita , Junya Shimizu , Tomoyuki Akiyama , Shinsuke Ninomiya , Jun-ichi Takanashi , Toshihide Kubo
      Schinzel-Giedion syndrome is a rare congenital malformation syndrome. Recently, SETBP1 was identified as the causative gene. Herein, we present a Japanese boy with Schinzel-Giedion syndrome resulting from a novel mutation in SETBP1 in order to establish the clinical features and serial MRI findings associated with the syndrome. On the third day of life, the boy was referred to our hospital because of facial abnormalities and feeding difficulty. Midfacial retraction, frontal bossing, deep groove under the eyes, upturned nose, low-set ears, bilateral cryptorchidism, and generalized hypertrichosis were identified on admission. At the age of 7 months, epileptic spasms in series occurred. Based on characteristic facial and skeletal abnormalities and severe developmental delay, we clinically diagnosed him with Schinzel-Giedion syndrome. Direct sequencing of the SETBP1 gene revealed a heterozygous mutation (p.Ile871Ser) in exon 4. Although neither cardiac defect nor choanal stenosis were present in our case, the phenotype of our case was nearly identical to those of previously reported cases confirmed by genetic analysis. Serial MRI from the age of 1 month–3 years revealed progressive brain atrophy, especially in the white matter and basal ganglia. However, myelination was age-appropriate and no obvious abnormal signals in the white matter were seen. Diffusion weighted imaging revealed no abnormal findings. Accumulation of MRI data including diffusion weighted imaging from Schinzel-Giedion syndrome cases is needed to understand the mechanism underlying progressive brain atrophy in this syndrome.


      PubDate: 2015-07-14T11:16:47Z
       
  • ISPD gene homozygous deletion identified by SNP array confirms prenatal
           manifestation of Walker–Warburg syndrome
    • Abstract: Publication date: August 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 8
      Author(s): Marie Trkova , Vera Krutilkova , Dagmar Smetanova , Vera Becvarova , Eva Hlavova , Nada Jencikova , Jana Hodacova , Lenka Hnykova , Hana Hroncova , Jiri Horacek , David Stejskal
      Walker–Warburg syndrome (WWS) is a rare form of autosomal recessive, congenital muscular dystrophy that is associated with brain and eye anomalies. Several genes encoding proteins involved in abnormal α-dystroglycan glycosylation have been implicated in the aetiology of WWS, most recently the ISPD gene. Typical WWS brain anomalies, such as cobblestone lissencephaly, hydrocephalus and cerebellar malformations, can be prenatally detected through routine ultrasound examinations. Here, we report two karyotypically normal foetuses with multiple brain anomalies that corresponded to WWS symptoms. Using a SNP-array examination on the amniotic fluid DNA, a homozygous microdeletion was identified at 7p21.2p21.1 within the ISPD gene. Published data and our findings led us to the conclusion that a homozygous segmental intragenic deletion of the ISPD gene causes the most severe phenotype of Walker–Warburg syndrome. Our results also clearly supports the use of chromosomal microarray analysis as a first-line diagnostic test in patients with a foetus with one or more major structural abnormalities identified on ultrasonographic examination.


      PubDate: 2015-07-14T11:16:47Z
       
  • 3 generation pedigree with paternal transmission of the 22q11.2 deletion
           syndrome: Intrafamilial phenotypic variability
    • Abstract: Publication date: April 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 4
      Author(s): Elfi Vergaelen , Ann Swillen , Hilde Van Esch , Stephan Claes , Gert Van Goethem , Koenraad Devriendt
      In this case report, we present a paternal transmission of a classic 3 Mb 22q11.2 deletion syndrome (22q11.2 DS) in a 3 generation family. In this family a young girl, her father, her uncle and her grandfather were diagnosed with this disorder. All carriers showed phenotypic expression, there were no unaffected siblings in the second or third generation. Presenting symptoms in the patient in first generation (grandfather) were psoriatic arthritis, thrombocytopenia and a right aortic arch. There was no intellectual disability. The second generation uncle was known with a severe intellectual disability, mild facial characteristics, a septal defect and a clubfoot, whereas the second generation father had a tetralogy of Fallot, no intellectual disability and minimal facial characteristics. The third generation daughter had a moderate intellectual disability, hypernasal speech, triphalangeal thumb, severe speech and language development delay, pronounced facial characteristics and a diagnosis of ADHD. It was notable that the expression in the two brothers of the second generation gives two very different clinical phenotypes with a severe intellectual disability in the oldest brother. This report describes a pronounced clinical variability in a 3 generation familial 22q11.2 deletion with paternal transmission. We can assume that several mechanisms play an important role in the heterogeneity and part of the answer should be found in the genetic background underlying the 22q11.2 deletion. In addition in this family the neuropsychiatric phenotype and intellectual disability seem to be associated with a lower level of social and occupational functioning while a congenital heart disease does not. This clinical report illustrates that a detailed description of these patients can be very informative and still increase the knowledge on this heterogonous syndrome. For the clinicians working with these patients it emphasizes the need for a multidisciplinary approach that takes into account the individual needs.


      PubDate: 2015-07-14T11:16:47Z
       
  • Frameshift mutations in the insulin gene leading to prolonged molecule of
           insulin in two families with Maturity-Onset Diabetes of the Young
    • Abstract: Publication date: April 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 4
      Author(s): Lenka Dusatkova , Petra Dusatkova , Jan Vosahlo , Klara Vesela , Ondrej Cinek , Jan Lebl , Stepanka Pruhova
      Mutations in the insulin (INS) gene rarely occur in patients with Maturity-Onset Diabetes of the Young (MODY). We aimed to describe in detail two MODY families with INS mutations. The INS gene was screened by direct sequencing. The probands and their affected relatives underwent a mixed-meal test. Mutation predictions were modeled using I-TASSER and were visualized by Swiss-PdbViewer. A novel heterozygous frameshift mutation p.Gln78fs in the INS gene was found in three generations of patients with clinically distinct diabetes. The single nucleotide deletion (c.233delA) is predicted to change and prolong amino acid sequence, resulting in aberrant proinsulin without native structures of C-peptide and A-chain. In the second family, the heterozygous mutation c.188-31G>A within the terminal intron was detected. The mother and her daughter were misdiagnosed as having type 1 diabetes since the ages of 6 and 2 years, respectively. This result is in contrast to the previously described carrier of the same mutation who was diagnosed with permanent neonatal diabetes. We identified a novel coding frameshift mutation and an intronic mutation in the INS gene leading to childhood-onset diabetes. INS mutations may result in various phenotypes, suggesting that additional mechanisms may be involved in the pathogenesis and clinical manifestation of diabetes.


      PubDate: 2015-07-14T11:16:47Z
       
  • Warsaw Breakage Syndrome – A further report, emphasising cutaneous
           findings
    • Abstract: Publication date: April 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 4
      Author(s): Claire Bailey , Alan E. Fryer , Mark Greenslade
      We report a new case of Warsaw Breakage syndrome (WABS) with 2 confirmed mutations in DDX11. Like the previous reported cases [Capo-Chichi et al., 2012; Van der Lelij et al., 2010], there was evidence of pre- and postnatal growth retardation, severe microcephaly, intellectual disability and facial dysmorphism. The patient had sensorineural hearing loss with evidence of bilateral hypoplastic cochleas on imaging, another feature which has been reported in the previous cases of WABS. In our case the patient exhibited a chronic rash of livedo reticularis with telangiectasia on her legs. Abnormally pigmented lesions and cutis mamorata were reported in the original WABS case.


      PubDate: 2015-07-14T11:16:47Z
       
  • A novel single nucleotide splice site mutation in FHL1 confirms an
           Emery-Dreifuss plus phenotype with pulmonary artery hypoplasia and facial
           dysmorphology
    • Abstract: Publication date: April 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 4
      Author(s): Anja E. Pen , Mette Nyegaard , Mingyan Fang , Hui Jiang , Rikke Christensen , Henning Mølgaard , Henning Andersen , Benedicte Parm Ulhøi , John R. Østergaard , Signe Væth , Mette Sommerlund , Arjan P.M. de Brouwer , Xiuqing Zhang , Uffe B. Jensen
      We describe a Danish family with an, until recently, unknown X-linked disease with muscular dystrophy (MD), facial dysmorphology and pulmonary artery hypoplasia. One patient died suddenly before age 20 and another was resuscitated from cardiac arrest at the age of 28. Linkage analysis pointed to a region of 25 Mb from 123.6 Mb to 148.4 Mb on chromosome X containing over 100 genes. Exome sequencing identified a single nucleotide splice site mutation c.502-2A > T, which is located 5' to exon 6 in the gene encoding four and a half LIM domain 1 (FHL1) protein. FHL1 expresses three main splice variants, known as FHL1A, FHL1B and FHL1C. In healthy individuals, FHL1A is the predominant splice variant and is mainly found in skeletal and cardiac muscle. The FHL1 transcript profiles from two affected individuals were investigated in skin fibroblasts with quantitative real-time PCR. This demonstrated loss of isoform A and B, and an almost 200-fold overexpression of isoform C confirming that lack of FHL1A and overexpression of FHL1C results in an extended phenotype of EDMD as recently shown by Tiffin et al. [2013].


      PubDate: 2015-07-14T11:16:47Z
       
  • A genealogical and clinical study of the phenotypical variation within the
           Swedish transthyretin His88Arg (p. His108Arg) amyloidosis family
    • Abstract: Publication date: April 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 4
      Author(s): Urban Hellman , Hans-Erik Lundgren , Per Westermark , Christina Stafberg , Hareth Nahi , Sascha Tachlinski , Michael Guggi , Max Flogegård , Mehmet Hamid , Stefan A. Escher , Ole B. Suhr
      In 2005 we reported the first case of transthyretin His88Arg (p. His108Arg) amyloidosis, a mutation characterised by cardiomyopathy. Six additional gene carriers of whom five have clinical symptoms of disease have now been identified in Sweden, and we have been able to identify a possible founder and to characterise the Swedish phenotype of the transthyretin (TTR) His88Arg mutation. Genealogical studies of church records were used to identify the individuals with the disease and their families. Routine clinical investigations of neurological and heart manifestation of the disease were utilised. We found that genealogically all seven individuals were related and originated from the same region in Sweden. Amyloid deposits were demonstrated in biopsies and the TTR His88Arg mutation was identified in all patients. Patients had a late onset disease (≥50 years of age) and all exhibited a severe amyloid cardiomyopathy. A pronounced peripheral axonal neuropathy was with certainty demonstrated in one patient only, who also was operated for a magnetic resonance confirmed spinal stenosis, however, without any effect on his neurological symptoms. Five of the patients had carpal tunnel syndrome. The first reported case is now deceased from cardiac failure. One patient has had a sequential heart and liver transplantation. One gene carrier had no symptoms or findings of disease on latest evaluation at the age of 44. In conclusion: the Swedish TTRHis88Arg patients all have a common Swedish founder. Cardiomyopathy with heart failure, as well as carpal tunnel syndrome and spinal stenosis were early signs of disease; but peripheral neuropathy was present in one patient before symptoms of cardiomyopathy so the phenotypical presentation of this mutation is variable.


      PubDate: 2015-07-14T11:16:47Z
       
  • Focus group discussions on secondary variants and next-generation
           sequencing technologies
    • Abstract: Publication date: April 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 4
      Author(s): Gabrielle M. Christenhusz , Koenraad Devriendt , Hilde Van Esch , Kris Dierickx
      The clinical application of new genetic technologies will be and already is of great benefit to children with unexplained developmental disabilities or congenital anomalies. In most cases, it will be their parents who, together with medical professionals, make decisions about what should be disclosed and how the information will be used. We conducted eight exploratory focus group discussions with stakeholders to provide a broad sketch of concerns and ideas around the communication of results from next-generation sequencing technologies involving children. Stakeholders included those with (grand-) children of various ages and those without children; those involved professionally with genetics and those who were not; and a range of ages. Participants were asked to focus on which secondary variants they would and would not want disclosed about their (hypothetical) children or themselves. While the literature often concentrates on the medical and scientific characteristics of secondary variants, focus group participants were also interested in factors involving the parent-child relationship and the broader context. This resulted in more flexibility surrounding the types of secondary variants disclosed to parents than much of the literature currently supports. In addition, participants would on occasion use the same factors to argue opposing positions. The “Family Illness Paradigms model” can help explain this seeming contradiction. This model emphasises the importance of how the family reacts to personal and family experiences of disease and loss, more than the fact of having these experiences.


      PubDate: 2015-07-14T11:16:47Z
       
  • De novo deletion of HOXB gene cluster in a patient with failure to thrive,
           developmental delay, gastroesophageal reflux and bronchiectasis
    • Abstract: Publication date: June–July 2015
      Source:European Journal of Medical Genetics, Volume 58, Issues 6–7
      Author(s): Sander Pajusalu , Tiia Reimand , Oivi Uibo , Maire Vasar , Inga Talvik , Olga Zilina , Pille Tammur , Katrin Õunap
      We report a female patient with a complex phenotype consisting of failure to thrive, developmental delay, congenital bronchiectasis, gastroesophageal reflux and bilateral inguinal hernias. Chromosomal microarray analysis revealed a 230 kilobase deletion in chromosomal region 17q21.32 (arr[hg19] 17q21.32(46 550 362–46 784 039)×1) encompassing only 9 genes – HOXB1 to HOXB9. The deletion was not found in her mother or father. This is the first report of a patient with a HOXB gene cluster deletion involving only HOXB1 to HOXB9 genes. By comparing our case to previously reported five patients with larger chromosomal aberrations involving the HOXB gene cluster, we can suppose that HOXB gene cluster deletions are responsible for growth retardation, developmental delay, and specific facial dysmorphic features. Also, we suppose that bilateral inguinal hernias, tracheo-esophageal abnormalities, and lung malformations represent features with incomplete penetrance. Interestingly, previously published knock-out mice with targeted heterozygous deletion comparable to our patient did not show phenotypic alterations.


      PubDate: 2015-07-14T11:16:47Z
       
  • Antenatal presentation of hereditary lymphedema type I
    • Abstract: Publication date: June–July 2015
      Source:European Journal of Medical Genetics, Volume 58, Issues 6–7
      Author(s): E. Boudon , Y. Levy , T. Abossolo , François Cartault , P. Brouillard , M. Vikkula , M. Kieffer-Traversier , D. Ramful , J.L. Alessandri
      Fetal edema can present as limited subcutaneous edema, fluid accumulation in body cavities or hydrops fetalis. Hydrops fetalis is the end stage of a variety of fetal/maternal disorders and nonimmune etiology represents more than 3/4 of cases. Lymphatic dysplasia may account for a subset of patients with nonimmune and “idiopathic” hydrops fetalis, fetal chylous ascites or chylothorax. We present two unrelated patients with antenatal features of hereditary lymphedema syndrome, in whom Milroy disease was diagnosed after birth. At least, 20 genes have been identified to cause primary lymphedema, with sometimes antenatal features. Hereditary lymphedema syndrome should be considered in cases of nonimmune hydrops fetalis/fetal edema after ruling out the more common etiologies.


      PubDate: 2015-07-14T11:16:47Z
       
  • Unusual retrospective prenatal findings in a male newborn with Timothy
           syndrome type 1
    • Abstract: Publication date: June–July 2015
      Source:European Journal of Medical Genetics, Volume 58, Issues 6–7
      Author(s): J. Román Corona-Rivera , Ernesto Barrios-Prieto , Rafael Nieto-García , Raffaella Bloise , Silvia Priori , Carlo Napolitano , Lucina Bobadilla-Morales , Alfredo Corona-Rivera , Eugenio Zapata-Aldana , Christian Peña-Padilla , Jehú Rivera-Vargas , Eva Chavana-Naranjo
      Timothy syndrome 1 (TS1) is a multisystem disorder characterized by severe QT prolongation and potentially lethal ventricular arrhythmias in the first years of life, plus other cardiac and extracardiac manifestations caused by mutation in the CACNA1C gene, a CaV1.2 L-type calcium channel. Here, we report retrospectively an unusual fetal presentation on a second patient with TS1 with fetal hydrops due to a congenital AV block and its postnatal diagnosis by a marked prolongation of the corrected QTc interval of 570 ms and a missense mutation, p.Gly406Arg, in exon 8A of CACNA1C gene. The observed manifestations in our patient during fetal period indicate a severe form and they were probably exacerbated by the maternal use of amitriptyline during the first 4 months of pregnancy. Unfortunately, he died at 3 months-old due a ventricular tachycardia and fibrillation related to a septic event. Although difficult to diagnose, possibly most fetuses with TS1 have symptoms of long QT syndrome. Despite the fatal outcome for our patient, an early diagnosis of TS may help to prevent life-threatening events or early death in future patients, especially in developing countries where availability of therapies such as cardioverter defibrillator are very limited, or require time for its funding.


      PubDate: 2015-07-14T11:16:47Z
       
  • Left ventricular non compaction with aortic valve anomalies: a recurrent
           feature of 22q11.2 distal deletion syndrome
    • Abstract: Publication date: Available online 2 July 2015
      Source:European Journal of Medical Genetics
      Author(s): M.Cristina Digilio , Paolo Versacci , Laura Bernardini , Antonio Novelli , Bruno Marino , Bruno Dallapiccola



      PubDate: 2015-07-14T11:16:47Z
       
  • Germline mutations and genotype–phenotype associations in head and
           neck paraganglioma patients with negative family history in China
    • Abstract: Publication date: Available online 19 June 2015
      Source:European Journal of Medical Genetics
      Author(s): W.D. Zhu , Z.Y. Wang , Y.C. Chai , X.W. Wang , D.Y. Chen , H. Wu
      The aim of this study was to assess the frequency of germline mutations and to explore genotype–phenotype associations in Chinese head and neck paraganglioma (HNPGL) patients without family history. Twenty-six Chinese patients with a diagnosis of HNPGL(14 male and 12 female, respectively)were recruited, who were followed up from 2000 to 2012. Genomic DNA was obtained from resected tumor tissues and peripheral blood samples. Seven genes, Succinate dehydrogenase complex A,B,C,D (SDHA, SDHB, SDHC, SDHD), succinate dehydrogenase complex assembly factor 2 (SDHAF2), TMEM127 (transmembrane protein 127) and VHL (Von Hippel-Lindau), were screened by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) was performed to search for potential large deletions or duplications of SDHB, SDHC, SDHD, SDHAF1 and SDHAF2. The total frequency of germline mutations was 30.8% (8/26), including 5 cases with missense mutation p.Met1Ile in SDHD, 1 case with missense mutation p.Tyr216Cys in SDHB, and 1 case with a novel truncation mutation p.Gln44Ter in SDHAF2. MLPA showed one patient with malignant HNPGL had heterozygous deletions of exon1, 2, 3, 7 and 8 in SDHB. Mutations in SDHD were the leading cause of HNPGL in this study. Mutation carriers were younger than non-mutation carriers (p < 0.01) and more likely to suffer from multiple tumors (p = 0.048), especially with mutations in SDHD. The presence of mutation was associated with the development of larger tumors (p = 0.021). This study confirmed that the missense mutation p.Met1Ile at the start codon in SDHD was a hotspot in chinese patients with HNPGLs. We recommend genetic analysis in patients below 45 years, especially SDHD gene.


      PubDate: 2015-07-14T11:16:47Z
       
  • Inherited 1q21.1q21.2 duplication and 16p11.2 deletion: a two-hit case
           with more severe clinical manifestations
    • Abstract: Publication date: Available online 8 July 2015
      Source:European Journal of Medical Genetics
      Author(s): Sophie Brisset , Yline Capri , Audrey Briand-Suleau , Lucie Tosca , Domitille Gras , Anne-Laure Fauret-Amsellem , Dominique Pineau , Julien Saada , Valérie Ortonne , Alain Verloes , Michel Goossens , Gérard Tachdjian , Corinne Métay
      We report paternally inherited duplication of 1q12q21.2 of 5.8 Mb associated with maternally inherited deletion of 16p11.2 of 545 Kb, this latter first identified in a fetus exhibiting an absent nasal bone detected during pregnancy. During the neonatal period, the young boy presented developmental delay, epilepsy, congenital anomalies and overweight. The clinical features of the proband with two rearrangements were more severe than in either of the parents carrying only one or the other mutation. Thus our data support a two-hit model in which the concomitant presence of these two copy-number variations exacerbates the neurodevelopmental phenotype.


      PubDate: 2015-07-14T11:16:47Z
       
  • Chromosomal aberrations in idiopathic polyhydramnios: A Systematic Review
           and Meta-Analysis
    • Abstract: Publication date: Available online 14 July 2015
      Source:European Journal of Medical Genetics
      Author(s): Lena Sagi-Dain , Shlomi Sagi
      The objective of this meta-analysis was to summarize the existing literature examining the risk of chromosomal aberrations in idiopathic polyhydramnios. Search was conducted by a research librarian in five databases. Language and time restrictions were not applied. By independent screening of titles and abstracts, two investigators selected original researches examining the risk of chromosomal aberrations in idiopathic polyhydramnios. Twenty articles were included, encompassing a total of 1729 pregnancies with idiopathic polyhydramnios. The average rate of chromosomal aberrations in these cases was 2.8±3.7%, ranging between 0% to 13.8%. No studies were found examining the relative risk for chromosomal abnormalities in low-risk women with idiopathic polyhydramnios. An analysis of seven case-control trials, including women at high risk for aneuploidy, yielded a relative risk of 3.09 (95% confidence interval 1.92-4.97) for chromosomal aberration. Overall quality of evidence was rated as very low using Grading of Recommendations Assessment, Development and Evaluation criteria. In conclusion, the suboptimal quality of the evidence precludes from drawing any solid recommendations regarding routine karyotype testing in idiopathic polyhydramnios cases, especially in women at low risk for chromosomal aberrations. Future high-quality trials addressing the discussed methodological shortcomings should be conducted to assess this important issue.


      PubDate: 2015-07-14T11:16:47Z
       
  • Variable expressivity of a familial 1.9 Mb microdeletion in 3q28
           leading to haploinsufficiency of TP63: Refinement of the critical region
           for a new microdeletion phenotype
    • Abstract: Publication date: August 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 8
      Author(s): Emanuela Ponzi , Alessia Asaro , Daniela Orteschi , Maurizio Genuardi , Marcella Zollino , Fiorella Gurrieri
      We report on a 3-year-old male with intellectual disability (ID), characteristic facial features, polydactyly and epilepsy carrying a paternally inherited 3q28 deletion of 1.9 Mb. The father, carrying the same deletion, presents with cleft palate, nail dystrophy and learning difficulties. The deleted region in this family is one of the smallest so far reported among genomic deletions affecting 3q27–3q28 for which some phenotypic descriptions are available. In particular, since the phenotype of our proband is strikingly similar to that previously described in a patient with a 9.3 Mb deletion, the deletion identified in this report contributes to the definition of the molecular boundaries of a genomic region responsible for a distinct clinical phenotype. Within the deleted interval there are 9 annotated genes, including TP63. Gain of function mutations of TP63 are known to be responsible for a group of conditions with distal limb and ectodermal involvement, such as ADULT, EEC, LMS, and SHFM4 syndromes. Interestingly, our cases demonstrate a milder phenotypic effect for loss of function of this gene.


      PubDate: 2015-07-14T11:16:47Z
       
  • A Novel Oculo-Skeletal syndrome with intellectual disability caused by a
           particular MAB21L2 mutation
    • Abstract: Publication date: August 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 8
      Author(s): Denise Horn , Trine Prescott , Gunnar Houge , Kristin Brække , Karen Rosendahl , Gen Nishimura , David R. FitzPatrick , Jürgen Spranger
      We describe a novel recognizable phenotype characterized by anophthalmia, a distinctive skeletal dysplasia and intellectual disability. Radiographic anomalies include severe rhizomelic shortness of the limbs and abnormal joint formation. Recent exome studies showed that these characteristics are part of the phenotypic spectrum of MAB21L2 gene mutations which cause a range of structural eye malformations such as microphthalmia/anophthalmia and ocular coloboma. The two unrelated individuals described here in detail are heterozygous carriers of the same de novo missense mutation c.151C > T (p.Arg51Cys) in MAB21L2.


      PubDate: 2015-07-14T11:16:47Z
       
  • Lenz-Majewski syndrome: Report of a case with novel mutation
           in PTDSS1 gene
    • Abstract: Publication date: August 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 8
      Author(s): Parag M. Tamhankar , Lakshmi Vasudevan , Vandana Bansal , Shyla R. Menon , Harshavardhan M. Gawde , Aruna D'Souza , Shiny Babu , Shweta Kondurkar , Rashmi Adhia , Dhanjit Kumar Das
      Lenz-Majewski syndrome (LMS) is an extremely rare syndrome characterized by osteosclerosis, intellectual disability, characteristic facies and distinct craniofacial, dental, cutaneous and distal – limb anomalies. Recently, mutations in PTDSS1 gene have been identified as causative in six unrelated individuals. We report the seventh mutation proven case of LMS and provide a concise review of all known patients till date.


      PubDate: 2015-07-14T11:16:47Z
       
  • Exome sequencing reveals a novel WDR45 frameshift mutation and inherited
           POLR3A heterozygous variants in a female with a complex phenotype and
           mixed brain MRI findings
    • Abstract: Publication date: August 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 8
      Author(s): Mohamed Khalifa , Lena Naffaa
      WDR45 and POLR3A are newly recognized genes; each is associated with a distinct neurodegenerative disease. WDR45 is an X-linked gene associated with a dominant form of Neurodegeneration with Brain Iron Accumulation (NBIA), manifested by progressive disabilities, dystonia, cognitive decline, spastic paraplegia, neuropsychiatric abnormalities and iron deposition in the basal ganglia on brain imaging. POLR3A, on the other hand, is an autosomal gene, and its mutations cause a recessive form of a hypomyelination with leukodystrophy disease, also known as 4H syndrome, characterized by congenital Hypomyelination with thinning of the corpus callosum, Hypodontia and Hypogonadotropic Hypogonadism. We report on a female child with severe intellectual disability, aphasia, short stature, ataxia, failure to thrive and structural brain abnormalities. Brain MRI obtained in late infancy showed hypomyelination involving the central periventricular white matter and thinning of the corpus callosum with no evidence of iron accumulation. Brain MRI obtained in childhood showed stable hypomyelination, with progressive iron accumulation in the basal ganglia, in particular in the globus pallidus and substantia nigra. Whole Exome Sequencing (WES) identified a novel WDR45 frameshift deleterious mutation in Exon 9 (c.587-588del) and also revealed three POLR3A missense heterozygous variants. The first is a maternally inherited novel missense variant in exon 4 (c.346A > G). Exon 13 carried two heterozygous missense variants, a maternally inherited variant (c.1724A > T) and a paternally inherited variant (1745G > A). These variants are considered likely damaging. The patient's complex clinical phenotype and mixed brain MRI findings might be attributed to the confounding effects of the expression of these two mutant genes.


      PubDate: 2015-07-14T11:16:47Z
       
  • Chanarin-Dorfman syndrome: Genotype-Phenotype Correlation
    • Abstract: Publication date: April 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 4
      Author(s): Banu Guzel Nur , Pinar Gencpinar , Ayse Yuzbasıoglu , Serap Dokmeci Emre , Ercan Mihci
      Chanarin-Dorfman syndrome is an autosomal recessive lipid storage disease characterized by non-bullous congenital ichthyosiform erythroderma, and involvement of the liver, muscles and central nervous system due to a multisystemic accumulation of neutral lipids in various types of cells. Less than 100 affected individuals have been reported worldwide, the majority from the Mediterranean and Middle-East countries, especially Turkey. We present clinical and molecular data of four affected relatives with Chanarin-Dorfman syndrome homozygous for a N209X mutation in ABHD5, and provide a short review by comparing patients with N209X homozygous mutations to patients with other ABHD5 mutations. No major clinical differences exist between individuals with an N209X mutation and those with other mutations, which argues against a genotype/phenotype correlation.


      PubDate: 2015-07-14T11:16:47Z
       
  • Novel nonsense mutation in the PTRF gene underlies congenital generalized
           lipodystrophy in a consanguineous Saudi family
    • Abstract: Publication date: April 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 4
      Author(s): Musharraf Jelani , Saleem Ahmed , Mona Mohammad Almramhi , Hussein Sheikh Ali Mohamoud , Khadijah Bakur , Waseem Anshasi , Jun Wang , Jumana Yousuf Al-Aama
      Congenital generalized lipodystrophies (CGLs) are a heterogeneous group of rare, monogenic disorders characterized by loss of sub-cutaneous fat, muscular hypertrophy, acanthosis nigricans, hepatomegaly, cardiac arrhythmias, impaired metabolism and mental retardation. Four different but overlapping phenotypes (CGL1-4) have been identified, which are caused by mutations in AGPAT2 at 9q34.3, BSCL2 at 11q13, CAV1 at 7q31.1, and PTRF at 17q21.2. In this study, we performed genome-wide homozygosity mapping of two affected and one unaffected subject in a Saudi family using a 300K HumanCytoSNPs12v12.1 array with the Illumina iScan system. A common homozygous region at chromosome 17q22.1, from 34.4 to 45.3 Mb, was identified in both the affected individuals. The region is flanked by SNPs rs139433362 and rs185263326, which encompass the PTRF gene. Bidirectional DNA sequencing of the PTRF gene covering all of the coding exons and exon–intron boundaries was performed in all family members. Sequencing analysis identified a novel homozygous nonsense mutation in the PTRF gene (c.550G>T; p.Glu184*), leading to a premature stop codon. To the best of our knowledge, we present a novel mutation of PTRF from Saudi Arabia and our findings broaden the mutation spectrum of PTRF in the familial CGL4 phenotype. Homozygosity mapping coupled with candidate gene sequencing is an effective tool for identifying the causative pathogenic variants in familial cases.


      PubDate: 2015-07-14T11:16:47Z
       
  • Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe
           intellectual disability and autistic features
    • Abstract: Publication date: May 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 5
      Author(s): Nathalie Fieremans , Hilde Van Esch , Thomy de Ravel , Jozef Van Driessche , Stefanie Belet , Marijke Bauters , Guy Froyen
      Intellectual disability (ID) is a very heterogeneous disorder with over 100 ID genes located on the X chromosome alone. Of these, KDM5C and IQSEC2 are located adjacent to each other at the Xp11.22 locus. While mutations in either of these genes are associated with severe ID in males, female carriers are mostly unaffected. Here, we report on a female patient with severe ID and autistic features carrying a de novo 0.4 Mb deletion containing six coding genes including KDM5C and IQSEC2. X-inactivation analysis revealed skewing in a lymphocyte-derived cell line from this patient with preferential inactivation of the mutant X chromosome. As the brain-expressed KDM5C and IQSEC2 genes escape X-inactivation, deletion of these alleles could still be detrimental despite skewing of X-inactivation. Indeed, mutations in either of both genes have been reported in a few female ID patients. Expression analysis in the patients' cell line revealed decreased KDM5C mRNA levels compared to female controls. IQSEC2 levels could not be compared due to very low expression in blood. Overall, our data suggest that heterozygous loss-of-function of the escape genes KDM5C and/or IQSEC2 can contribute to severe ID in female patients and should be taken into account in diagnostics.


      PubDate: 2015-07-14T11:16:47Z
       
  • Microduplications of 3p26.3p26.2 containing CRBN gene in patients with
           intellectual disability and behavior abnormalities
    • Abstract: Publication date: May 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 5
      Author(s): Sorina M. Papuc , Karl Hackmann , Joris Andrieux , Catherine Vincent-Delorme , Magdalena Budişteanu , Aurora Arghir , Evelin Schrock , Andreea C. Ţuţulan-Cuniţă , Nataliya Di Donato
      We report on the clinical data and molecular cytogenetic findings in three unrelated patients presenting with intellectual disability and behavior abnormalities. An overlapping microduplication involving 3p26.2-26.3 was identified in these patients. All three aberrations were confirmed and proven to be parentally inherited. The sizes of the duplications were different, with a common minimal region of 423,754 bp containing two genes – TRNT1 and CRBN. Here, we hypothesize that the copy number gain of CRBN gene might be responsible for developmental delay/intellectual disability.


      PubDate: 2015-07-14T11:16:47Z
       
  • Subtelomeric 6p25 deletion/duplication: Report of a patient with new
           clinical findings and genotype–phenotype correlations
    • Abstract: Publication date: May 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 5
      Author(s): Natália D. Linhares , Marta Svartman , Tatiane C. Rodrigues , Carla Rosenberg , Eugênia R. Valadares
      The 6p terminal deletions are rare and present variability of clinical features, which increases the importance of reporting additional cases in order to better characterize genotype–phenotype correlations. We report a 12-year-old girl with a de novo deletion in 6p25.1-pter characterized by high-resolution karyotyping and FISH. Further analysis using oligonucleotide array-CGH revealed a 5.06 Mb 6p25.1-pter deletion associated with a contiguous 1 Mb 6p25.1 duplication. The patient presented normal growth, developmental delay, frontal bossing, severe hypertelorism, corectopia, wide and depressed nasal bridge, mild learning disability, hearing loss and diffuse leukopathy. Additionaly, she presented peculiar phenotypic features reported herein for the first time in 6p25 deletion syndrome: cerebrospinal fluid fistula and bones resembling those seen in 3-M syndrome. The distinctive phenotype of the 6p25 deletion syndrome has been mainly correlated with the FOXC1 and FOXF2 genes deletions, both related mainly to eye development. We also consider the SERPINB6 as a candidate for sensorineural hearing loss and TUBB2A as a candidate for our patient's skeletal features. In addition, as our patient had a duplication including NRN1, a gene related with neurodevelopment, synaptic plasticity and cognitive dysfunction in schizophrenia, we suggest that this gene could be associated with her white matter abnormalities and neurocognitive phenotype.


      PubDate: 2015-07-14T11:16:47Z
       
  • Proteus syndrome: Report of a case with AKT1 mutation in a dental cyst
    • Abstract: Publication date: May 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 5
      Author(s): Marie-Cécile Valéra , Fréderic Vaysse , Eric Bieth , Michel Longy , Claude Cances , Isabelle Bailleul-Forestier
      Proteus syndrome (PS) is a sporadic and rare congenital disorder characterized by a patchy or mosaic postnatal overgrowth, sometimes involving the face. The onset of overgrowth typically occurs in infancy and can commonly involve skin, connective tissue, central nervous system, eyes and viscera. The progressive overgrowth causes severe complications, such as skeletal deformities, cystic lung disease, invasive lipomas, connective tissue hyperplasia, benign and malignant tumours and deep venous thrombosis with pulmonary embolism, which can cause premature death. This disorder is caused by somatic mosaicism for a specific activating AKT1 mutation that would be lethal in a non-mosaic state. In this report, current knowledge of the aetiology, the diagnosis and the craniofacial manifestations of the disorder are reviewed. The short-term management of a 7-year-old patient with unusual oral manifestations is described. For the first time mutation of AKT1 (c.49G > A) gene was detected both in cranial exostosis and in central odontogenic fibroma of the lower jaw.


      PubDate: 2015-07-14T11:16:47Z
       
  • Familial transmission of 5p13.2 duplication due to maternal der(X)ins(X;5)
    • Abstract: Publication date: May 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 5
      Author(s): Lauren C. Walters-Sen , Kathy Windemuth , Katie Angione , Jenisha Nandhlal , Jeff M. Milunsky
      Submicroscopic duplications of 5p13 have been recently reported in several cases, warranting the description of a new clinical entity (Chromosome 5p13 Duplication Syndrome; MIM 613174). These microduplications, while variable in size, all contain at least part of the NIPBL gene. Patients with duplications in this region present with intellectual disability/developmental delay (ID/DD) and dysmorphic facies. In addition, skeletal and brain abnormalities have been variably reported, as well as propensity for obesity in adulthood and hypotonia. We report a family with two affected sons and two affected daughters, each carrying a duplication at 5p13.2 encompassing the 3′ portion of SLC1A3 and the 5' portion of NIPBL. Upon confirming the SNP microarray finding by FISH in the proband, it was discovered that the 5p13.2 duplication was located on the short arm of the X chromosome. Further FISH studies on the family demonstrated that all affected children and their mother carried a derivative X chromosome with insertion of material from 5p13.2 into the intermediate region of Xp [der(X)ins(X;5)(p2'2.1;p13.2p13.2)]. To our knowledge, this is the first report of an inherited duplication of 5p13.2 with multiple affected family members. This family underscores the need to confirm array findings by FISH, both in the proband and family members, to discern implications for pathogenicity and more accurately define the recurrence risk.


      PubDate: 2015-07-14T11:16:47Z
       
  • Variable expression pattern in Donnai-Barrow syndrome: Report of two novel
           LRP2 mutations and review of the literature
    • Abstract: Publication date: May 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 5
      Author(s): Ola Khalifa , Zahra Al-Sahlawi , Faiqa Imtiaz , Khushnooda Ramzan , Rabab Allam , Abeer Al-Mostafa , Maaly Abdel-Fattah , Gheid Abuharb , Michael Nester , Alain Verloes , Hamad Al-Zaidan
      Donnai-Barrow syndrome (DBS; MIM 222448) is characterized by typical craniofacial anomalies (major hypertelorism with bulging eyes), high grade myopia, deafness and low molecular weight proteinuria. The disorder results from mutations in the low density lipoprotein receptor-related protein 2 gene LRP2 that maps to chromosome 2q31.1. LRP2 encodes megalin, a multi-ligand endocytic receptor. Herein, we describe the clinical presentation of 4 patients from 2 unrelated Saudi families. Two novel LRP2 mutations, a homozygous nonsense mutation (c.4968C>G; p.Tyr1656*) and a missense mutation (c.12062G>A; p.Cys4021Tyr), were detected in the first and second family respectively. Interestingly, intrafamilial phenotypic variability was observed in one family, while DBS features were atypical in the second family. Differential diagnosis of DBS includes several syndromes associating hypertelorism with high grade myopia, and several syndromal forms of CDH, which are briefly summarized in this study.


      PubDate: 2015-07-14T11:16:47Z
       
  • Phenotype and genotype in 103 patients with tricho-rhino-phalangeal
           syndrome
    • Abstract: Publication date: May 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 5
      Author(s): Saskia M. Maas , Adam C. Shaw , Hennie Bikker , Hermann-Josef Lüdecke , Karin van der Tuin , Magdalena Badura-Stronka , Elga Belligni , Elisa Biamino , Maria Teresa Bonati , Daniel R. Carvalho , JanMaarten Cobben , Stella A. de Man , Nicolette S. Den Hollander , Nataliya Di Donato , Livia Garavelli , Sabine Grønborg , Johanna C. Herkert , A. Jeannette M. Hoogeboom , Aleksander Jamsheer , Anna Latos-Bielenska , Anneke Maat-Kievit , Cinzia Magnani , Carlo Marcelis , Inge B. Mathijssen , Maartje Nielsen , Ellen Otten , Lilian B. Ousager , Jacek Pilch , Astrid Plomp , Gemma Poke , Anna Poluha , Renata Posmyk , Claudine Rieubland , Margharita Silengo , Marleen Simon , Elisabeth Steichen , Connie Stumpel , Katalin Szakszon , Edit Polonkai , Jenneke van den Ende , Antony van der Steen , Ton van Essen , Arie van Haeringen , Johanna M. van Hagen , Joke B.G.M. Verheij , Marcel M. Mannens , Raoul C. Hennekam
      Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1, and TRPS II, caused by a contiguous gene deletion affecting (amongst others) TRPS1 and EXT1. We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype–phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5 it remained uncertain whether TRPS1 was partially or completely deleted. Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella. The facial manifestations in patients with TRPS I and TRPS II do not show a significant difference. In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened. Nails of fingers and toes are typically thin and dystrophic. The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses. Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally. Variability for all findings, also within a single family, can be marked. Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate in severity. Missense mutations are located exclusively in exon 6 and 7 of TRPS1. Other mutations are located anywhere in exons 4–7. Whole gene deletions are common but have variable breakpoints. Most of the phenotype in patients with TRPS II is explained by the deletion of TRPS1 and EXT1, but haploinsufficiency of RAD21 is also likely to contribute. Genotype-phenotype studies showed that mutations located in exon 6 may have somewhat more pronounced facial characteristics and more marked shortening of hands and feet compared to mutations located elsewhere in TRPS1, but numbers are too small to allow firm conclusions.


      PubDate: 2015-07-14T11:16:47Z
       
  • Phenotype–genotype correlations for clinical variants caused by CYLD
           mutations
    • Abstract: Publication date: May 2015
      Source:European Journal of Medical Genetics, Volume 58, Issue 5
      Author(s): Nikoletta Nagy , Katalin Farkas , Lajos Kemény , Márta Széll
      Brooke-Spiegler syndrome (BSS; OMIM 605041) is an autosomal dominant condition characterized by skin appendageal neoplasms including cylindromas, trichoepitheliomas, and/or spiradenomas. In 1996, the gene locus for BSS was mapped to 16q12-13, and, in 2000, mutations in the cylindromatosis (CYLD) gene were determined to cause BSS, familial cylindromatosis (FC; OMIM 132700) and multiple familial trichoepithelioma type 1 (MFT1; OMIM 601606). The CYLD gene encodes an enzyme with deubiquitinase activity. To date, a total of 95 different diseases-causing mutations have been published for the CYLD gene. A summary of mutations identified in Hungarian patients and a review of previously published mutations are presented in this update. The majority of the sequence changes are frameshift (48%), nonsense (27%), missense (12%) and splice-site (11%) mutations; however, two in-frame deletions have also been reported. Most mutations are located in exons 9–20. Analysis of the identified CYLD gene mutations and the observed BSS, FC and MFT1 clinical phenotypes of the patients revealed significant genotype–phenotype correlations. Elucidation of these genotype–phenotype correlations is critical for the diagnosis of these rare monogenic skin diseases. In addition, characterizing these correlations may promote the understanding of their mechanisms and may hopefully contribute to the development of future therapeutic modalities.


      PubDate: 2015-07-14T11:16:47Z
       
  • Array-based DNA methylation analysis in individuals with developmental
           delay/intellectual disability and normal molecular karyotype
    • Abstract: Publication date: Available online 21 May 2015
      Source:European Journal of Medical Genetics
      Author(s): Julia Kolarova , Imke Tangen , Susanne Bens , Gabriele Gillessen-Kaesbach , Jana Gutwein , Monika Kautza , Malgorzata Rydzanicz , Ulrich Stephani , Reiner Siebert , Ole Ammerpohl , Almuth Caliebe
      Despite recent progress in molecular karyotyping and clinical sequencing the cause of intellectual disability in a considerable subset of individuals affected by this phenotype remains elusive. As intellectual disability is also a feature of various imprinting disorders and some monogenic forms of intellectual disability are caused by epigenetic modifiers we hypothesized that changes in DNA methylation might be associated with or even causative in some cases of intellectual disability. Therefore, we performed a DNA methylation analysis of peripheral blood samples from 82 patients with intellectual disability and additional features using the HumanMethylation450 BeadChip. The findings were compared to that of 19 normal controls. Differentially methylated loci were validated by bisulfite pyrosequencing. On a global level, we failed to detect a robust DNA methylation signature segregating individuals with intellectual disability from controls. Using an individual approach, we identified 157 regions showing individual DNA methylation changes in at least one patient. These correlated to 107 genes including genes linked to conditions associated with intellectual disability, namely COLEC11, SHANK2, GLI2 and KCNQ2, as well as imprinted genes like FAM50B and MEG3. The latter was suggestive of an undiagnosed Temple syndrome which could be confirmed by diagnostic tests. Subsequent in-depth analysis of imprinted loci revealed DNA methylation changes at additional imprinted loci, i.e. PPIEL, IGF2R, MEG8 and MCTS2/HM13, in up to five patients. Our findings indicate that imprinting disorders are rare but probably under-diagnosed in patients with intellectual disability and moreover point to DNA methylation changes as potential alternative means to identify deregulated genes involved in the pathogenesis of intellectual disability.


      PubDate: 2015-07-14T11:16:47Z
       
  • Identical by descent L1CAM mutation in two apparently unrelated families
           with intellectual disability without L1 syndrome
    • Abstract: Publication date: June–July 2015
      Source:European Journal of Medical Genetics, Volume 58, Issues 6–7
      Author(s): Marie Shaw , Tzu Ying Yap , Lyndal Henden , Melanie Bahlo , Alison Gardner , Vera M. Kalscheuer , Eric Haan , Louise Christie , Anna Hackett , Jozef Gecz
      Mutations in the L1 Cell Adhesion Molecule (L1CAM) gene (MIM#308840) cause a variety of X-linked recessive neurological disorders collectively called L1 syndrome. Using massively parallel sequencing (MPS) of the X-chromosome exome, we identified a novel missense variant in L1CAM in two Caucasian families with mild-moderate intellectual disability without obvious L1 syndrome features. These families were not known to be related. SNP data extracted from MPS identified a 5.6 cM tract of identity by descent (IBD), encompassing the L1CAM gene, between the DNA of the two probands. This cannot be explained by chance alone and strongly implies that the two families are related. It also suggests that the L1CAM (NM_000425.3, c.604G > A, p.D202N) variant is pathogenic. This report also demonstrates the usefulness of additional information, which can be extracted from exome sequencing data.


      PubDate: 2015-07-14T11:16:47Z
       
  • A new hereditary congenital facial palsy case supports arg5 in HOX-DNA
           binding domain as possible hot spot for mutations
    • Abstract: Publication date: June–July 2015
      Source:European Journal of Medical Genetics, Volume 58, Issues 6–7
      Author(s): Zehra Oya Uyguner , Güven Toksoy , Umut Altunoglu , Hilal Ozgur , Seher Basaran , Hülya Kayserili
      Moebius syndrome (MBS) is a rare congenital disorder characterized by rhombencephalic mal development, mainly presenting with facial palsy with limited gaze abduction. Most cases are sporadic, possibly caused by a combination of environmental and genetic factors; however, no proven specific associations have been yet established. Hereditary congenital facial palsy (HCFP) is an autosomal dominant congenital dysinnervation syndrome, recognizable by the isolated dysfunction of the seventh cranial nerve. Mutant mice for Hoxb1 were reported to present with facial weakness, resembling MBS. Recently a homozygous mutation altering arg5 residue of HOXB1 homeodomain into cys5 was identified in two families with HCFP. We screened 95 sporadic patients diagnosed as MBS or HCFP for mutations in HOXB1. A novel homozygous alteration was identified in one HCFP case, affecting the same residue, resulting to his5. In silico protein analysis predicted stronger HOXB1-DNA binding properties for his5 than cys5 that resulted to milder phenotype. It should be noted that, inclusive of the previous report, only two mutations revealed in HOXB1 associated with HCFP involved the same amino acid arg5 in HOXB1 residing in HOXB1-DNA-PBX1 ternary complex.


      PubDate: 2015-07-14T11:16:47Z
       
  • Eight patients with Williams syndrome and craniosynostosis
    • Abstract: Publication date: June–July 2015
      Source:European Journal of Medical Genetics, Volume 58, Issues 6–7
      Author(s): Kimiko Ueda , Junji Yamada , Osamu Takemoto , Nobuhiko Okamoto
      Williams syndrome (WS) is a well-known genetic syndrome caused by a microdeletion on chromosome 7q11.23 encompassing the elastin gene. It is characterized by distinctive facies, congenital cardiovascular malformations, intellectual disabilities, and various other manifestations. Some patients were reported with craniosynostosis. Here, we report 8 WS cases diagnosed with craniosynostosis using three-dimensional cranial computed tomography. These findings suggest that craniosynostosis may occur more frequently in WS patients than expected.


      PubDate: 2015-07-14T11:16:47Z
       
  • Low-level mosaicism of a de novo derivative chromosome 9 from a
           t(5;9)(q35.1;q34.3) has a major phenotypic impact
    • Abstract: Publication date: June–July 2015
      Source:European Journal of Medical Genetics, Volume 58, Issues 6–7
      Author(s): B. Hervé , J. Roume , S. Cognard , D. Fauvert , D. Molina-Gomes , F. Vialard
      Microdeletion and microduplication syndromes are well-known causes of developmental delay and/or malformations of differing severity. Although homogeneous abnormalities can now be detected relatively easily using microarray technologies, they are more difficult to detect and interpret in cases of mosaicism. Here, we report on a male infant with a mosaic de novo derivative chromosome 9, featuring a 10.2 Mb 5q35 duplication (including the NSD1 gene) and a 687 kb 9q34 deletion (including EHMT1). The infant presented developmental delay, short stature, brachy/plagiocephaly and hyperactivity. The proportion of abnormal cells was 50% in saliva (in a microarray analysis) and 25% in lymphocytes (in a FISH analysis). Despite the low-level mosaicism in lymphocytes, this imbalance appears to be responsible for a distinctive phenotype (suggesting the presence of variable clinical expression and/or major somatic mosaicism).


      PubDate: 2015-07-14T11:16:47Z
       
  • Brain malformations in a patient with deletion 2p16.1: A refinement
           of the phenotype to BCL11A
    • Abstract: Publication date: June–July 2015
      Source:European Journal of Medical Genetics, Volume 58, Issues 6–7
      Author(s): Tugce B. Balci , Sarah L. Sawyer , Jorge Davila , Peter Humphreys , David A. Dyment
      Microdeletions of 2p15-16.1 have been reported in 15 patients with a recognizable syndrome of dysmorphic features, intellectual disability and microcephaly. Facial features include telecanthus, short palpebral fissures, epicanthal folds, a broad nasal root, smooth and long philtrum and large ears. Brain malformations can be observed in this syndrome and include hypoplasia of the corpus callosum and a simplified cortical gyral pattern. Case reports have narrowed the critical region of the neurodevelopmental phenotype to a region that spans the B-cell CLL/lymphoma 11A (BCL11A) gene. Here we present a 3-year-old normocephalic girl with moderate development delay and dysmorphic features including a prominent forehead, telecanthus, depressed nasal bridge, thin upper vermilion and a small chin. Magnetic resonance imaging shows enlargement of the lateral, third and fourth ventricles and hypoplastic corpus callosum, cerebellar vermis and pons. Array CGH revealed a 0.875 Mb de novo deletion at 2p16.1 that includes only BCL11A. The moderate delays, hypoplastic and dysmorphic corpus callosum and hippocampi and the facial features are in keeping with the previously described 2p15-16.1 microdeletion syndrome. However, hypoplasia of the pons and cerebellum are not commonly recognized features and are reminiscent of the brain malformations observed in individuals with a mutation in CASK. CASK is known to interact with BCL11A in the normal growth of axons. This case report highlights the role of BCL11A in 2p15-16.1 microdeletion syndrome and the unique phenotype suggests a common pathway for BCL11A and other genes in neurodevelopment.


      PubDate: 2015-07-14T11:16:47Z
       
  • Xp21 deletion in female patients with intellectual disability: Two new
           cases and a review of the literature
    • Abstract: Publication date: June–July 2015
      Source:European Journal of Medical Genetics, Volume 58, Issues 6–7
      Author(s): Solveig Heide , Alexandra Afenjar , Patrick Edery , Damien Sanlaville , Boris Keren , Alexandre Rouen , Alinoë Lavillaureix , Capucine Hyon , Diane Doummar , Jean-Pierre Siffroi , Sandra Chantot-Bastaraud
      Xp21 continuous gene deletion syndrome is characterized by complex glycerol kinase deficiency (GK), adrenal hypoplasia congenital (NROB1), intellectual disability and/or Duchenne muscular dystrophy (DMD). The clinical features depend on the size of the deletion, as well as on the number and the nature of the encompassed genes. More than 100 male patients have been reported so far, while only a few cases of symptomatic female carriers have been described. We report here detailed clinical features and X chromosome inactivation analysis in two unrelated female patients with overlapping Xp21 deletions presenting with intellectual disability and inconstant muscular symptoms.


      PubDate: 2015-07-14T11:16:47Z
       
 
 
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