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Journal Cover European Journal of Medical Genetics
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   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1769-7212
   Published by Elsevier Homepage  [3175 journals]
  • Pancreatic hemi-agenesis in MEN1: A clinical report
    • Authors: Wouter J. Vinck; Frank Van de Mierop; François Van Mieghem; Maarten Vinck; Herman Becq; Geneviève Michils
      Pages: 181 - 184
      Abstract: Publication date: April 2018
      Source:European Journal of Medical Genetics, Volume 61, Issue 4
      Author(s): Wouter J. Vinck, Frank Van de Mierop, François Van Mieghem, Maarten Vinck, Herman Becq, Geneviève Michils
      We first describe a patient with multiple endocrine neoplasia type 1 (MEN1) and dorsal pancreatic hemi-agenesis. Previously, pancreas divisum has been reported in MEN1. Recent data in mice have elucidated the molecular mechanisms of pancreatic endoderm specification. Disinhibition of hedgehog signaling appears to be important in how Gata4 and Gata6 variants cause pancreatic agenesis. Disinhibition of hedgehog signaling has also been observed in Men1 knockout pancreatic islets. Although we cannot exclude a spurious association between dorsal pancreatic hemi-agenesis and MEN1 in our patient, we argue that developmental abnormalities of the pancreas may have to be considered as possibly related to the MEN1 phenotype.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2017.11.013
  • Missense mutation of TTC7A mimicking tricho-hepato-enteric (SD/THE)
           syndrome in a patient with very-early onset inflammatory bowel disease
    • Authors: João Farela Neves; Isabel Afonso; Luis Borrego; Catarina Martins; Ana Isabel Cordeiro; Conceição Neves; Caroline Lacoste; Catherine Badens; Alexandre Fabre
      Pages: 185 - 188
      Abstract: Publication date: April 2018
      Source:European Journal of Medical Genetics, Volume 61, Issue 4
      Author(s): João Farela Neves, Isabel Afonso, Luis Borrego, Catarina Martins, Ana Isabel Cordeiro, Conceição Neves, Caroline Lacoste, Catherine Badens, Alexandre Fabre
      Tricho-hepato-enteric syndrome (SD/THE) and Multiple intestinal atresia with combined immune deficiency (MIA-CID) are autosomal recessive disorders that present immunological and gastrointestinal features. There are two different phenotypes of patients with TTC7A mutations: the severe form, caused by null mutations and leading to the classical MIA-CID; and the mild form, caused by missense mutations and leading to predominant features of VEO-IBD, less severe immunological involvement and hair abnormalities. We expand the knowledge about TTC7A deficiency, describing a patient with the mild phenotype of TTC7A deficiency but presenting overlapping features of SD/THE and MIA-CID: intestinal atresia and inflammatory bowel disease evocative of MIA-CID, but also dental abnormalities, huge forehead, liver abnormalities, autoimmune thyroiditis and hypogammaglobulinemia, evocative of SD/THE.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2017.11.014
  • A higher rare CNV burden in the genetic background potentially contributes
           to intellectual disability phenotypes in 22q11.2 deletion syndrome
    • Authors: Matthew Jensen; R. Frank Kooy; Tony J. Simon; Edwin Reyniers; Santhosh Girirajan; Flora Tassone
      Pages: 209 - 212
      Abstract: Publication date: April 2018
      Source:European Journal of Medical Genetics, Volume 61, Issue 4
      Author(s): Matthew Jensen, R. Frank Kooy, Tony J. Simon, Edwin Reyniers, Santhosh Girirajan, Flora Tassone
      The 22q11.2 deletion syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by a hemizygous deletion of 30–40 contiguous genes on chromosome 22, many of which have not been well characterized. Clinical features seen in patients with this deletion, including intellectual disability, are not completely penetrant and vary in severity between patients, suggesting the involvement of variants elsewhere in the genome in the manifestation of the phenotype. Given that it is a relatively rare disorder (1/2000-6000 in humans), limited research has shed light into the contribution of these second-site variants to the developmental pathogenesis that underlies 22q11DS. As CNVs throughout the genome might constitute such a genetic risk factor for variability in the 22q11DS phenotypes such as intellectual disability, we sought to determine if the overall burden of rare CNVs in the genetic background influenced the phenotypic variability. We analyzed CNV and clinical data from 66 individuals with 22q11DS, and found that 77% (51/66) of individuals with the 22q11DS also carry additional rare CNVs (<0.1% frequency). We observed several trends between CNV burden and phenotype, including that the burden of large rare CNVs (>200 Kb in size) was significantly higher in 22q11DS individuals with intellectual disability than with normal IQ. Our analysis shows that rare CNVs may contribute to intellectual disability 22q11DS, and further analysis on larger 22q11DS cohorts should be performed to confirm this correlation.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2017.11.016
  • Recontacting in light of new genetic diagnostic techniques for patients
           with intellectual disability: Feasibility and parental perspectives
    • Authors: Gea Beunders; Melodi Dekker; Oscar Haver; Hanne J. Meijers-Heijboer; Lidewij Henneman
      Pages: 213 - 218
      Abstract: Publication date: April 2018
      Source:European Journal of Medical Genetics, Volume 61, Issue 4
      Author(s): Gea Beunders, Melodi Dekker, Oscar Haver, Hanne J. Meijers-Heijboer, Lidewij Henneman
      A higher diagnostic yield from new diagnostic techniques makes re-evaluation in patients with intellectual disability without a causal diagnosis valuable, and is currently only performed after new referral. Active recontacting might serve a larger group of patients. We aimed to evaluate parental perspectives regarding recontacting and its feasibility in clinical genetic practice. A recontacting pilot was performed in two cohorts of children with intellectual disability. In cohort A, parents were recontacted by phone and in cohort B by letter, to invite them for a re-evaluation due to the new technologies (array CGH and exome sequencing, respectively). Parental opinions, preferences and experiences with recontacting were assessed by a self-administered questionnaire, and the feasibility of this pilot was evaluated. 47 of 114 questionnaires were returned. In total, 87% of the parents believed that all parents should be recontacted in light of new insights, 17% experienced an (positive or negative) emotional reaction. In cohort A, approached by phone, 36% made a new appointment for re-evaluation, and in cohort B, approached by letter, 4% did. Most parents have positive opinions on recontacting. Recontacting might evoke emotional responses that may need attention. Recontacting is feasible but time-consuming and a large additional responsibility for clinical geneticists.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2017.11.017
  • A report of three families with FBN1-related acromelic dysplasias and
           review of literature for genotype-phenotype correlation in geleophysic
    • Authors: S.W. Cheng; Ho-Ming Luk; YoYo W.Y. Chu; Yuet-Ling Tung; Elanie Yin-Wah Kwan; Ivan Fai-Man Lo; Brian Hon-Yin Chung
      Pages: 219 - 224
      Abstract: Publication date: April 2018
      Source:European Journal of Medical Genetics, Volume 61, Issue 4
      Author(s): S.W. Cheng, Ho-Ming Luk, YoYo W.Y. Chu, Yuet-Ling Tung, Elanie Yin-Wah Kwan, Ivan Fai-Man Lo, Brian Hon-Yin Chung
      Acromelic dysplasia is a heterogeneous group of rare skeletal dysplasias characterized by distal limb shortening. Weill-Marchesani syndrome (WMS), Geleophysic dysplasia (GD) and Acromicric dysplasia (AD) are clinically distinct entities within this group of disorders and are characterized by short stature, short hands, stiff joints, skin thickening, facial anomalies, normal intelligence and skeletal abnormalities. Mutations of the Fibrillin-1 (FBN1) gene have been reported to cause AD, GD and related phenotypes. We reported three families with acromelic short stature. FBN1 analysis showed that all affected individuals carry a heterozygous missense mutation c.5284G > A (p.Gly1762Ser) in exon 42 of the FBN1 gene. This mutation was previously reported to be associated with GD. We reviewed the literature and compared the clinical features of the patients with FBN1 mutations to those with A Distintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2) mutations. We found that tip-toeing gait, long flat philtrum and thin upper upper lip were more consistently found in GD patients with ADAMTSL2 mutations than in those with FBN1 mutations. The results have shed some light on the phenotype-genotype correlation in this group of skeletal disorders. A large scale study involving multidisciplinary collaboration would be needed to consolidate our findings.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2017.11.018
  • Atopic disorders in CHARGE syndrome: A retrospective study and literature
    • Authors: Fang Kong; Donna M. Martin
      Pages: 225 - 229
      Abstract: Publication date: April 2018
      Source:European Journal of Medical Genetics, Volume 61, Issue 4
      Author(s): Fang Kong, Donna M. Martin
      Background Atopic disorders have been reported in CHARGE syndrome, but the prevalence and underlying mechanisms are not known. Methods We performed a retrospective study of atopic disorders in 23 individuals with CHARGE syndrome, and reviewed other published reports of atopic disorders in CHARGE syndrome. We assayed for enrichment of atopic disorders in CHARGE syndrome based on gender and presence of a CHD7 pathogenic variant. Results In our cohort, 65% (15/23) of individuals with CHARGE syndrome were found to have a pathogenic CHD7 variant. Overall, 65% (15/23) of individuals with CHARGE had atopic disorders. Among the 23 individuals with CHARGE, 22% (5/23) had food allergy, 26% (6/23) exhibited drug allergy, 22% (5/23) had contact allergy, 9% (2/23) had allergic rhinitis, and 22% (5/23) had asthma. In our cohort, the proportion of males to females with CHARGE and atopic disorders was 11:4 (P < 0.01), and there was no significant difference between atopic disorders in individuals with CHD7 pathogenic variants and those without CHD7 pathogenic variants (P > 0.05). Conclusion In our cohort of 23 individuals with CHARGE syndrome, 15 (65%) exhibited atopic disorders, with a slight male predominance.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2017.11.019
  • Improved molecular platform for the gene therapy of rare diseases by liver
           protein secretion
    • Authors: Mickael Quiviger; Aristeidis Giannakopoulos; Sebastien Verhenne; Corinne Marie; Eleana F. Stavrou; Karen Vanhoorelbeke; Zsuzsanna Izsvák; Simon F. De Meyer; Aglaia Athanassiadou; Daniel Scherman
      Abstract: Publication date: Available online 26 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Mickael Quiviger, Aristeidis Giannakopoulos, Sebastien Verhenne, Corinne Marie, Eleana F. Stavrou, Karen Vanhoorelbeke, Zsuzsanna Izsvák, Simon F. De Meyer, Aglaia Athanassiadou, Daniel Scherman
      Many rare monogenic diseases are treated by protein replacement therapy, in which the missing protein is repetitively administered to the patient. However, in several cases, the missing protein is required at a high and sustained level, which renders protein therapy far from being adequate. As an alternative, a gene therapy treatment ensuring a sustained effectiveness would be particularly valuable. Liver is an optimal organ for the secretion and systemic distribution of a therapeutic transgene product. Cutting edge non-viral gene therapy tools were tested in order to produce a high and sustained level of therapeutic protein secretion by the liver using the hydrodynamic delivery technique. The use of S/MAR matrix attachment region provided a slight, however not statistically significant, increase in the expression of a reporter gene in the liver. We have selected the von Willebrand Factor (vWF) gene as a particularly challenging large gene (8.4 kb) for liver delivery and expression, and also because a high vWF blood concentration is required for disease correction. By using the optimized miniplasmid pFAR free of antibiotic resistance gene together with the Sleeping Beauty transposon and the hyperactive SB100X transposase, we have obtained a sustainable level of vWFblood secretion by the liver, at 65% of physiological level. Our results point to the general use of this plasmid platform using the liver as a protein factory to treat numerous rare disorders by gene therapy.

      PubDate: 2018-04-26T10:11:04Z
      DOI: 10.1016/j.ejmg.2018.04.010
  • A novel NKX3-2 mutation associated with perinatal lethal phenotype of
           spondylo-megaepiphyseal-metaphyseal dysplasia in a neonate
    • Authors: Pelin Ozlem Simsek-Kiper; Can Kosukcu; Ozlem Akgun-Dogan; Rahsan Gocmen; Gulen Eda Utine; Tutku Soyer; Ayse Korkmaz-Toygar; Gen Nishimura; Mehmet Alikasifoglu; Koray Boduroglu
      Abstract: Publication date: Available online 25 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Pelin Ozlem Simsek-Kiper, Can Kosukcu, Ozlem Akgun-Dogan, Rahsan Gocmen, Gulen Eda Utine, Tutku Soyer, Ayse Korkmaz-Toygar, Gen Nishimura, Mehmet Alikasifoglu, Koray Boduroglu
      Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) is an autosomal recessive skeletal dysplasia, characterized by disproportionate short stature with a short and stiff neck and trunk. SMMD is caused by inactivating mutations in NKX3-2, which encodes a homeobox-containing protein. Because of the rarity of the disorder, the diagnostic feature has not been fully established yet. We describe an affected newborn with dysmorphic facial features and severe short trunk. The patient required immediate intubation at the delivery room and duodenal atresia was detected during his course in neonatal intensive care unit. Skeletal survey revealed total absence of the ossification of the vertebral bodies, pubis, and ischia. Mainly the femora was short and broad with mild flaring of the metaphyses. The downward sloping or tented appearance of the ribs was distinctive. A diagnosis of SMMD was made on clinical and radiological grounds. Molecular analysis revealed homozygosity for a novel mutation, c.507-508delCA (p.Gly171Cysfs*55) in exon 2 of NKX3-2. The patient was operated on postnatal day 7 for duodenal atresia. In the post-operative period he developed sepsis and respiratory failure and he died on postnatal day 14. Although no neuroradiologic imaging could be performed, the findings of clubfoot, neuromuscular respiratory insufficiency requiring invasive mechanical ventilation and downward sloping or tented appearance of the ribs were suggestive of very early cervical cord compression leading to perinatal mortality. To our knowledge this patient yet represents one of the most severe postnatal phenotypes of SMMD.

      PubDate: 2018-04-26T10:11:04Z
      DOI: 10.1016/j.ejmg.2018.04.013
  • Is it research or is it clinical' Revisiting an old frontier through
           the lens of next-generation sequencing technologies
    • Authors: Gabrielle Bertier; Anne Cambon-Thomsen; Yann Joly
      Abstract: Publication date: Available online 25 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Gabrielle Bertier, Anne Cambon-Thomsen, Yann Joly
      As next-generation sequencing technologies (NGS) are increasingly used in the clinic, one issue often pointed out in the literature is the fact that their implementation “blurs the line” between research and healthcare. Indeed, NGS data obtained through research study may have clinical significance, and patients may consent that their data is shared in international databases used in research. This blurred line may increase the risk of therapeutic misconception, or that of over-reporting incidental findings. The law has been used to impose a distinction between the two contexts, but this distinction may not always be as clear in the practice of clinical genomics. To illustrate this, we reviewed the legal frameworks in France and Quebec on the matter, and asked the opinion of stakeholders who use NGS to help cancer and rare disease patients in practice. We found that while there are clear legal distinctions between research and clinical care, bridges between the two contexts exist, and the law focuses on providing appropriate protections to persons, whether they are patients or research participants. The technology users we interviewed expressed that their use of NGS was designed to help patients, but harbored elements pertaining to research as well as care. We hence saw that NGS technologies are often used with a double objective, both individual care and the creation of collective knowledge. Our results highlight the importance of moving towards research-based care, where clinical information can be progressively enriched with evolutive research results. We also found that there can be a misalignment between scientific experts’ views and legal norms of what constitutes research or care, which should be addressed. Our method allowed us to shed light on a grey zone at the edge between research and care, where the full benefits of NGS can be yielded. We believe that this and other evidence from the realities of clinical research practice can be used to design more stable and responsible personalized medicine policies.

      PubDate: 2018-04-26T10:11:04Z
      DOI: 10.1016/j.ejmg.2018.04.009
  • Identification of two 14q32 deletions involving DICER1 associated with the
           development of DICER1-related tumors
    • Authors: John C. Herriges; Sara Brown; Maria Longhurst; Jillian Ozmore; John B. Moeschler; Aura Janze; Jeanne Meck; Sarah T. South; Erica F. Andersen
      Abstract: Publication date: Available online 24 April 2018
      Source:European Journal of Medical Genetics
      Author(s): John C. Herriges, Sara Brown, Maria Longhurst, Jillian Ozmore, John B. Moeschler, Aura Janze, Jeanne Meck, Sarah T. South, Erica F. Andersen
      DICER1 encodes an RNase III endonuclease protein that regulates the production of small non-coding RNAs. Germline mutations in DICER1 are associated with an autosomal dominant hereditary cancer predisposition syndrome that confers an increased risk for the development of several rare childhood and adult-onset tumors, the most frequent of which include pleuropulmonary blastoma, ovarian sex cord-stromal tumors, cystic nephroma, and thyroid gland neoplasia. The majority of reported germline DICER1 mutations are truncating sequence-level alterations, suggesting that a loss-of-function type mechanism drives tumor formation in DICER1 syndrome. However, reports of patients with germline DICER1 whole gene deletions are limited, and thus far, only two have reported an association with tumor development. Here we report the clinical findings of three patients from two unrelated families with 14q32 deletions that encompass the DICER1 locus. The deletion identified in Family I is 1.4 Mb and was initially identified in a 6-year-old male referred for developmental delay, hypotonia, macrocephaly, obesity, and behavioral problems. Subsequent testing revealed that this deletion was inherited from his mother, who had a clinical history that included bilateral multinodular goiter and papillary thyroid carcinoma. The second deletion is 5.0 Mb and was identified in a 15-year-old female who presented with autism, coarse facial features, Sertoli-Leydig cell tumor, and Wilms’ tumor. These findings provide additional supportive evidence that germline deletion of DICER1 confers an increased risk for DICER1-related tumor development, and provide new insight into the clinical significance of deletions involving the 14q32 region.

      PubDate: 2018-04-26T10:11:04Z
      DOI: 10.1016/j.ejmg.2018.04.011
  • Extending the clinical and genetic spectrum of ARID2 related intellectual
           disability. A case series of 7 patients
    • Authors: Gabriella Gazdagh; Moira Blyth; Ingrid Scurr; Peter D. Turnpenny; Sarju G. Mehta; Ruth Armstrong; Meriel McEntagart; Ruth Newbury-Ecob; Edward S. Tobias; Shelagh Joss
      Abstract: Publication date: Available online 23 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Gabriella Gazdagh, Moira Blyth, Ingrid Scurr, Peter D. Turnpenny, Sarju G. Mehta, Ruth Armstrong, Meriel McEntagart, Ruth Newbury-Ecob, Edward S. Tobias, Shelagh Joss
      In the last 3 years de novo sequence variants in the ARID2 (AT-rich interaction domain 2) gene, a subunit of the SWI/SNF complex, have been linked to intellectual disabilities in 3 case reports including one which describes frameshift mutations in ARID2 in 2 patients with features resembling Coffin-Siris syndrome. Coffin-Siris syndrome (CSS) is a rare congenital syndrome characterized by intellectual deficit, coarse facial features and hypoplastic or absent fifth fingernails and/or toenails among other features. Mutations in a number of different genes encoding SWI/SNF chromatin remodelling complex proteins have been described but the underlying molecular cause remains unknown in approximately 40% of patients with CSS. Here we describe 7 unrelated individuals, 2 with deletions of the ARID2 region and 5 with de novo truncating mutations in the ARID2 gene. Similarities to CSS are evident. Although hypertrichosis and hypoplasia of the fifth finger nail and distal phalanx do not appear to be common in these patients, toenail hypoplasia and the presence of Wormian bones might support the involvement of ARID2.

      PubDate: 2018-04-26T10:11:04Z
      DOI: 10.1016/j.ejmg.2018.04.014
  • Phenotype variability in Hajdu-Cheney syndrome
    • Authors: Miriam Regev; Ben Pode-Shakked; Jeffrey M. Jacobson; Annick Raas-Rothschild; David B. Goldstein; Yair Anikster
      Abstract: Publication date: Available online 23 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Miriam Regev, Ben Pode-Shakked, Jeffrey M. Jacobson, Annick Raas-Rothschild, David B. Goldstein, Yair Anikster
      Hajdu Cheney syndrome is a rare autosomal dominant skeletal dysplasia, with multi-organ involvement, caused by pathogenic variants in NOTCH2. It is characterized by progressive focal bone destruction, including acro-osteolysis and generalized osteoporosis, craniofacial anomalies, hearing loss, cardiovascular involvement and polycystic kidneys. Distinct radiographic findings, such as a serpentine fibula, may aid in facilitating the diagnosis. Despite several dozens of cases described in the literature, diagnosis often remains elusive, resulting in many cases in a delay in diagnosis reaching adolescence or adulthood. We report herein two unrelated patients of Turkish/Lebanese Jewish and Ashkenazi Jewish descent, each presenting with distinctclinical challenges and subsequently distinct diagnostic odysseys leading to their molecular diagnosis. These illustrative clinical descriptions underscore the wide phenotypic variability of HCS, and further contribute to the current knowledge regarding this rare entity.

      PubDate: 2018-04-26T10:11:04Z
      DOI: 10.1016/j.ejmg.2018.04.015
  • Auto-immune disorders in a child with PIK3CD variant and 22q13 deletion
    • Authors: Kyoko Kiyota; Koh-ichiro Yoshiura; Ryoko Houbara; Hiroaki Miyahara; Seigo Korematsu; Kenji Ihara
      Abstract: Publication date: Available online 17 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Kyoko Kiyota, Koh-ichiro Yoshiura, Ryoko Houbara, Hiroaki Miyahara, Seigo Korematsu, Kenji Ihara
      22q13 deletion syndrome is a genetic disorder caused by the deletion or disruption of the segment of the long arm of chromosome 22. The characteristic clinical features of this syndrome include delayed expressive speech, autistic behavior and hypotonia, and clinically severe complications associated with autoimmunity are rarely reported. We herein report a girl with 22q13 deletion syndrome complicated with multiple inflammatory and autoimmune diseases during early childhood. We performed whole-exome sequencing to identify the genes responsible for her autoimmune diseases and identified the de novo variant p.R512W in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) gene. We suspected it to be the disease-causing variant at the conserved residue in PIK(3)C p110δ. Alternatively, haplo-insufficiency of SHANK3 or other genes by 22q13 deletion and the PIK3CD variant might have synergistically contributed to the onset of the distinctive clinical manifestations in this patient.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.04.008
  • Expansion of the clinical spectrum of frontometaphyseal dysplasia 2 caused
           by the recurrent mutation p.Pro485Leu in MAP3K7
    • Authors: Alice Costantini; Carina Wallgren-Pettersson; Outi Mäkitie
      Abstract: Publication date: Available online 14 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Alice Costantini, Carina Wallgren-Pettersson, Outi Mäkitie
      Frontometaphyseal dysplasia 2 (FMD2) is a skeletal dysplasia with supraorbital hyperostosis combined with undermodeling of the bones, joint contractures and some extraskeletal features. It is caused by heterozygous mutations in MAP3K7, encoding the Mitogen-Activated Protein 3-Kinase 7. MAP3K7 is activated by TGF-β and plays an important role in osteogenesis. Less than 20 patients with FMD2 and MAP3K7 mutations have been described thus far. The majority of the patients harbor a recurrent missense mutation, NM_003188.3: c.1454C > T [NP_003179.1: p.(Pro485Leu)], which leads to a more severe phenotype than mutations in other domains. Here we describe an additional patient with FMD2 caused by the recurrent c.1454C > T MAP3K7 mutation, identified as a de novo variant by whole-genome sequencing. The 17-year-old boy has the characteristic skeletal and facial features of FMD2. However, some novel features were also observed, including growth retardation and spina bifida occulta. In line with other patients harboring the same mutation he also showed keloid scars and had no intellectual disability. This report expands the clinical spectrum of FMD2 caused by the recurrent c.1454C > T [p.(Pro485Leu)] mutation in MAP3K7.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.04.004
  • Chronic intestinal pseudo-obstruction syndrome and gastrointestinal
           malrotation in an infantwith schaaf-yang syndrome - Expanding the
           phenotypic spectrum
    • Authors: Allan Bayat; Michael Bayat; Ricardo Lozoya; Christian P. Schaaf
      Abstract: Publication date: Available online 13 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Allan Bayat, Michael Bayat, Ricardo Lozoya, Christian P. Schaaf
      We report a novel patient with the phenotypic characteristics of Schaaf-Yang syndrome. In addition, the patient has a severe chronic digestive malfunction, rendering him dependent on intermittent enteral supplementation. To our knowledge, this is the first report of Schaaf-Yang syndrome associated with severe chronic digestive malfunction manifesting with both a malrotation and signs of a chronic intestinal pseudo-obstruction.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.04.007
  • Analysis of intragenic USH2A copy number variation unveils broad spectrum
           of unique and recurrent variants
    • Authors: Christina A. Austin-Tse; Diana L. Mandelker; Andrea M. Oza; Heather Mason-Suares; Heidi L. Rehm; Sami S. Amr
      Abstract: Publication date: Available online 12 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Christina A. Austin-Tse, Diana L. Mandelker, Andrea M. Oza, Heather Mason-Suares, Heidi L. Rehm, Sami S. Amr
      Given that all forms of Usher syndrome (USH) present with hearing loss in advance of retinal disease, the syndromic nature of the disorder is rarely appreciated when critical management decisions are being made. As a result, molecular diagnostics are crucial in guiding the management of USH patients. While 11 genes have been associated with USH, the USH2A gene is one of the largest contributors. Approximately 20% of suspected USH probands that undergo USH2A sequencing at our laboratory receive an inconclusive result due to the identification of a monoallelic disease-causing variant in USH2A. Many studies suggest that intragenic deletions and duplications represent an important USH2A variant type that can be missed by sequencing assays if supplemental algorithms or testing methods are not applied. To gain a comprehensive view of the contribution of USH2A CNVs to USH, we conducted prospective and retrospective screening in 700 hearing loss probands. Fourteen individuals with 11 unique USH2A CNVs are reported, including one pathogenic multi-exon duplication. Additionally, we mapped deletion breakpoints and performed a meta-analysis of USH2A CNVs to evaluate recurrence and underlying mechanisms. This analysis revealed breakpoint grouping within three introns, raising the possibility of CNV-susceptible regions within the gene. Overall, our data highlight the diversity of pathogenic CNVs in this gene, demonstrating that the comprehensive, high-resolution USH2A CNV analysis methods employed here are essential components of clinical genetic testing for USH.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.04.006
  • MARS variant associated with both recessive interstitial lung and liver
           disease and dominant Charcot-Marie-Tooth disease
    • Authors: Jonathan Rips; Rebecca Meyer-Schuman; Oded Breuer; Reuven Tsabari; Avraham Shaag; Shoshana Revel-Vilk; Shimon Reif; Orly Elpeleg; Anthony Antonellis; Tamar Harel
      Abstract: Publication date: Available online 12 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Jonathan Rips, Rebecca Meyer-Schuman, Oded Breuer, Reuven Tsabari, Avraham Shaag, Shoshana Revel-Vilk, Shimon Reif, Orly Elpeleg, Anthony Antonellis, Tamar Harel
      Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNA with cognate amino acids during protein translation. Non-canonical functions are increasingly recognized, and include transcription and translation control and extracellular signaling. Monoallelic mutations in genes encoding several ARSs have been identified in axonal Charcot-Marie-Tooth (CMT2) disease, whereas biallelic mutations in ARS loci have been associated with multi-tissue syndromes, variably involving the central nervous system, lung, and liver. We report a male infant of non-consanguineous origin, presenting with successive onset of transfusion-dependent anemia, hypothyroidism, cholestasis, interstitial lung disease, and developmental delay. Whole-exome sequencing (WES) revealed compound heterozygosity for two variants (p.Tyr307Cys and p.Arg618Cys) in MARS, encoding methionyl-tRNA synthetase. Biallelic MARS mutations are associated with interstitial lung and liver disease (ILLD). Interestingly, the p.Arg618Cys variant, inherited from an unaffected father, was previously reported in a family with autosomal dominant late-onset CMT2. Yeast complementation assays confirmed pathogenicity of p.Arg618Cys, yet suggested retained function of p.Tyr307Cys. Our findings underscore the phenotypic variability associated with ARS mutations, and suggest genetic or environmental modifying factors in the onset of monoallelic MARS-associated CMT2.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.04.005
  • A de novo 921 Kb microdeletion at 11q13.1 including neurexin 2 in a boy
           with developmental delay, deficits in speech and language without autistic
    • Authors: Haiming Yuan; Xiaoxiu Li; Qingming Wang; Wei Yang; Jiage Song; Xizi Hu; Yiping Shen
      Abstract: Publication date: Available online 11 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Haiming Yuan, Xiaoxiu Li, Qingming Wang, Wei Yang, Jiage Song, Xizi Hu, Yiping Shen
      Microdeletions at 11q13.1 are very rare. At present only two patients with 11q13.1 deletion involving neurexin 2 (NRXN2) have been reported. Both patients exhibited autistic features, which supported the role of NRXN2 in autism pathogenicity. It is currently unknown whether heterozygous deletion of NRXN2 is of high penetrance or if it is sufficient to result in autism behaviors. Here we reported a 2-year-9-month old boy with developmental delay, short stature, significant language delay and other congenital anomalies. In contrast to previously reported cases, the boy did not present with autistic behaviors and did not meet the clinical diagnosis of autism. A de novo 921 kb microdeletion at 11q13.1 was detected by chromosomal microarray analysis (CMA). Whole Exome Sequencing (WES) was also employed for our patient. The deletion was confirmed and no additional pathogenic variants were detected. We compared our patient's genomic information and clinical features with those of two previously reported individuals. Three patients shared similar deleted intervals and had similar clinical features except for autistic behaviors. This study suggested that NRXN2 gene had incomplete penetrance for autistic behavioral phenotype. The finding is of interest for genetic counseling and clinical management to patients with NRXN2 defects.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.04.002
  • An atypical phenotype of a patient with infantile spinal muscular atrophy
           with respiratory distress type 1 (SMARD 1)
    • Authors: Shuiyan Wu; Ting Chen; Ying Li; Linqi Chen; Qiuqin Xu; Fei Xiao; Zhenjiang Bai
      Abstract: Publication date: Available online 11 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Shuiyan Wu, Ting Chen, Ying Li, Linqi Chen, Qiuqin Xu, Fei Xiao, Zhenjiang Bai
      Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive disease characterized by infancy-onset diaphragmatic palsy and symmetrical distal muscular weakness. SMARD1 is caused by loss-of-function mutations in IGHMBP2 gene. In this article, we report a male SMARD1 patient with two compound heterozygous mutations (NM_002180.2: c.688C > G; p.(Gln230Glu)) and (NM_002180.2: c.1737C > A; p.(Phe579Leu)), one of which (c.688C > G; ClinVar accession: SUB3344743: SCV000612189) is novel. He suffered from diaphragmatic palsy and distal muscular weakness from 6 months of age. His lower limbs were at first in hypertonia, and then gradually progressed into hypotonia. More interestingly, bronchoscopy has shown the diffuse tracheobronchomalacia, which had been reported only once in a SMARD1 patient who also had the same mutation (c.1737C > A) as our patient. We constructed the model of IGHMBP2 and mapped both mutations in the structure to analyze the structural impact of both mutations (c.688C > G and c.1737C > A) on the IGHMBP2 protein, which showed that mutation c.688C > G reduces greatly the stability of domain 1A of IGHMBP2, while the structural impact of c.1737C > A is not extensive.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.04.001
  • Genetic analysis of Charcot-Marie-Tooth disease in Denmark and the
           implementation of a next generation sequencing platform
    • Authors: Signe Vaeth; Rikke Christensen; Morten Dunø; Dorte Launholt Lildballe; Kasper Thorsen; John Vissing; Kirsten Svenstrup; Jens Michael Hertz; Henning Andersen; Uffe Birk Jensen
      Abstract: Publication date: Available online 11 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Signe Vaeth, Rikke Christensen, Morten Dunø, Dorte Launholt Lildballe, Kasper Thorsen, John Vissing, Kirsten Svenstrup, Jens Michael Hertz, Henning Andersen, Uffe Birk Jensen
      Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of hereditary polyneuropathies. Variants in more than 80 different genes have been associated with the disorder. In recent years, the introduction of next generation sequencing (NGS) techniques have completely changed the genetic diagnostic approach from the analysis of a handful of genes to the analysis of all genes associated with CMT in a single run. In this study we describe the CMT diagnostics in Denmark in 1992–2012, prior to the implementation of NGS, by combining laboratory- and national registry data. We investigate the effect of implementing a targeted NGS approach of 63 genes associated with CMT in the diagnostic laboratory setting. This was performed by analyzing a cohort of 195 samples from patients previously analyzed by Sanger sequencing and quantitative analysis for the common causes of CMT without reaching a molecular diagnosis. A total of 1442 CMT analyses were performed in Denmark in the period 1992–2012; a disease-causing variant was detected in 21.6% of the cases. Interestingly, the diagnosis was genetically confirmed in significantly more women than men; 25.9% compared to18.5%. In our study cohort, we found a 5.6% increase in the diagnostic yield with the introduction of a targeted NGS approach.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.04.003
  • Benign hereditary chorea and deletions outside NKX2-1: What's the role of
    • Authors: Federica Invernizzi; Giovanna Zorzi; Andrea Legati; Giovanni Coppola; Pio D'Adamo; Nardo Nardocci; Barbara Garavaglia; Daniele Ghezzi
      Abstract: Publication date: Available online 3 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Federica Invernizzi, Giovanna Zorzi, Andrea Legati, Giovanni Coppola, Pio D'Adamo, Nardo Nardocci, Barbara Garavaglia, Daniele Ghezzi
      Heterozygous point mutations or deletions of the NKX2-1 gene cause benign hereditary chorea (BHC) or a various combinations of primary hypothyroidism, respiratory distress and neurological disorders. Deletions proximal to, but not encompassing, NKX2-1 have been described in few subjects with brain-lung-thyroid syndrome. We report on a three-generation Italian family, with 6 subjects presenting BHC and harboring a genomic deletion adjacent to NKX2-1 and including the gene MBIP, recently proposed to be relevant for the pathogenesis of brain-lung-thyroid syndrome. We observed a clear reduction of NKX2-1 transcript levels in fibroblasts from our patients compared to controls; this finding suggests that MBIP deletion affects NKX2-1 expression, mimicking haploinsufficiency caused by classical NKX2-1 related mutations.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.03.011
  • Phenotypic consequences of gene disruption by a balanced de novo
           translocation involving SLC6A1 and NAA15
    • Authors: Karolina Pesz; Victor Murcia Pienkowski; Agnieszka Pollak; Piotr Gasperowicz; Maciej Sykulski; Joanna Kosińska; Magdalena Kiszko; Bogusława Krzykwa; Magdalena Bartnik-Głaska; Beata Nowakowska; Małgorzata Rydzanicz; Maria Małgorzata Sasiadek; Rafał Płoski
      Abstract: Publication date: Available online 3 April 2018
      Source:European Journal of Medical Genetics
      Author(s): Karolina Pesz, Victor Murcia Pienkowski, Agnieszka Pollak, Piotr Gasperowicz, Maciej Sykulski, Joanna Kosińska, Magdalena Kiszko, Bogusława Krzykwa, Magdalena Bartnik-Głaska, Beata Nowakowska, Małgorzata Rydzanicz, Maria Małgorzata Sasiadek, Rafał Płoski
      Mapping of de novo balanced chromosomal translocations (BCTs) in patients with sporadic poorly characterized disease(s) is an unbiased method of finding candidate gene(s) responsible for the observed symptoms. We present a paediatric patient suffering from epilepsy, developmental delay (DD) and atrial septal defect IIº (ASD) requiring surgery. Karyotyping indicated an apparently balanced de novo reciprocal translocation 46,XX,t(3;4)(p25.3;q31.1), whereas aCGH did not reveal any copy number changes. Using shallow mate-pair whole genome sequencing and direct Sanger sequencing of breakpoint regions we found that translocation disrupted SLC6A1 and NAA15 genes. Our results confirm two previous reports indicating that loss of function of a single allele of SLC6A1 causes epilepsy. In addition, we extend existing evidence that disruption of NAA15 is associated with DD and with congenital heart defects.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.03.013
  • Novel mutations in the ciliopathy-associated gene CPLANE1 (C5orf42) cause
           OFD syndrome type VI rather than Joubert syndrome
    • Authors: Carine Bonnard; Mohammad Shboul; Seyed Hassan Tonekaboni; Alvin Yu Jin Ng; Sumanty Tohari; Kakaly Ghosh; Angeline Lai; Jiin Ying Lim; Ene Choo Tan; Louise Devisme; Morgane Stichelbout; Adila Alkindi; Nazreen Banu; Zafer Yüksel; Jamal Ghoumid; Nadia Elkhartoufi; Lucile Boutaud; Alessia Micalizzi; Maggie Siewyan Brett; Byrappa Venkatesh; Enza Maria Valente; Tania Attié-Bitach; Bruno Reversade; Ariana Kariminejad
      Abstract: Publication date: Available online 30 March 2018
      Source:European Journal of Medical Genetics
      Author(s): Carine Bonnard, Mohammad Shboul, Seyed Hassan Tonekaboni, Alvin Yu Jin Ng, Sumanty Tohari, Kakaly Ghosh, Angeline Lai, Jiin Ying Lim, Ene Choo Tan, Louise Devisme, Morgane Stichelbout, Adila Alkindi, Nazreen Banu, Zafer Yüksel, Jamal Ghoumid, Nadia Elkhartoufi, Lucile Boutaud, Alessia Micalizzi, Maggie Siewyan Brett, Byrappa Venkatesh, Enza Maria Valente, Tania Attié-Bitach, Bruno Reversade, Ariana Kariminejad
      Mutations in CPLANE1 (previously known as C5orf42) cause Oral-Facial-Digital Syndrome type VI (OFD6) as well as milder Joubert syndrome (JS) phenotypes. Seven new cases from five unrelated families diagnosed with pure OFD6 were systematically examined. Based on the clinical manifestations of these patients and those described in the literature, we revised the diagnostic features of OFD6 and include the seven most common characteristics: 1) molar tooth sign, 2) tongue hamartoma and/or lobulated tongue, 3) additional frenula, 4) mesoaxial polydactyly of hands, 5) preaxial polydactyly of feet, 6) syndactyly and/or bifid toe, and 7) hypothalamic hamartoma. By whole or targeted exome sequencing, we identified seven novel germline recessive mutations in CPLANE1, including missense, nonsense, frameshift and canonical splice site variants, all causing OFD6 in these patients. Since CPLANE1 is also mutated in JS patients, we examined whether a genotype-phenotype correlation could be established. We gathered and compared 46 biallelic CPLANE1 mutations reported in 32 JS and 26 OFD6 patients. Since no clear correlation between paired genotypes and clinical outcomes could be determined, we concluded that patient's genetic background and gene modifiers may modify the penetrance and expressivity of CPLANE1 causal alleles. To conclude, our study provides a comprehensive view of the phenotypic range, the genetic basis and genotype-phenotype association in OFD6 and JS. The updated phenotype scoring system together with the identification of new CPLANE1 mutations will help clinicians and geneticists reach a more accurate diagnosis for JS-related disorders.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.03.012
  • Neonatal hyperinsulinemic hypoglycemia in a patient with 9p deletion
    • Authors: Allan Bayat; Maria Kirchhoff; Camilla Gøbel Madsen; Sven Kreiborg
      Abstract: Publication date: Available online 27 March 2018
      Source:European Journal of Medical Genetics
      Author(s): Allan Bayat, Maria Kirchhoff, Camilla Gøbel Madsen, Sven Kreiborg
      We report the clinical and neuroradiological findings in a young boy harboring the 9p deletion syndrome including the novel findings of thalamic infarction and germinal matrix haemorrhage and neonatal hyperinsulinemic hypoglycemia. Both the hypoglycemic events and the ventriculomegaly found in this patient have previously only been reported in two patients, while the thalamic infarction and germinal matrix haemorrhage are novel features.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.03.009
  • Speech and language delay in a patient with WDR4 mutations
    • Authors: Xiang Chen; Yanyan Gao; Lin Yang; Bingbing Wu; Xinran Dong; Bo Liu; Yulan Lu; Wenhao Zhou; Huijun Wang
      Abstract: Publication date: Available online 26 March 2018
      Source:European Journal of Medical Genetics
      Author(s): Xiang Chen, Yanyan Gao, Lin Yang, Bingbing Wu, Xinran Dong, Bo Liu, Yulan Lu, Wenhao Zhou, Huijun Wang
      Primordial dwarfism (PD) is mainly characterized by growth deficiency with heterogeneous phenotypes. A group of genes are known to be associated with PD or PD-related syndrome. WD repeat domain 4 (WDR4) is recently reported to be responsible for PD. Here we report a 6-year-old boy from a non-consanguineous couple with motor and speech delay as well as intellectual disability. Whole exome sequencing (WES) identified a missense mutation (NM_033661.4:c.491A > C; p.(Asp164Ala)) and a small insertion (NM_033661.4:c.940dupC; p.(Leu314Profs*16)) of WDR4 in this patient. Two novel mutations confirmed by Sanger sequencing are from father and mother respectively according to a recessive inheritance pattern. Asp164Ala located in functional region is predicted to be deleterious by two kinds of algorithm. The small insertion causing a frameshift mutation leads to truncated protein. In this study, we present two novel WDR4 mutations responsible for PD in a 6-year-old patient, expanding the molecular and phenotype spectrum of WDR4-related PD.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.03.007
  • Long-term predictors for psychological outcome of pre-symptomatic testing
           for late-onset neurological diseases
    • Authors: Susana Lêdo; Ana Ramires; Ângela Leite; Maria Alzira Pimenta Dinis; Jorge Sequeiros
      Abstract: Publication date: Available online 23 March 2018
      Source:European Journal of Medical Genetics
      Author(s): Susana Lêdo, Ana Ramires, Ângela Leite, Maria Alzira Pimenta Dinis, Jorge Sequeiros
      This longitudinal study aimed at determining predicting variables for middle and long-term psychological disturbance due pre-symptomatic testing (PST) for two late-onset neurological diseases, Huntington disease (HD) and TTR (transthyretin protein) familial amyloid polyneuropathy (FAP) Val30Met (now classified as Val50Met). 196 clinical records of persons who performed PST at least three years ago and answered to the two stages of evaluation (before PST and least 3 years after disclosure of results) were analysed. For this purpose, regression analysis was performed, showing that the Positive Symptom Distress Index (PSDI), psychoticism, somatization and paranoid ideation dimensions assume predictive value in the middle and long-term impact for total anxiety and PSDI. The result of PST was not a relevant predictor. The application of an evaluation instrument of various psychopathological dimensions played a fundamental role in the detection of clinical situations that may arise several years later after PST. Attention should be paid to providing psychological support to persons at-risk who, at the pre-test phase, present some psychopathology indices before pursuing with genetic testing.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.03.010
  • Pericentromeric regions of homozygosity on the X chromosome: Another
           likely benign population variant
    • Authors: Elizabeth S. Barrie; Yu Li; Devon Lamb-Thrush; Sayaka Hashimoto; Theodora Matthews; Danielle Mouhlas; Robert Pyatt; Shalini C. Reshmi; Julie M. Gastier-Foster; Ruthann Pfau; Caroline Astbury
      Abstract: Publication date: Available online 20 March 2018
      Source:European Journal of Medical Genetics
      Author(s): Elizabeth S. Barrie, Yu Li, Devon Lamb-Thrush, Sayaka Hashimoto, Theodora Matthews, Danielle Mouhlas, Robert Pyatt, Shalini C. Reshmi, Julie M. Gastier-Foster, Ruthann Pfau, Caroline Astbury
      Purpose While chromosomal regions of homozygosity (ROH) may implicate genes in known recessive disorders, their correlation to disease pathogenicity remains unclear. ROH around the centromere of the X chromosome (pericentromeric, pROH) is regarded as benign, although this has not been empirically demonstrated. Methods We examined microarray results from 122 female individuals harboring ROH bordering the X centromere. Results Consecutive ROH was most frequently observed for regions Xp11.23 to Xp11.21 and Xq11.1 to Xq12, with an average total size of 16.5 Mb. X chromosome pROH was unlikely related to phenotype in 41% (50/122) of cases due to other explanations: likely pathogenic deletion/duplication (17%, 21/122), apparently unaffected female (7%, 8/122), other clinical explanation (7%, 9/122), or consanguinity (10%, 12/122). Of the remaining cases with pROH as the only finding, four genes were associated with recessive disorders that overlapped one or more clinical features reported in our probands (KDM5C, FGD1, ZC4H2, and LAS1L). X chromosome pROH observed in our cohort overlapped with previously reported regions. Conclusions pROH on the X chromosome are commonly observed in both affected individuals with alternate causes of disease as well as in unaffected individuals, suggesting that X chromosome pROH has no clinically significant effect on phenotype.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.02.008
  • 15q24.1 BP4-BP1 microdeletion unmasking paternally inherited functional
           polymorphisms combined with distal 15q24.2q24.3 duplication in a patient
           with epilepsy, psychomotor delay, overweight, ventricular arrhythmia
    • Authors: Minh-Tuan Huynh; Anne-Sophie Lambert; Lucie Tosca; François Petit; Christophe Philippe; Frédéric Parisot; Virginie Benoît; Agnès Linglart; Sophie Brisset; Cong Toai Tran; Gérard Tachdjian; Aline Receveur
      Abstract: Publication date: Available online 14 March 2018
      Source:European Journal of Medical Genetics
      Author(s): Minh-Tuan Huynh, Anne-Sophie Lambert, Lucie Tosca, François Petit, Christophe Philippe, Frédéric Parisot, Virginie Benoît, Agnès Linglart, Sophie Brisset, Cong Toai Tran, Gérard Tachdjian, Aline Receveur
      15q24 microdeletion and microduplication syndromes are genetic disorders caused by non-allelic homologous recombination between low-copy repeats (LCRs) in the 15q24 chromosome region. Individuals with 15q24 microdeletion and microduplication syndromes share a common 1.2 Mb critical interval, spanning from LCR15q24B to LCR15q24C. Patients with 15q24 microdeletion syndrome exhibit distinct dysmorphic features, microcephaly, variable developmental delay, multiples congenital anomalies while individuals with reciprocal 15q24 microduplication syndrome show mild developmental delay, facial dysmorphism associated with skeletal and genital abnormalities. We report the first case of a 10 year-old girl presenting mild developmental delay, psychomotor retardation, epilepsy, ventricular arrhythmia, overweight and idiopathic central precocious puberty. 180K array-CGH analysis identified a 1.38 Mb heterozygous interstitial 15q24.1 BP4-BP1 microdeletion including HCN4 combined with a concomitant 2.6 Mb heterozygous distal 15q24.2q24.3 microduplication. FISH analysis showed that both deletion and duplication occurred de novo in the proband. Of note, both copy number imbalances did not involve the 1.2 Mb minimal deletion/duplication critical interval of the 15q24.1q24.2 chromosome region (74.3–75.5 Mb). Sequencing of candidate genes for epilepsy and obesity showed that the proband was hemizygous for paternal A-at risk allele of BBS4 rs7178130 and NPTN rs7171755 predisposing to obesity, epilepsy and intellectual deficits. Our study highlights the complex interaction of functional polymorphisms and/or genetic variants leading to variable clinical manifestations in patients with submicroscopic chromosomal aberrations.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.03.005
  • Clinic, pathogenic mechanisms and drug testing of two inherited
           thrombocytopenias, ANKRD26- and MYH9-related diseases
    • Authors: Alessandra Balduini; Hana Raslova; Christian A. Di Buduo; Alessandro Donada; Matthias Ballmaier; Manuela Germeshausen; Carlo L. Balduini
      Abstract: Publication date: Available online 13 March 2018
      Source:European Journal of Medical Genetics
      Author(s): Alessandra Balduini, Hana Raslova, Christian A. Di Buduo, Alessandro Donada, Matthias Ballmaier, Manuela Germeshausen, Carlo L. Balduini
      Inherited thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by low platelet count resulting in impaired hemostasis. Patients can have spontaneous hemorrhages and/or excessive bleedings provoked by hemostatic challenges as trauma or surgery. To date, ITs encompass 32 different rare monogenic disorders caused by mutations of 30 genes. This review will focus on the major discoveries that have been made in the last years on the diagnosis, treatment and molecular mechanisms of ANKRD26-Related Thrombocytopenia and MYH9-Related Diseases. Furthermore, we will discuss the use a Thrombopoietin mimetic as a novel approach to treat the thrombocytopenia in these patients. We will propose the use of a new 3D bone marrow model to study the mechanisms of action of these drugs and to test their efficacy and safety in patients. The overall purpose of this review is to point out that important progresses have been made in understanding the pathogenesis of ANKRD26-Related Thrombocytopenia and MYH9-Related Diseases and new therapeutic approaches have been proposed and tested. Future advancement in this research will rely in the development of more physiological models to study the regulation of human platelet biogenesis, disease mechanisms and specific pharmacologic targets.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.01.014
  • Potential role of gender specific effect of leptin receptor deficiency in
           an extended consanguineous family with severe early-onset obesity
    • Authors: Mohammad Reza Dehghani; Mohammad Yahya Vahidi Mehrjardi; Nafi Dilaver; Masoud Tajamolian; Samaneh Enayati; Pirooz Ebrahimi; Mahsa M. Amoli; Sadaf Farooqi; Reza Maroofian
      Abstract: Publication date: Available online 12 March 2018
      Source:European Journal of Medical Genetics
      Author(s): Mohammad Reza Dehghani, Mohammad Yahya Vahidi Mehrjardi, Nafi Dilaver, Masoud Tajamolian, Samaneh Enayati, Pirooz Ebrahimi, Mahsa M. Amoli, Sadaf Farooqi, Reza Maroofian
      Congenital Leptin receptor (LEPR) deficiency is a rare genetic cause of early-onset morbid obesity characterised by severe early onset obesity, major hyperphagia, hypogonadotropic hypogonadism and immune and neuroendocrine/metabolic dysfunction. We identified a homozygous loss-of-function mutation, NM_002303.5:c.464 T > G; p.(Tyr155*), in the LEPR in an extended consanguineous family with multiple individuals affected by early-onset severe obesity and hyperphagia. Interestingly, the LEPR-deficient adult females have extremely high body mass index (BMI) with hypogonadal infertility, the BMI of the affected males began to decline around the onset of puberty (13–15 years) with fertility being preserved. These findings lead to the speculation that LEPR deficiency may have a gender-specific effect on the regulation of body weight. In order to elucidate gender-specific effects of LEPR deficiency on reproduction further investigations are needed. The limitations of this study are that our conclusion is based on observations of two males and two females. Further LEPR deficient males and females are required for comparison in order to support this finding more confidently.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.03.006
  • Pitfalls in molecular diagnosis of Friedreich ataxia
    • Authors: Giulia Barcia; Myriam Rachid; Maryse Magen; Zahra Assouline; Michel Koenig; Benoit Funalot; Christine Barnerias; Agnès Rötig; Arnold Munnich; Jean-Paul Bonnefont; Julie Steffann
      Abstract: Publication date: Available online 9 March 2018
      Source:European Journal of Medical Genetics
      Author(s): Giulia Barcia, Myriam Rachid, Maryse Magen, Zahra Assouline, Michel Koenig, Benoit Funalot, Christine Barnerias, Agnès Rötig, Arnold Munnich, Jean-Paul Bonnefont, Julie Steffann
      Freidreich ataxia (FRDA) is the most common hereditary ataxia, nearly 98% of patients harbouring homozygous GAA expansions in intron 1 of the FXN gene (NM_000144.4). The remaining patients are compound heterozygous for an expansion and a point mutation or an exonic deletion. Molecular screening for FXN expansion is therefore focused on (GAA)n expansion analysis, commonly performed by triplet repeat primed PCR (PT-PCR). We report on an initial pitfall in the molecular characterization of a 15 year-old girl with Freidreich ataxia (FRDA) who carried a rare deletion in intron 1 of the FXN gene. Due to this deletion TP-PCR failed to amplify the GAA expansion. This exceptional configuration induced misinterpretation of the molecular defect in this patient, who was first reported as having no FXN expansion. NGS analysis of a panel of 212 genes involved in nuclear mitochondrial disorders further revealed an intragenic deletion encompassing exons 4–5 of the FXN gene. Modified TP-PCR analysis confirmed the presence of a classical (GAA)n expansion located in trans. This case points out the possible pitfalls in molecular diagnosis of FRDA in affected patients and their relatives: detection of the FXN expansion may be impaired by several non-pathological or pathological variants around the FXN (GAA)n repeat. We propose a new molecular strategy to accurately detect expansion by TP-PCR in FRDA patients.

      PubDate: 2018-04-18T09:25:50Z
      DOI: 10.1016/j.ejmg.2018.03.004
  • 2 new cases of pontocerebellar hypoplasia type 10 identified by whole
           exome sequencing in a Turkish family
    • Authors: Mohamed Wafik; John Taylor; Tracy Lester; Richard J. Gibbons; Deborah J. Shears
      Abstract: Publication date: Available online 4 January 2018
      Source:European Journal of Medical Genetics
      Author(s): Mohamed Wafik, John Taylor, Tracy Lester, Richard J. Gibbons, Deborah J. Shears
      Pontocerebellar hypoplasia type 10 (PCH10) is a progressive autosomal recessive neurodegenerative disorder that has been recently described in association with cleavage and polyadenylation factor I subunit 1 (CLP1) mutations. To date, all reported cases have the same homozygous missense mutation in the CLP1 gene suggesting a founder mutation. CLP1 is an RNA kinase involved in tRNA splicing and maturation. There is evidence that the mutation is associated with functionally impaired kinase activity and subsequent defective tRNA processing. Through whole exome sequencing, we identified the same mutation in an extended family of Turkish origin. Both children presented with severe psychomotor delay, progressive microcephaly, and constipation. However, intrafamilial phenotypic variability is suggested due to the variability in their brain abnormalities and clinical features.

      PubDate: 2018-01-10T14:41:38Z
      DOI: 10.1016/j.ejmg.2018.01.002
  • Further delineation of the SOX18-related Hypotrichosis, Lymphedema,
           Telangiectasia syndrome (HTLS)
    • Authors: Irene Valenzuela; Paula Fernández-Alvarez; Alberto Plaja; Gema Ariceta; Anna Sabaté-Rotés; Elena García-Arumí; Teresa Vendrell; Eduardo Tizzano
      Abstract: Publication date: Available online 4 January 2018
      Source:European Journal of Medical Genetics
      Author(s): Irene Valenzuela, Paula Fernández-Alvarez, Alberto Plaja, Gema Ariceta, Anna Sabaté-Rotés, Elena García-Arumí, Teresa Vendrell, Eduardo Tizzano
      The transcription factor SOX18 has been shown to play a role in the development of hair, blood and lymphatic vessels. Mutations in SOX18 result in hereditary lymphedema, with the unique clinical association of hypotrichosis and telangiectasia (HLTS). Some patients present with additional disease features which may be explained by the location of SOX18 mutation. We report a patient with hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) confirmed by detection of a novel mutation in the SOX18 gene. Few cases of HTLS have been reported in the literature. We reviewed all cases reported to date to delineate the clinical manifestations that allow us to prompt diagnosis of this syndrome for appropriate management and genetic counseling.

      PubDate: 2018-01-10T14:41:38Z
      DOI: 10.1016/j.ejmg.2018.01.001
  • PDD-NOS, psychotic features and executive function deficits in a boy with
           proximal 22q11.2 microduplication: Evolution of the psychiatric symptom
           profile from childhood to adolescence
    • Authors: L. Woestelandt; A. Novo; A. Philippe; N. Guyaux; M. Rio; S. Romano; L. Robel
      Abstract: Publication date: Available online 4 January 2018
      Source:European Journal of Medical Genetics
      Author(s): L. Woestelandt, A. Novo, A. Philippe, N. Guyaux, M. Rio, S. Romano, L. Robel
      22q11.2 microduplication (22q11.2DupS) is associated with a broad spectrum of phenotypes, including normality. Psychiatric disorders are described in 13% of these patients, including Attention Deficit and Hyperactivity Disorder (ADHD), Intellectual Deficiency (ID), and Autism Spectrum Disorder (ASD), but not schizophrenia. We report changes in the psychiatric symptom profile in the course of development of a young boy with a 22q11.2DupS syndrome, from early childhood to adolescence. The boy's psychiatric presentation was characterized by features of Pervasive Developmental Disorder (PDD), with ADHD in early childhood, a single psychotic episode in mid-infancy, and executive impairment in adolescence. We discuss the importance of an in-depth assessment of cognitive functions in children with22q11.2DupS throughout their development.

      PubDate: 2018-01-10T14:41:38Z
      DOI: 10.1016/j.ejmg.2018.01.003
  • Identification of a novel CTR9 germline mutation in a family with Wilms
    • Authors: António G. Martins; Ana T. Pinto; Rita Domingues; Branca M. Cavaco
      Abstract: Publication date: Available online 29 December 2017
      Source:European Journal of Medical Genetics
      Author(s): António G. Martins, Ana T. Pinto, Rita Domingues, Branca M. Cavaco
      Germline mutations in the WT1 gene have been identified in some families with Wilms tumor. Recently, the CTR9 gene was found to be mutated in three families with Wilms tumor, thus representing a novel predisposition gene for this disease. We identified a family with a history of Wilms tumor characterized by three affected siblings, one of them presenting an aggressive bilateral tumor. Here we investigated the involvement of WT1 and CTR9 genes in this family with Wilms tumor. The involvement of WT1 was first evaluated by Next generation sequencing in leukocytes DNA from one affected family member. Subsequently, the CTR9 gene was analyzed by Sanger sequencing in DNA and RNA from patients’ leukocytes and/or tumor. No mutations were detected in WT1. However, we identified a novel CTR9 germline variant, located in a consensus splice acceptor site, which was found to segregate with Wilms tumor in this family. We found that this variant leads to the skipping of the entire exon 9 in the mRNA, which is predicted to encode a truncated CTR9 protein, strongly suggesting that it is pathogenic. Additionally, we also detected loss of heterozygosity in the index case tumor, which is consistent with CTR9 being a tumor suppressor gene, confirming also its contribution to familial Wilms tumor etiology. The identification of a novel CTR9 germline mutation will improve the present knowledge on the molecular basis of familial Wilms tumor. Importantly, it will help in the genetic counselling and may also lead to earlier diagnosis in other family members and future generations.

      PubDate: 2018-01-04T12:29:02Z
      DOI: 10.1016/j.ejmg.2017.12.010
  • Distal deletion at 22q11.2 as differential diagnosis in Craniofacial
           Microsomia: Case report and literature review
    • Authors: Samira Spineli-Silva; Luciana M. Bispo; Vera L. Gil-da-Silva-Lopes; Társis P. Vieira
      Abstract: Publication date: Available online 27 December 2017
      Source:European Journal of Medical Genetics
      Author(s): Samira Spineli-Silva, Luciana M. Bispo, Vera L. Gil-da-Silva-Lopes, Társis P. Vieira
      Craniofacial Microsomia (CFM) also known as Oculo-auriculo-vertebral Spectrum (OAVS) or Goldenhar Syndrome, presents wide phenotypic and etiological heterogeneity. It affects mainly the structures originated from the first and second pharyngeal arches. In addition, other major anomalies may also be found, including congenital heart diseases. In this study, we report a patient with distal deletion in the 22q11.2 region and a phenotype which resembles CFM. The proband is a girl, who presented bilateral preauricular tags, left auditory canal stenosis, malar hypoplasia, cleft lip and palate, mild asymmetry of soft tissue in face, congenital heart disease, intestinal atresia, annular pancreas and hydronephrosis. The genomic imbalances investigation by Multiplex Ligation-dependent Probe Amplification (MLPA) and Chromosomal Microarray Analysis (CMA) revealed a distal deletion of 1,048 kb at 22q11.2 encompassing the region from Low Copy Repeats (LCRs) D to E. We did review of the literature and genotype-phenotype correlation. This is the sixth case of distal 22q11.2 deletion resembling CFM and the second encompassing the region between LCRs D to E. All cases share some phenotypic signs, such as preauricular tags, facial asymmetry, cleft lip and palate, and congenital heart diseases. Candidate genes in this region have been studied by having an important role in pharyngeal arches developmental and in congenital heart diseases, such as HIC2, YPEL1and MAPK1/ERK2. This case corroborates the phenotypic similarity between 22q11.2 distal deletion and CFM/OAVS. It also contributes to genotype-phenotype correlation and reinforces that candidate genes for CFM, in the 22q11.2 region, might be located between LCRs D and E.

      PubDate: 2018-01-04T12:29:02Z
      DOI: 10.1016/j.ejmg.2017.12.013
  • Chromatin modifications of hTERT gene in hTERT-immortalized human
           mesenchymal stem cells upon exposure to radiation
    • Authors: Nedime Serakinci; Pınar Mega Tiber; Oya Orun
      Abstract: Publication date: Available online 27 December 2017
      Source:European Journal of Medical Genetics
      Author(s): Nedime Serakinci, Pınar Mega Tiber, Oya Orun
      Regulation of telomerase activity is thought to participate in the cellular response to ionizing radiation. Epigenetic mechanisms play a role in this regulation, as well as other mechanisms such as transcription, phosphorylation, etc. Here, we investigated chromatin modifications in telomerase promoter upon exposure to ionizing radiation in human mesenchymal stem cells (hMSC) and telomerase-immortalized hMSCs (hMSC-telo1) together with a hMSC-telo1 cell line in which TRF2 expression was partially repressed (siTRF2 hMSC-telo1). Histone methylations and acetylations were compared in all cell lines after exposure to various doses of ionizing radiation (0.1, 1, 2.5 and 15 Gy) using chromatin immunoprecipitation assay. hTERT gene was shown to be quickly regulated through H3, H4 acetylations, as well as with H3K4 and H3K9 methylations, following radiation exposure, although the kinetic of hMSC-telo1 cells were different, indicative of the higher radioresistivity of these cells. To the author's surprise, there was an upregulation of endogenous telomerase activity in the hMSC-telo1 cells, even though the cells had already expressed high levels of ectopic hTERT. Our results show that telomerase regulation is one of the primary actions in response to damage and epigenetic factors play a major role in this regulation. Our results also suggested that partial silencing of TRF2 enhances the radiosensitivity of these cells, and endogenous telomerase is upregulated upon radiation, even under ectopic expression of hTERT in these cells.

      PubDate: 2018-01-04T12:29:02Z
      DOI: 10.1016/j.ejmg.2017.12.014
  • The TBR1-related autistic-spectrum-disorder phenotype and its clinical
    • Authors: J.H. McDermott; D.D.D. Study; J. Clayton-Smith; T.A. Briggs
      Abstract: Publication date: Available online 27 December 2017
      Source:European Journal of Medical Genetics
      Author(s): J.H. McDermott, D.D.D. Study, J. Clayton-Smith, T.A. Briggs
      A diverse range of genetic aberrations can lead to Autistic Spectrum Disorder (ASD) and many of these have been identified via Next Generation Sequencing (NGS) as part of large scale consortium studies. ASD is a phenotypically variable disorder and detailed clinical descriptions are essential to appreciate genotype-phenotype relationships. In this report, we provide a comprehensive clinical description of a child with ASD in whom a TBR1 variant was identified. We review this case in the context of the current TBR1 literature and highlight the variable spectrum of disease associated with this gene. The phenotypic information outlined within the literature is incomplete, exemplifying the limitations of massively-parallel sequencing studies with regards to clinical annotation. We suggest that future reporting of ASD variants should include standardised phenotypic descriptions. This would develop a more thorough understanding of genotype-phenotype relationship, so allowing us to better counsel and support our patients.

      PubDate: 2017-12-27T11:25:14Z
      DOI: 10.1016/j.ejmg.2017.12.009
  • Telangiectasias in Ataxia Telangiectasia: Clinical significance, role of
           ATM deficiency and potential pathophysiological mechanisms
    • Authors: M.H.D. Schoenaker; N.J.H. Van Os; M. Van der Flier; M. Van Deuren; M.M. Seyger; A.M.R. Taylor; C.M.R. Weemaes; M.A.A.P. Willemsen
      Abstract: Publication date: Available online 26 December 2017
      Source:European Journal of Medical Genetics
      Author(s): M.H.D. Schoenaker, N.J.H. Van Os, M. Van der Flier, M. Van Deuren, M.M. Seyger, A.M.R. Taylor, C.M.R. Weemaes, M.A.A.P. Willemsen
      Ataxia Telangiectasia (AT) is named after the two key clinical features that characterize its classical phenotype, namely a progressive cerebellar gait disorder (ataxia) and vascular anomalies (telangiectasias) visible in the conjunctivae and skin. AT is an autosomal recessively inherited disorder, caused by mutations in the ATM gene that encodes the ATM protein. While the ataxia is subject of many publications, the telangiectasias are under emphasised. We here describe the observation that the absence or presence of ATM protein and the level of residual ATM kinase activity are related to the occurrence of telangiectasias and describe the clinical consequences of these vascular malformations. Finally, we hypothesize that ATM dysfunction dysregulates angiogenesis.

      PubDate: 2017-12-27T11:25:14Z
      DOI: 10.1016/j.ejmg.2017.12.012
  • Expanding the FANCO/RAD51C associated phenotype: Cleft lip and palate and
           lobar holoprosencephaly, two rare findings in Fanconi anemia
    • Authors: Adeline Jacquinet; Lindsay Brown; Jessica Sawkins; Pengfei Liu; Denise Pugash; Margot I. Van Allen; Millan S. Patel
      Abstract: Publication date: Available online 24 December 2017
      Source:European Journal of Medical Genetics
      Author(s): Adeline Jacquinet, Lindsay Brown, Jessica Sawkins, Pengfei Liu, Denise Pugash, Margot I. Van Allen, Millan S. Patel
      Fanconi anemia is a rare chromosome instability disorder with a highly variable phenotype. In the antenatal and neonatal periods, the diagnosis is usually suggested by the presence of typical congenital abnormalities such as intrauterine growth retardation, microcephaly and radial ray defects. We report a newborn female with a prenatal diagnosis of Fanconi anemia, complementation group O (FANCO). Antenatal ultrasounds identified symmetrical intrauterine growth retardation, complex heart defect as well as brain anomalies, overlapping fingers and cleft lip and palate. Imperforate anus was detected after birth. Compound heterozygous RAD51C variants c. [571+5G > A]; [c.935G > A] were detected by prenatal whole exome sequencing and cellular hypersensitivity to DNA interstrand crosslinking agents (DEB, MMC) was confirmed after birth. With only one previously described homozygous RAD51C variant to date, our findings expand the phenotypic spectrum of FANCO and suggest it should be part of the antenatal differential diagnosis for trisomy 13 and 18, due to the presence of atypical findings such as cleft lip and palate, holoprosencephaly, growth restriction and overlapping fingers.

      PubDate: 2017-12-24T10:52:11Z
      DOI: 10.1016/j.ejmg.2017.12.011
  • Refinement of the critical 7p22.1 deletion region: Haploinsufficiency of
           ACTB is the cause of the 7p22.1 microdeletion-related developmental
    • Authors: Orazio Palumbo; Maria Accadia; Pietro Palumbo; Maria Pia Leone; Antonio Scorrano; Teresa Palladino; Raffaella Stallone; Maria Clara Bonaglia; Massimo Carella
      Abstract: Publication date: Available online 20 December 2017
      Source:European Journal of Medical Genetics
      Author(s): Orazio Palumbo, Maria Accadia, Pietro Palumbo, Maria Pia Leone, Antonio Scorrano, Teresa Palladino, Raffaella Stallone, Maria Clara Bonaglia, Massimo Carella
      Non-recurrent microdeletion (≤2 Mb in size) in 7p22.1 is a rarely described cytogenetic aberration, only recently reported in patients with developmental delay/intellectual disability, short stature and microcephaly. The size of the deletions ranged from 0.37 to 1.5 Mb, and reported genotype-phenotype correlations identified a minimum deleted region of 0.37 Mb involving the FBLX18, ACTB, FSCN1, RNF216 and ZNF815P genes. The authors suggested that deletion of ACTB, which encodes β-actin, an essential component of the cytoskeleton, could be responsible for the clinical features observed in the patients with a 7p22.1 microdeletion. Here, we describe a 23-month-old child displaying developmental delay, short stature, microcephaly and distinctive facial features. Chromosomal microarray analysis performed using high-resolution SNP-array platform revealed a de novo interstitial 60 Kb microdeletion in the 7p22.1 region (from 5,509,127 bp to 5,569,096 bp, hg19) encompassing only two genes: FBXL18 and ACTB. To the best of our knowledge, this is the smallest deletion at 7p22.1 to date reported in medical literature (Pubmed). Combining our data with phenotypic and genotypic data of cases from literature, we were able to narrow the minimal critical region, which contained only two genes, i.e., FBXL18 and ACTB. Our finding is useful to perform a more accurate genotype-phenotype correlation and strongly strengthen the hypothesis that haploinsufficiency of ACTB is the main cause of the clinical phenotype observed in the patients with 7p22.1 microdeletions, facilitating genetic diagnosis and counseling.

      PubDate: 2017-12-24T10:52:11Z
      DOI: 10.1016/j.ejmg.2017.12.008
  • Developmental and cytogenetic assessments of preimplantation embryos
           derived from in-vivo or in-vitro matured human oocytes
    • Authors: Farzaneh Fesahat; Mohammad Hasan Sheikhha; Seyed Mehdi Kalantar; Nasim Tabibnejad; Razieh Dehghani Firouzabadi; Hojjatollah Saeedi; Mohammad Ali Khalili
      Abstract: Publication date: Available online 8 December 2017
      Source:European Journal of Medical Genetics
      Author(s): Farzaneh Fesahat, Seyed Mehdi Kalantar, Mohammad Hasan Sheikhha, Hojjatollah Saeedi, Fatemeh Montazeri, Razieh Dehghani Firouzabadi, Mohammad Ali Khalili
      Aneuploidy is of great relevance to embryo selection, as it represents one of the important causes of implantation failure. Furthermore, immature oocytes, retrieved during gonadotrophin-stimulated IVF cycles, are generally discarded in clinics; whereas, there was no detectable comprehensive evidence on higher rates of aneuploidy based on maturity status on the day of oocyte retrieval. As well, the correlation between embryo morphology on aneuploidy remains unclear. The aim was to evaluate the developmental and genetic integrity of human preimplantation embryos from rescue in-vitro matured MII stage oocytes as well as in vivo matured oocytes. 541 rescue in-vitro matured oocytes as case as well as 659 in-vivo matured oocytes as control were used for the developmental assay. Finally, 121 cleaved embryos with good quality were analyzed by FISH technique for the detection of chromosomes X, Y, 13, 15, 16, 18, 21 and 22. The fertilization rates were 61.62% and 61.76% in case and control groups, respectively. Also, embryo formation rates of 89.1% vs. 92.2% were recorded for case and control groups, respectively. Good quality embryos on day 3 were 62.54% in case and 68.36% in control groups. There were insignificant differences in fertilization, embryo formation and quality between the groups. Total abnormality in 35 of the 60 embryos was 58.5% in case and 62.3% in control (p < 0.05). There were significant differences between aneuploidy rates of embryos using only sex chromosome preimplantation genetic screening (PGS) and sex chromosome in combination with autosomal chromosomes PGS in case (58.5% vs 28.3%, p = 0.000) and control groups (62.3% vs 21.3%; p = 0.000). The results demonstrated that a high proportion of good quality embryos were aneuploid in both patient groups with no obvious increase in aneuploidies as a result of rescue IVM application. Furthermore, the morphological characteristics of embryos do not completely consistent with chromosomal content. Despite the Rescue IVM is currently not a routine procedure in association with IVF, our finding suggested a viable option for young infertile women facing cancellation of their IVF treatment due to ovarian over-response or resistance factors as well as patients with low functional ovarian reserve considering good quality of embryos from rescue IVM-MII oocytes.

      PubDate: 2017-12-12T06:57:28Z
      DOI: 10.1016/j.repbio.2017.11.002
  • Copy number variants in people with autism spectrum disorders and
           co-morbid psychosis
    • Authors: Felicity Larson; John Arrand Digby Tantam Peter Jones Anthony Holland
      Abstract: Publication date: Available online 7 December 2017
      Source:European Journal of Medical Genetics
      Author(s): Felicity V. Larson, John R. Arrand, Digby Tantam, Peter B. Jones, Anthony J. Holland
      The genetic association between autism spectrum disorder (ASD) and psychotic disorders such as schizophrenia is complicated and mirrors the clinical overlap between these conditions to some degree. However, no studies to date have examined the genetics of individuals dually diagnosed with both ASD and psychosis. In this study, we present findings of copy number variants (CNVs) from a study of 116 well-characterised individuals with this dual diagnosis. DNA was extracted and arrayed using the Affymetrix CytoScan HD 2.8M array or the Affymetrix Cytogenetics arrays and compared with existing samples from the Database of Genomic Variants and the Simons Simplex Collection of CNVs from individuals with ASD and their families. Twenty-seven novel CNVs ≥20k base pairs were identified in the sample, most occurring in only a single individual, although two were found in two female participants. Forty-nine rare CNVs (<1.5% rate in general population) were also found at significantly higher frequencies than expected. The findings may provide evidence for areas of further study in the understanding of the development of both ASD and psychosis due to the number of affected genetic regions that have not previously been linked to these conditions.

      PubDate: 2017-12-12T06:57:28Z
  • Surprisingly good outcome in antenatal diagnosis of severe hydrocephalus
           related to CCDC88C deficiency
    • Authors: Mathew Wallis; Alessandra Baumer Wiam Smaili Imane Cherkaoui Jaouad Abdelaziz
      Abstract: Publication date: Available online 7 December 2017
      Source:European Journal of Medical Genetics
      Author(s): Mathew Wallis, Alessandra Baumer, Wiam Smaili, Imane Cherkaoui Jaouad, Abdelaziz Sefiani, Erica Jacobson, Lucy Bowyer, David Mowat, Anita Rauch
      Non-syndromic congenital hydrocephalus is aetiologically diverse and while a genetic cause is frequently suspected, it often cannot be confirmed. The most common genetic cause is L1CAM-related X-linked hydrocephalus and that explains only 5%–10% of all male cases. This underlines a current limitation in our understanding of the genetic burden of non-syndromic congenital hydrocephalus, especially for those cases with likely autosomal recessive inheritance. Additionally, the prognosis for most cases of severe congenital hydrocephalus is poor, with most of the surviving infants displaying significant intellectual impairment despite surgical intervention. It is for this reason that couples with an antenatal diagnosis of severe hydrocephalus are given the option, and may opt, for termination of the pregnancy. We present two families with CCDC88C-related recessive congenital hydrocephalus with children who had severe hydrocephalus. Those individuals who were shunted within the first few weeks of life, who did not require multiple surgical revisions, and who had a more distal truncating variant of the CCDC88C gene met their early childhood developmental milestones in some cases. This suggests that children with CCDC88C-related autosomal recessive hydrocephalus can have normal developmental outcomes under certain circumstances. We recommend CCDC88C analysis in cases of severe non-syndromic congenital hydrocephalus, especially when aqueduct stenosis with or without a medial diverticulum is seen, in order to aid prognosis discussion.

      PubDate: 2017-12-12T06:57:28Z
  • Pakistan Genetic Mutation Database (PGMD); A centralized Pakistani mutome
           data source
    • Authors: Iqbal Qasim; Bilal Ahmad Muzammil Ahmad Khan Niamatullah Khan Noor
      Abstract: Publication date: Available online 7 December 2017
      Source:European Journal of Medical Genetics
      Author(s): Iqbal Qasim, Bilal Ahmad, Muzammil Ahmad Khan, Niamatullah Khan, Noor Muhammad, Sulman Basit, Saadullah Khan
      The development and advancement of next generation sequencing have not only sped up the process of identifying rare variants, but have also enabled scientists to explore all variants in a single individual. The Pakistani population has a high ratio of first degree consanguinity, which is why it is a rich source for various kinds of genetic disorders. Due to the heterogeneous composition of Pakistani population, the likelihood of genetic heterogeneity for each disorder is high. Therefore, the compilation and organization of such vast genetic data is necessary to facilitate access for analysis and interpretation to researchers and medical geneticists. The increased research on Pakistani ethnic families for disease gene identification has revealed many mutations, which has led us to develop a Pakistani mutome database entitled “Pakistan Genetic Mutation Database (PGMD)”. In PGMD, the medico-genetic information about diseases are mainly compiled into Syndromic and Non-syndromic disorders. It is a public database, which can be freely accessed from At present, we have registered more than 1000 mutations, reported in about 130 different kinds of genetic disorders. Practically, PGMD will assist researchers, clinicians, and geneticists in genetic counseling and screening of population-specific mutations, which will also aid in personalized healthcare.

      PubDate: 2017-12-12T06:57:28Z
  • Redefining the phenotypic spectrum of de novo heterozygous CDK13 variants:
           Three patients without cardiac defects
    • Authors: Tomoko Uehara; Toshiki Takenouchi; Rika Kosaki; Kenji Kurosawa; Seiji Mizuno; Kenjiro Kosaki
      Abstract: Publication date: Available online 6 December 2017
      Source:European Journal of Medical Genetics
      Author(s): Tomoko Uehara, Toshiki Takenouchi, Rika Kosaki, Kenji Kurosawa, Seiji Mizuno, Kenjiro Kosaki
      Recently, 7 patients with de novo constitutional non-synonymous mutations in the CDK13 gene were ascertained through a trio exome analysis of a large cohort of 610 patients with congenital cardiac diseases. Despite another report describing 9 additional patients, the clinical spectrum of this condition has yet to be defined. Herein, we report 3 patients with heterozygous constitutional CDK13 mutations, who were ascertained through exome analysis of children with intellectual disability and minor anomalies, who lacked cardiac anomalies. Two patients had a c.2149G > A, p.Gly717Arg mutation, and one had a c.2525A > G, p. Asn842Ser mutation. A review of the previously described patients and those described herein has enabled the following points to be clarified. First, congenital heart diseases are not an essential feature (13/19). Second, nasal features may help syndromic recognition (14/16). Third, widely spaced and peg-shaped teeth may represent a previously unappreciated diagnostic clue for this newly identified syndrome. Here, we show that p.Gly717Arg represents a hotspot in addition to p.Asn842Ser. We suggest that this CDK13-related disorder may represent a clinically recognizable syndrome.

      PubDate: 2017-12-12T06:57:28Z
      DOI: 10.1016/j.ejmg.2017.12.004
  • A novel NR2F2 loss-of-function mutation predisposes to congenital heart
    • Authors: Xiao-Hui Qiao; Qian Wang Juan Wang Xing-Yuan Liu Ying-Jia Ri-Tai
      Abstract: Publication date: Available online 6 December 2017
      Source:European Journal of Medical Genetics
      Author(s): Xiao-Hui Qiao, Qian Wang, Juan Wang, Xing-Yuan Liu, Ying-Jia Xu, Ri-Tai Huang, Song Xue, Yan-Jie Li, Min Zhang, Xin-Kai Qu, Ruo-Gu Li, Xing-Biao Qiu, Yi-Qing Yang
      Congenital heart defect (CHD) is the most common type of birth defect in humans and a leading cause of infant morbidity and mortality. Previous studies have demonstrated that genetic defects play a pivotal role in the pathogenesis of CHD. However, the genetic basis of CHD remains poorly understood due to substantial genetic heterogeneity. In this study, the coding exons and splicing boundaries of the NR2F2 gene, which encodes a pleiotropic transcription factor required for normal cardiovascular development, were sequenced in 168 unrelated patients with CHD, and a novel mutation (c.247G > T, equivalent to p.G83X) was detected in a patient with double outlet right ventricle as well as ventricular septal defect. Genetic scanning of the mutation carrier's relatives available showed that the mutation was present in all affected family members but absent in unaffected family members. Analysis of the index patient's pedigree displayed that the mutation co-segregated with CHD, which was transmitted as an autosomal dominant trait with complete penetrance. The nonsense mutation was absent in 230 unrelated, ethnically-matched healthy individuals used as controls. Functional deciphers by using a dual-luciferase reporter assay system revealed that the mutant NR2F2 protein had no transcriptional activity as compared with its wild-type counterpart. Furthermore, the mutation abrogated the synergistic transcriptional activation between NR2F2 and GATA4, another core cardiac transcription factor associated with CHD. This study firstly associates NR2F2 loss-of-function mutation with an increased susceptibility to double outlet right ventricle in humans, which provides further significant insight into the molecular mechanisms underpinning CHD, suggesting potential implications for genetic counseling of CHD families and personalized treatment of CHD patients.

      PubDate: 2017-12-12T06:57:28Z
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