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  • 1.
    Arzoo, Pakeeza Shaiq
    et al.
    Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Klar, Joakim
    Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Bergendal, Birgitta
    National Oral Disability Centre, The Institute for Postgraduate Dental Education, Jönköping, Sweden.
    Norderyd, Johanna
    Jönköping University, School of Health and Welfare, HHJ. CHILD.
    Dahl, Niklas
    Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    WNT10A mutations account for ¼ of population-based isolated oligodontia and show phenotypic correlations2014In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 164, no 2, p. 353-359Article in journal (Refereed)
    Abstract [en]

    A large proportion (>50%) of patients with isolated oligodontia were recently reported with WNT10A mutations. We have analyzed a population-based cohort of 102 individuals diagnosed with non-syndromic oligodontia and a mean of 8.2 missing teeth. The cohort included 94 families and screening of WNT10A identified that 26 probands (27.7%) had at least one WNT10A variant. When we included the MSX1, PAX9, AXIN2, EDA, EDAR, and EDARADD genes, 38.3% of probands were positive for a mutation. Biallelic WNT10A mutations were strongly associated with a larger number of missing teeth (11.09) when compared to both monoallelic WNT10 mutations (6.82) and the group without mutations in WNT10A, MSX1, PAX9, AXIN2, EDA, EDAR, or EDARADD (7.77). Genotype–phenotype analysis of individuals with WNT10A mutations showed that premolars were the most common missing teeth. Furthermore, biallelic WNT10A mutations were associated with absence of maxillary and mandibular molars as well as mandibular central incisors. Maxillary central incisors were always present. Thus, our study indicates that WNT10A mutations are associated with both the type and numbers of missing teeth. Furthermore, we show that this population-based cohort of isolated oligodontia had a considerably lower frequency of mutated WNT10A alleles and a lower mean number of missing teeth when compared to patients recruited from dental specialist centers.

  • 2.
    Arzoo, Pakeeza Shaiq
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Klar, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Bergendal, Birgitta
    Norderyd, Johanna
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    WNT10A Mutations Account for 1/4 of Population- Based Isolated Oligodontia and Show Phenotypic Correlations2014In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 164, no 2, p. 353-359Article in journal (Refereed)
    Abstract [en]

    A large proportion (>50%) of patients with isolated oligodontia were recently reported with WNT10A mutations. We have analyzed a population-based cohort of 102 individuals diagnosed with non-syndromic oligodontia and a mean of 8.2 missing teeth. The cohort included 94 families and screening of WNT10A identified that 26 probands (27.7%) had at least one WNT10A variant. When we included the MSX1, PAX9, AXIN2, EDA, EDAR, and EDARADD genes, 38.3% of probands were positive for a mutation. Biallelic WNT10A mutations were strongly associated with a larger number of missing teeth (11.09) when compared to both monoallelic WNT10 mutations (6.82) and the group without mutations in WNT10A, MSX1, PAX9, AXIN2, EDA, EDAR, or EDARADD (7.77). Genotype-phenotype analysis of individuals with WNT10A mutations showed that premolars were the most common missing teeth. Furthermore, biallelic WNT10A mutations were associated with absence of maxillary and mandibular molars as well as mandibular central incisors. Maxillary central incisors were always present. Thus, our study indicates that WNT10A mutations are associated with both the type and numbers of missing teeth. Furthermore, we show that this population-based cohort of isolated oligodontia had a considerably lower frequency of mutated WNT10A alleles and a lower mean number of missing teeth when compared to patients recruited from dental specialist centers. (c) 2013 Wiley Periodicals, Inc.

  • 3.
    Bergendal, Birgitta
    et al.
    Odontologiska Institutionen i Jönköping.
    Klar, Joakim
    Uppsala University.
    Stecksén-Blicks, Christina
    Umeå University.
    Norderyd, Johanna
    Odontologiska Institutionen i Jönköping.
    Dahl, Niklas
    Uppsala University.
    Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSX1, and PAX9 genes2011In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 155, no 7, p. 1616-1622Article in journal (Refereed)
    Abstract [en]

    Oligodontia is defined as the congenital lack of six or more permanent teeth, excluding third molars. Oligodontia as well as hypodontia (lack of one or more permanent teeth) are highly heritable conditions associated with mutations in the AXIN2, MSX1, PAX9, EDA, and EDAR genes. Here we define the prevalence of mutations in the AXIN2, MSX1, PAX9, EDA, and EDAR genes, and the novel candidate gene EDARADD in a cohort of 93 Swedish probands with non-syndromic, isolated oligodontia. Mutation screening was performed using denaturing gradient gel electrophoresis and DNA sequence analysis. Analyses of the coding sequences of the six genes showed sequence alterations predicted to be damaging or potentially damaging in ten of 93 probands (10.8%). Mutations were identified in the EDARADD (n = 1), AXIN2 (n = 3), MSX1 (n = 2), and PAX9 (n = 4) genes, respectively. None of the 10 probands with mutations had other self-reported symptoms from ectodermal tissues. The oral parameters were similar when comparing individuals with and without mutations but a family history of oligodontia was three times more frequent for probands with mutations. EDARADD mutations have previously been reported in a few families segregating hypohidrotic ectodermal dysplasia and this is, to our knowledge, the first report of an EDARADD mutation associated with isolated oligodontia.

  • 4. Bergendal, Birgitta
    et al.
    Klar, Joakim
    Stecksén-Blicks, Christina
    Umeå University, Faculty of Medicine, Department of Odontology.
    Norderyd, Johanna
    Dahl, Niklas
    Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSX1, and PAX9 genes2011In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 155, no 7, p. 1616-1622Article in journal (Refereed)
    Abstract [en]

    Oligodontia is defined as the congenital lack of six or more permanent teeth, excluding third molars. Oligodontia as well as hypodontia (lack of one or more permanent teeth) are highly heritable conditions associated with mutations in the AXIN2, MSX1, PAX9, EDA, and EDAR genes. Here we define the prevalence of mutations in the AXIN2, MSX1, PAX9, EDA, and EDAR genes, and the novel candidate gene EDARADD in a cohort of 93 Swedish probands with non-syndromic, isolated oligodontia. Mutation screening was performed using denaturing gradient gel electrophoresis and DNA sequence analysis. Analyses of the coding sequences of the six genes showed sequence alterations predicted to be damaging or potentially damaging in ten of 93 probands (10.8%). Mutations were identified in the EDARADD (n = 1), AXIN2 (n = 3), MSX1 (n = 2), and PAX9 (n = 4) genes, respectively. None of the 10 probands with mutations had other self-reported symptoms from ectodermal tissues. The oral parameters were similar when comparing individuals with and without mutations but a family history of oligodontia was three times more frequent for probands with mutations. EDARADD mutations have previously been reported in a few families segregating hypohidrotic ectodermal dysplasia and this is, to our knowledge, the first report of an EDARADD mutation associated with isolated oligodontia.

  • 5.
    Djoussé, L
    et al.
    USA.
    Knowlton, B
    Hayden, M
    Almqvist, E W
    Brinkman, R
    Ross, C
    Margolis, R
    Rosenblatt, A
    Durr, A
    Dode, C
    Morrison, P J
    Novelletto, A
    Frontali, M
    Trent, R J A
    McCusker, E
    Gómez-Tortosa, E
    Mayo, D
    Jones, R
    Zanko, A
    Nance, M
    Abramson, R
    Suchowersky, O
    Paulsen, J
    Harrison, M
    Yang, Q
    Cupples, L A
    Gusella, J F
    MacDonald, M E
    Myers, R H
    Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease.2003In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 119A, no 3, p. 279-82Article in journal (Refereed)
    Abstract [en]

    Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.

  • 6.
    Edman Ahlbom, Bodil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Goetz, P
    Korenberg, JR
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Seemenova, E
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Zech, Lore
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Molecular analysis of chromosome 21 in a patient with a phenotype of down syndrome and apparently normal karyotype1996In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 63, no 4, p. 566-572Article in journal (Refereed)
    Abstract [en]

    Down syndrome (DS) is caused in most cases by the presence of an extra chromosome 21. It has been shown that the DS phenotype is produced by duplication of only a small part of the long arm of chromosome 21, the 21q22 region, including and distal to locus D21S55. We present molecular investigations on a woman with clinically typical DS but apparently normal chromosomes. Her parents were consanguineous and she had a sister with a DS phenotype, who died at the age of 15 days. Repeated cytogenetic investigations (G-banding and high resolution banding) on the patient and her parents showed apparently normal chromosomes. Autoradiographs of quantitative Southern blots of DNAs from the patient, her parents, trisomy 21 patients, and normal controls were analyzed after hybridization with unique DNA sequences regionally mapped on chromosome 21. Sequences D21S59, D21S1, D21S11, D21S8, D21S17, D21S55, ERG, D21S15, D21S112, and COL6A1 were all found in two copies. Fluorescent in situ hybridization with a chromosome 21-specific genomic library showed no abnormalities and only two copies of chromosome 21 were detected. Nineteen markers from the critical region studied with polymerase chain reaction amplification of di- and tetranucleotide repeats did not indicate any partial trisomy 21. From this study we conclude that the patient does not have any partial submicroscopic trisomy for any segment of chromosome 21. It seems reasonable to assume that she suffers from an autosomal recessive disorder which is phenotypically indistinguishable from DS.

  • 7.
    Ekvall, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjörs, Kerstin
    Cent Hosp Vasteras, Dept Pediat, Vasteras, Sweden.
    Jonzon, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Vihinen, Mauno
    Lund Univ, Dept Expt Med Sci, Lund, Sweden.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome2014In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 164, no 3, p. 579-587Article in journal (Refereed)
    Abstract [en]

    Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present.

  • 8.
    Englund, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Jonsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Zander, Cecilia Soussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Annerén, Göran
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Changes in mortality and causes of death in the Swedish Down syndrome population2013In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 161A, no 4, p. 642-649Article in journal (Refereed)
    Abstract [en]

    During the past few decades age at death for individuals with Down syndrome (DS) has increased dramatically. The birth frequency of infants with DS has long been constant in Sweden. Thus, the prevalence of DS in the population is increasing. The aim of the present study was to analyze mortality and causes of death in individuals with DS during the period 19692003. All individuals with DS that died between 1969 and 2003 in Sweden, and all individuals born with DS in Sweden between 1974 and 2003 were included. Data were obtained from the Swedish Medical Birth Register, the Swedish Birth Defects Register, and the National Cause of Death Register. Median age at death has increased by 1.8 years per year. The main cause of death was pneumonia. Death from congenital heart defects decreased. Death from atherosclerosis was rare but more frequent than reported previously. Dementia was not reported in any subjects with DS before 40 years of age, but was a main or contributing cause of death in 30% of the older subjects. Except for childhood leukemia, cancer as a cause of death was rare in all age groups. Mortality in DS, particularly infant mortality, has decreased markedly during the past decades. Median age at death is increasing and is now almost 60 years. Death from cancer is rare in DS, but death from dementia is common.

  • 9.
    Kruszka, Paul
    et al.
    NIH, Med Genet Branch, Natl Human Genome Res Inst, 35 Convent Dr,Room 1B203, Bethesda, MD 20892 USA..
    Addissie, Yonit A.
    NIH, Med Genet Branch, Natl Human Genome Res Inst, 35 Convent Dr,Room 1B203, Bethesda, MD 20892 USA..
    Yarnell, Colin M. P.
    NIH, Med Genet Branch, Natl Human Genome Res Inst, 35 Convent Dr,Room 1B203, Bethesda, MD 20892 USA..
    Hadley, Donald W.
    NIH, Med Genet Branch, Natl Human Genome Res Inst, 35 Convent Dr,Room 1B203, Bethesda, MD 20892 USA..
    Sacoto, Maria J. Guillen
    NIH, Med Genet Branch, Natl Human Genome Res Inst, 35 Convent Dr,Room 1B203, Bethesda, MD 20892 USA..
    Platte, Petra
    Univ Wurzburg, Clin Psychol & Psychotherapy, Dept Biol Psychol, Wurzburg, Germany..
    Paelecke, Yvonne
    Univ Wurzburg, Clin Psychol & Psychotherapy, Dept Biol Psychol, Wurzburg, Germany..
    Collmann, Hartmut
    Univ Wurzburg, Dept Neurosurg, Sect Pediat Neurosurg, Wurzburg, Germany..
    Snow, Nicole
    Univ New S Wales, Sydney Childrens Hosp, Sydney, NSW, Australia.;Garvan Inst, Kinghorn Ctr Clin Gen, Sydney, NSW, Australia..
    Schweitzer, Tilmann
    Univ Wurzburg, Dept Neurosurg, Sect Pediat Neurosurg, Wurzburg, Germany..
    Boyadjiev, Simeon A.
    Univ Calif Davis, Genet Sect, Dept Pediat, Sacramento, CA 95817 USA..
    Aravidis, Christos
    Akad Univ Hosp, Dept Clin Genet, Uppsala, Sweden..
    Hall, Samantha E.
    Boston Childrens Hosp, Dept Plast & Oral Surg, Boston, MA USA..
    Mulliken, John B.
    Boston Childrens Hosp, Dept Plast & Oral Surg, Boston, MA USA..
    Roscioli, Tony
    Univ Wurzburg, Dept Neurosurg, Sect Pediat Neurosurg, Wurzburg, Germany.;Univ New S Wales, Sydney Childrens Hosp, Sydney, NSW, Australia..
    Muenke, Maximilian
    NIH, Med Genet Branch, Natl Human Genome Res Inst, 35 Convent Dr,Room 1B203, Bethesda, MD 20892 USA..
    Muenke syndrome: An international multicenter natural history study2016In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 170, no 4, p. 918-929Article in journal (Refereed)
    Abstract [en]

    Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal, and calcaneal fusions, and behavioral differences. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings. Muenke syndrome constitutes the most common syndromic form of craniosynostosis, with an incidence of 1 in 30,000 births and is defined by the presence of the p.Pro250Arg mutation in FGFR3. Participants were recruited from international craniofacial surgery and genetic clinics. Affected individuals, parents, and their siblings, if available, were enrolled in the study if they had a p.Pro250Arg mutation in FGFR3. One hundred and six patients from 71 families participated in this study. In 51 informative probands, 33 cases (64.7%) were inherited. Eighty-five percent of the participants had craniosynostosis (16 of 103 did not have craniosynostosis), with 47.5% having bilateral and 28.2% with unilateral synostosis. Females and males were similarly affected with bicoronal craniosynostosis, 50% versus 44.4% (P=0.84), respectively. Clefting was rare (1.1%). Hearing loss was identified in 70.8%, developmental delay in 66.3%, intellectual disability in 35.6%, attention deficit/hyperactivity disorder in 23.7%, and seizures in 20.2%. In patients with complete skeletal surveys (upper and lower extremity x-rays), 75% of individuals were found to have at least a single abnormal radiographical finding in addition to skull findings. This is the largest study of the natural history of Muenke syndrome, adding valuable clinical information to the care of these individuals including behavioral and cognitive impairment data, vision changes, and hearing loss.

  • 10. Kvarnung, Malin
    et al.
    Lindstrand, Anna
    Malmgren, Helena
    Thastrom, Anders
    Jacobson, Lena
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundin, Johanna
    Blennow, Elisabeth
    Inherited mosaicism for the supernumerary marker chromosome in cat eye syndrome: Inter- and intra-individual variation and correlation to the phenotype2012In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 158A, no 5, p. 1111-1117Article in journal (Refereed)
    Abstract [en]

    We have studied a family with repeated transmission of mosaicism for a supernumerary marker chromosome (SMC), giving rise to varying symptoms of the cat eye syndrome (CES) in the offspring. The frequency of the SMC was investigated using FISH with probes from the CES critical region on lymphocytes as well as buccal cells. The same probes were used to study the frequency of the SMC in spermatozoa from the father. The SMC was characterized in detail using array-CGH and was found to correspond to a symmetrical cat eye SMC type I, with two extra copies of the most proximal part of 22q11, not extending into the classical 22q11.2 deletion region. Mosaicism for the SMC was detected in 4 out of 7 family members, the father and all his three children. The degree of mosaicism varied greatly between individuals as well as between tissues, with twice as many cells with the SMC in epithelial cells compared to blood. The highest frequency (almost 50%) was found in spermatozoa from the father. There was a direct correlation between the degree of mosaicism and the symptoms, varying from no obvious symptoms to classical CES. The study confirms the occurrence of direct transmission of SMC-mosaicism in CES. The results indicate that examination of parental epithelial cells should be preferred compared to blood cells in order to exclude a recurrence risk in parents of a child with CES. Interphase FISH analysis of spermatozoa is the most sensitive method to exclude paternal germ line mosaicsm. (c) 2012 Wiley Periodicals, Inc.

  • 11. Lindstrand, Anna
    et al.
    Malmgren, Helena
    Verri, Annapia
    Benetti, Elisa
    Eriksson, Maud
    Nordgren, Ann
    Anderlid, Britt-Marie
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Schoumans, Jacqueline
    Blennow, Elisabeth
    Molecular and clinical characterization of patients with overlapping 10p deletions2010In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 152A, no 5, p. 1233-1243Article in journal (Refereed)
    Abstract [en]

    Chromosome 10p terminal deletions have been associated with DiGeorge phenotype, and within the same genomic region haploinsufficiency of GATA3 causes the HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia). We have performed detailed molecular analysis of four patients with partial overlapping 10p deletions by using FISH-mapping, array-CGH, and custom-designed high-resolution oligonucleotide array. All four patients had mental retardation and speech impairment and three of them showed variable signs of HDR syndrome. In addition, two patients had autistic behaviors and had similar dysmorphic features giving them a striking physical resemblance. A review of the literature identified 10 previously published cases with similar 10p deletions and reliable molecular or molecular cytogenetic mapping data. The combined information of present and previous cases suggests that partial deletions of 10p14-p15 represent a syndrome with a distinct and more severe phenotype than previously assumed. The main characteristics include severe mental retardation, language impairment, autistic behavior, and characteristic clinical features. A critical region involved in mental retardation and speech impairment is defined within 1.6 Mb in 10p15.3. In addition, deletion of 4.3 Mb within 10p14 is associated with autism and characteristic clinical findings.

  • 12.
    Pettersson, Maria
    et al.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Bergendal, Birgitta
    Jönköping University, School of Health and Welfare. National Oral Disability Centre for Rare Disorders, The Institute for Postgraduate Dental Education, Jönköping, Sweden.
    Norderyd, Johanna
    Jönköping University, School of Health and Welfare, HHJ. CHILD. National Oral Disability Centre for Rare Disorders, The Institute for Postgraduate Dental Education, Jönköping, Sweden.
    Nilsson, Daniel
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Anderlid, Britt-Marie
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Nordgren, Ann
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Lindstrand, Anna
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Further evidence for specific IFIH1 mutation as a cause of Singleton-Merten syndrome with phenotypic heterogeneity2017In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 173, no 5, p. 1396-1399Article in journal (Refereed)
    Abstract [en]

    Singleton-Merten syndrome (MIM 182250) is an autosomal dominant inherited disorder characterized by early onset periodontitis, root resorption, osteopenia, osteoporosis, and aortic valve or thoracic aorta calcification. The disorder can have significant intrafamilial phenotypic variability. Here, we present a mother and daughter with Singleton-Merten syndrome harboring a previously described pathogenic missense mutation, c.2465G>A p.(Arg822Gln), in IFIH1 (interferon induced with helicase C domain 1), encoding MDA5 (Melanoma Differentiation-Associated protein 5). These data confirm the pathogenicity of IFIH1 c.2465G>A p.(Arg822Gln) for Singleton-Merten syndrome and affirm the striking phenotypic heterogeneity of this disorder. In addition, we expand the Singleton-Merten phenotype by adding severe systemic lupus erythematosus (SLE) to the clinical picture. Investigations of known SLE genes as well as a single nucleotide polymorphism suggested to be involved in development of SLE were normal. 

  • 13. Popovici, Cornel
    et al.
    Busa, Tiffany
    Boute, Odile
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Perret, Odile
    Sigaudy, Sabine
    Soedergren, Tommy
    Andrieux, Joris
    Moncla, Anne
    Philip, Nicole
    Whole ARX Gene Duplication is Compatible With Normal Intellectual Development2014In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 164A, no 9, p. 2324-2327Article in journal (Refereed)
    Abstract [en]

    We report here on four males from three families carrying de novo or inherited small Xp22.13 duplications including the ARX gene detected by chromosomal microarray analysis (CMA). Two of these males had normal intelligence. Our report suggests that, unlike other XLMR genes like MECP2 and FMR1, the presence of an extra copy of the ARX gene may not be sufficient to perturb its developmental functions. ARX duplication does not inevitably have detrimental effects on brain development, in contrast with the effects of ARX haploinsufficiency. The abnormal phenotype ascribed to the presence of an extra copy in some male patients may have resulted from the effect of another, not yet identified, chromosomal or molecular anomaly, alone or in association with ARX duplication.

  • 14.
    Porrmann, Joseph
    et al.
    Tech Univ Dresden, Inst Klin Genet, Dresden, Germany..
    Betcheva-Krajcir, Elitza
    Tech Univ Dresden, Inst Klin Genet, Dresden, Germany..
    Di Donato, Nataliya
    Tech Univ Dresden, Inst Klin Genet, Dresden, Germany..
    Kahlert, Anne-Karin
    Tech Univ Dresden, Inst Klin Genet, Dresden, Germany..
    Schallner, Jens
    Univ Klinikum Carl Gustav Carus, Childrens Hosp, Dresden, Germany..
    Rump, Andreas
    Tech Univ Dresden, Inst Klin Genet, Dresden, Germany..
    Schroeck, Evelin
    Tech Univ Dresden, Inst Klin Genet, Dresden, Germany..
    Dobritzsch, Doreen
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Roelofsen, Jeroen
    Univ Amsterdam, Dept Clin Chem, Lab Genet Metab Dis, Acad Med Ctr,Emma Childrens Hosp, Amsterdam, Netherlands..
    van Kuilenburg, Andre B. P.
    Univ Amsterdam, Dept Clin Chem, Lab Genet Metab Dis, Acad Med Ctr,Emma Childrens Hosp, Amsterdam, Netherlands..
    Tzschach, Andreas
    Tech Univ Dresden, Inst Klin Genet, Dresden, Germany..
    Novel PRPS1 gain-of-function mutation in a patient with congenital hyperuricemia and facial anomalies2017In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 173, no 10, p. 2736-2742Article in journal (Refereed)
    Abstract [en]

    Phosphoribosylpyrophosphate synthetase (PRPPS) superactivity (OMIM 300661) is a rare inborn error of purine metabolism that is caused by gain-of-function mutations in the X-chromosomal gene PRPS1 (Xq22.3). Clinical characteristics include congenital hyperuricemia and hyperuricosuria, gouty arthritis, urolithiasis, developmental delay, hypotonia, recurrent infections, short stature, and hearing loss. Only eight families with PRPPS superactivity and PRPS1 gain-of-function mutations have been reported to date. We report on a 7-year-old boy with congenital hyperuricemia, urolithiasis, developmental delay, short stature, hypospadias, and facial dysmorphisms. His mother also suffered from hyperuricemia that was diagnosed at age 13 years. A novel PRPS1 missense mutation (c.573G>C, p.[Leu191Phe]) was detected in the proband and his mother. Enzyme activity analysis confirmed superactivity of PRPP synthetase. Analysis of the crystal structure of human PRPPS suggests that the Leu191Phe mutation affects the architecture of both allosteric sites, thereby preventing the allosteric inhibition of the enzyme. The family reported here broadens the clinical spectrum of PRPPS superactivity and indicates that this rare metabolic disorder might be associated with a recognizable facial gestalt.

  • 15.
    Razzaghian, Hamid Reza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Shahi, Mehdi Hayat
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Forsberg, Lars A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Diaz de Ståhl, Teresita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Absher, Devin
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Westerman, Maxwell P.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Somatic Mosaicism for Chromosome X and Y Aneuploidies in Monozygotic Twins Heterozygous for Sickle Cell Disease Mutation2010In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 152A, no 10, p. 2595-2598Article in journal (Refereed)
    Abstract [en]

    Somatic genetic variation in health and disease is poorly explored. Monozygotic (MZ) twins are a suitable model for studies of somatic mosaicism since genetic differences in twins derived from the same zygote represent an irrefutable example of somatic variation. We report the analysis of a pair of generally healthy female MZ twins, discordant for somatic mosaicism for aneuploidy of chromosomes X and Y. Both twins are heterozygous carriers of sickle cell disease mutation. Genotyping of blood DNA from both twins using Illumina Human 610 SNP array revealed a copy number imbalance for chromosome X in a proportion of cells in one twin. Fluorescent in situ hybridization (FISH) analysis confirmed monosomy X (45,X) in 7% of proband nucleated blood cells. Unexpectedly, FISH analysis of cells from the other twin revealed 45,X and 46,XY lineages, both present in 1% of cells. The mechanism behind formation of these aneuploidies suggests several aberrant chromosome segregation events in meiosis and mitoses following conception. Our report contributes to the delineation of the frequency of somatic structural genomic variation in normal MZ twins. These results also illustrate the plasticity of the human genome for tolerating large copy number changes in healthy subjects and show the sensitivity of the Illumina platform for detection of aberrations that are present in a minority of the studied cells.

  • 16.
    Rehnberg, Malin
    et al.
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics. Linköping University, Faculty of Health Sciences.
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Letter: Novel L1CAM Splice Site Mutation in a Young Male With L1 Syndrome2011In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 155A, no 2, p. 439-441Article in journal (Other academic)
    Abstract [en]

    n/a

  • 17. Rendtorff, Nanna D.
    et al.
    Lodahl, Marianne
    Boulahbel, Houda
    Johansen, Ida R.
    Pandya, Arti
    Welch, Katherine O.
    Norris, Virginia W.
    Arnos, Kathleen S.
    Bitner-Glindzicz, Maria
    Emery, Sarah B.
    Mets, Marilyn B.
    Fagerheim, Toril
    Eriksson, Kristina
    Hansen, Lars
    Bruhn, Helene
    Möller, Claes
    Örebro University, School of Health and Medical Sciences.
    Lindholm, Sture
    Ensgaard, Stefan
    Lesperance, Marci M.
    Tranebjaerg, Lisbeth
    Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment2011In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 155A, no 6, p. 1298-1313Article in journal (Refereed)
    Abstract [en]

    Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome.

  • 18.
    Rogers, Amanda
    et al.
    Washington Univ, Dept Neurol, 660 S Euclid Ave,Campus Box 8111, St Louis, MO 63110 USA.
    Golumbek, Paul
    Washington Univ, Dept Neurol, 660 S Euclid Ave,Campus Box 8111, St Louis, MO 63110 USA.
    Cellini, Elena
    Univ Florence, Anna Meyer Childrens Hosp, Florence, Italy.
    Doccini, Viola
    Univ Florence, Anna Meyer Childrens Hosp, Florence, Italy.
    Guerrini, Renzo
    Univ Florence, Anna Meyer Childrens Hosp, Florence, Italy.
    Wallgren-Pettersson, Carina
    Univ Helsinki, Folkhaelsan Inst Genet, Dept Med & Clin Genet, Helsinki, Finland.
    Thuresson, Ann-Charlotte
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Gurnett, Christina A.
    Washington Univ, Dept Neurol, 660 S Euclid Ave,Campus Box 8111, St Louis, MO 63110 USA.
    De novo KCNA1 variants in the PVP motif cause infantile epileptic encephalopathy and cognitive impairment similar to recurrent KCNA2 variants2018In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 176, no 8, p. 1748-1752Article in journal (Refereed)
    Abstract [en]

    Derangements in voltage-gated potassium channel function are responsible for a range of paroxysmal neurologic disorders. Pathogenic variants in the KCNA1 gene, which encodes the voltage-gated potassium channel Kv1.1, are responsible for Episodic Ataxia Type 1 (EA1). Patients with EA1 have an increased incidence of epilepsy, but KCNA1 variants have not been described in epileptic encephalopathy. Here, we describe four patients with infantile-onset epilepsy and cognitive impairment who harbor de novo KCNA1 variants located within the Kv-specific Pro-Val-Pro (PVP) motif which is essential for channel gating. The first two patients have KCNA1 variants resulting in (p.Pro405Ser) and (p.Pro405Leu), respectively, and a set of identical twins has a variant affecting a nearby residue (p.Pro403Ser). Notably, recurrent de novo variants in the paralogous PVP motif of KCNA2 have previously been shown to abolish channel function and also cause early-onset epileptic encephalopathy. Importantly, this report extends the range of phenotypes associated with KCNA1 variants to include epileptic encephalopathy when the PVP motif is involved.

  • 19.
    Stattin, Eva-Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gudmundsson, Sanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundberg, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Bondeson, Marie-Louise
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Wilbe, Maria
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    A novel ECEL1 mutation expands the phenotype of distal arthrogryposis multiplex congenita type 5D to include pretibial vertical skin crease2018In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 176, no 6, p. 1405-1410Article in journal (Refereed)
    Abstract [en]

    Arthrogryposis multiplex congenita (AMC) is a heterogeneous disorder characterized by multiple joint contractures often in association with other congenital abnormalities. Pretibial linear vertical creases are a rare finding associated with arthrogryposis, and the etiology of the specific condition is unknown. We aimed to genetically and clinically characterize a boy from a consanguineous family, presenting with AMC and pretibial vertical linear creases on the shins. Whole exome sequencing and variant analysis revealed homozygous novel missense variants of ECEL1 (c.1163T > C, p.Leu388Pro, NM_004826) and MUSK (c.2572C > T, p.Arg858Cys, NM_005592). Both variants are predicted to have deleterious effects on the protein function, with amino acid positions highly conserved among species. The variants segregated in the family, with healthy mother, father, and sister being heterozygous carriers and the index patient being homozygous for both mutations. We report on a unique patient with a novel ECEL1 homozygous mutation, expanding the phenotypic spectrum of Distal AMC Type 5D to include vertical linear skin creases. The homozygous mutation in MUSK is of unknown clinical significance. MUSK mutations have previously shown to cause congenital myasthenic syndrome, a neuromuscular disorder with defects in the neuromuscular junction.

  • 20. Terhal, Paulien A.
    et al.
    Nievelstein, Rutger Jan A. J.
    Verver, Eva J. J.
    Topsakal, Vedat
    van Dommelen, Paula
    Hoornaert, Kristien
    Le Merrer, Martine
    Zankl, Andreas
    Simon, Marleen E. H.
    Smithson, Sarah F.
    Marcelis, Carlo
    Kerr, Bronwyn
    Clayton-Smith, Jill
    Kinning, Esther
    Mansour, Sahar
    Elmslie, Frances
    Goodwin, Linda
    van der Hout, Annemarie H.
    Veenstra-Knol, Hermine E.
    Herkert, Johanna C.
    Lund, Allan M.
    Hennekam, Raoul C. M.
    Megarbane, Andre
    Lees, Melissa M.
    Wilson, Louise C.
    Male, Alison
    Hurst, Jane
    Alanay, Yasemin
    Annerén, Göran
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Betz, Regina C.
    Bongers, Ernie M. H. F.
    Cormier-Daire, Valerie
    Dieux, Anne
    David, Albert
    Elting, Mariet W.
    van den Ende, Jenneke
    Green, Andrew
    van Hagen, Johanna M.
    Hertel, Niels Thomas
    Holder-Espinasse, Muriel
    den Hollander, Nicolette
    Homfray, Tessa
    Hove, Hanne D.
    Price, Susan
    Raas-Rothschild, Annick
    Rohrbach, Marianne
    Schroeter, Barbara
    Suri, Mohnish
    Thompson, Elizabeth M.
    Tobias, Edward S.
    Toutain, Annick
    Vreeburg, Maaike
    Wakeling, Emma
    Knoers, Nine V.
    Coucke, Paul
    Mortier, Geert R.
    A Study of the Clinical and Radiological Features in a Cohort of 93 Patients with a COL2A1 Mutation Causing Spondyloepiphyseal Dysplasia Congenita or a Related Phenotype2015In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 167A, no 3, p. 461-475Article in journal (Refereed)
    Abstract [en]

    Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n=64), others having SEMD (n=5), Kniest dysplasia (n=7), spondyloperipheral dysplasia (n=2), or Torrance-like dysplasia (n=2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders.

  • 21. Thierry, Gaelle
    et al.
    Beneteau, Claire
    Pichon, Olivier
    Flori, Elisabeth
    Isidor, Bertrand
    Popelard, Francoise
    Delrue, Marie-Ange
    Duboscq-Bidot, Laetitia
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    van Bon, Bregje W. M.
    Cailley, Dorothee
    Rooryck, Caroline
    Paubel, Agathe
    Metay, Corinne
    Dusser, Anne
    Pasquier, Laurent
    Beri, Mylene
    Bonnet, Celine
    Jaillard, Sylvie
    Dubourg, Christele
    Tou, Bassim
    Quere, Marie-Pierre
    Soussi Zander, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Toutain, Annick
    Lacombe, Didier
    Arveiler, Benoit
    de Vries, Bert B. A.
    Jonveaux, Philippe
    David, Albert
    Le Caignec, Cedric
    Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures2012In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 158A, no 7, p. 1633-1640Article in journal (Refereed)
    Abstract [en]

    Patients with a submicroscopic deletion at 1q43q44 present with intellectual disability (ID), microcephaly, craniofacial anomalies, seizures, limb anomalies, and corpus callosum abnormalities. However, the precise relationship between most of deleted genes and the clinical features in these patients still remains unclear. We studied 11 unrelated patients with 1q44 microdeletion. We showed that the deletions occurred de novo in all patients for whom both parents' DNA was available (10/11). All patients presented with moderate to severe ID, seizures and non-specific craniofacial anomalies. By oligoarray-based comparative genomic hybridization (aCGH) covering the 1q44 region at a high resolution, we obtained a critical deleted region containing two coding genesHNRNPU and FAM36Aand one non-coding geneNCRNA00201. All three genes were expressed in different normal human tissues, including in human brain, with highest expression levels in the cerebellum. Mutational screening of the HNRNPU and FAM36A genes in 191 patients with unexplained isolated ID did not reveal any deleterious mutations while the NCRNA00201 non-coding gene was not analyzed. Nine of the 11 patients did not present with microcephaly or corpus callosum abnormalities and carried a small deletion containing HNRNPU, FAM36A, and NCRNA00201 but not AKT3 and ZNF238, two centromeric genes. These results suggest that HNRNPU, FAM36A, and NCRNA00201 are not major genes for microcephaly and corpus callosum abnormalities but are good candidates for ID and seizures. 

  • 22.
    Thunstrom, Sofia
    et al.
    Sahlgrens University Hospital, Sweden.
    Sodermark, Liv
    Queen Silvia Childrens, Sweden.
    Ivarsson, Liz
    Queen Silvia Childrens Hospital, Sweden.
    Samuelsson, Lena
    Sahlgrens University Hospital, Sweden.
    Stefanova, Margarita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Sahlgrens University Hospital, Sweden; University of Gothenburg, Sweden.
    UBE2A Deficiency Syndrome: A Report of Two Unrelated Cases with Large Xq24 Deletions Encompassing UBE2A Gene2015In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 167A, no 1, p. 204-210Article in journal (Refereed)
    Abstract [en]

    Intragenic mutations of the UBE2A gene, as well as larger deletions of Xq24 encompassing UBE2A have in recent years been associated with a syndromic form of X-linked intellectual disability called UBE2A deficiency syndrome or X-linked intellectual disability type Nascimento (OMIM#300860). Common clinical features in these patients include moderate to severe intellectual disability (ID), heart defects, dysmorphic features such as high forehead, synophrys, prominent supraorbital ridges, almond-shaped and deep-set eyes, wide mouth, myxedematous appearance, hirsutism, onychodystrophy, and genital anomalies. This study investigates clinical and molecular data of two unrelated, affected males with chromosome Xq24 deletions encompassing UBE2A. Both have been followed from birth until two years of age. A review of the previously published patients with deletions encompassing UBE2A is provided. Besides the common features, the two boys show anomalies not previously described, such as retinal coloboma, esophageal atresia with esophageal fistula, long fingers, camptodactyly, clinodactyly, and long broad toes. Analyses of the phenotype-genotype correlations suggest considerable prevalence of heart defects in the group of patients with larger deletions of Xq24 in comparison to the patients having intragenic UBE2A mutations. However, further studies are needed in order to establish statistically reliable phenotype-genotype correlations of this syndrome.

  • 23.
    Wester, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Edeby, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Clinical and molecular characterization of individuals with 18p deletion: a genotype-phenotype correlation2006In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 140A, no 11, p. 1164-1171Article in journal (Refereed)
    Abstract [en]

    The deletion 18p syndrome is one of the most common chromosome abnormalities. The medical problems are mental and postnatal growth retardation, and sometimes malformations of the heart and brain. The individuals have some typical features, which might be easy to overlook and which are: ptosis, strabismus, hypertelorism, broad flat nose, micrognathia, big and low set ears. The aims of present study were to clinically and molecularly characterize the syndrome further in seven subjects with de novo 18p deletions and to perform genotype–phenotype correlation. All seven subjects had terminal deletions and no interstitial deletion was observed with subtelomeric FISH analyses. To define the extent of the 18p deletions and the parental origin of the deletion microsatellite- and FISH analyses were performed on genomic DNA and on lymphoblastoid cell lines of the study participants. Totally 19 chromosomes, 18 specific polymorphic microsatellite markers, and 5 BAC clones were used. The results revealed that the deletions were located in the centromeric region at 18p11.1 in four of the seven subjects. In the remaining three the breakpoints were located distal to 18p11.1 (18p11.21-p11.22). Four of the individuals had a paternal and three a maternal origin of the deletion. Genotype–phenotype correlation of the seven subjects suggests a correlation between the extent of the deleted region and the mental development. All the four children with a deletion in the centromeric region at 18p11.1 had a mental retardation (MR). Two of the three children with a more distal breakpoint (distal 18p11.21) had a normal mental development and one had a border-line mental retardation. There might be a critical region for the mental retardation located between 18p11.1 and 18p11.21. The children with a breakpoint at 18p11.1 had all a broad face, which was observed in only one of those with a more distal breakpoint, otherwise no genotype–phenotype correlation of the features was observed.

1 - 23 of 23
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