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The 11q Terminal Deletion Disorder Jacobsen Syndrome is a Syndromic Primary Immunodeficiency.

https://arctichealth.org/en/permalink/ahliterature275933
Source
J Clin Immunol. 2015 Nov;35(8):761-8
Publication Type
Article
Date
Nov-2015
Author
Virgil A S H Dalm
Gertjan J A Driessen
Barbara H Barendregt
Petrus M van Hagen
Mirjam van der Burg
Source
J Clin Immunol. 2015 Nov;35(8):761-8
Date
Nov-2015
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
B-Lymphocytes - immunology
Child
Chromosome Deletion
Chromosomes, Human, Pair 11 - genetics
Denmark
Female
Germinal Center - immunology
Humans
Immunologic Deficiency Syndromes - epidemiology - immunology
Infection - epidemiology - immunology
Jacobsen Distal 11q Deletion Syndrome - epidemiology - immunology
Male
Young Adult
Abstract
Jacobsen syndrome (JS) is a rare contiguous gene syndrome caused by partial deletion of the long arm of chromosome 11. Clinical features include physical and mental growth retardation, facial dysmorphism, thrombocytopenia, impaired platelet function and pancytopenia. In case reports, recurrent infections and impaired immune cell function compatible with immunodeficiency were described. However, Jacobsen syndrome has not been recognized as an established syndromic primary immunodeficiency.
To evaluate the presence of immunodeficiency in a series of 6 patients with JS.
Medical history of 6 patients with JS was evaluated for recurrent infections. IgG, IgA, IgM and specific antibodies against S. pneumoniae were measured. Response to immunization with a polysaccharide vaccine (Pneumovax) was measured and B and T lymphocyte subset analyses were performed using flowcytometry.
Five out of 6 patients suffered from recurrent infections. These patients had low IgG levels and impaired response to S. pneumoniae polysaccharide vaccination. Moreover, we also found a significant decrease in the absolute number of memory B cells, suggesting a defective germinal center function. In a number of patients, low numbers of T lymphocytes and NK cells were found.
Most patients with JS suffer from combined immunodeficiency in the presence of recurrent infections. Therefore, we consider JS a syndromic primary immunodeficiency. Early detection of immunodeficiency may reduce the frequency and severity of infections. All JS patients should therefore undergo immunological evaluation. Future studies in a larger cohort of patients will more precisely define the pathophysiology of the immunodeficiency in JS.
Notes
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PubMed ID
26566921 View in PubMed
Less detail

15q11.2 CNV affects cognitive, structural and functional correlates of dyslexia and dyscalculia.

https://arctichealth.org/en/permalink/ahliterature287813
Source
Transl Psychiatry. 2017 Apr 25;7(4):e1109
Publication Type
Article
Date
Apr-25-2017
Author
M O Ulfarsson
G B Walters
O. Gustafsson
S. Steinberg
A. Silva
O M Doyle
M. Brammer
D F Gudbjartsson
S. Arnarsdottir
G A Jonsdottir
R S Gisladottir
G. Bjornsdottir
H. Helgason
L M Ellingsen
J G Halldorsson
E. Saemundsen
B. Stefansdottir
L. Jonsson
V K Eiriksdottir
G R Eiriksdottir
G H Johannesdottir
U. Unnsteinsdottir
B. Jonsdottir
B B Magnusdottir
P. Sulem
U. Thorsteinsdottir
E. Sigurdsson
D. Brandeis
A. Meyer-Lindenberg
H. Stefansson
K. Stefansson
Source
Transl Psychiatry. 2017 Apr 25;7(4):e1109
Date
Apr-25-2017
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Chromosome Aberrations
Chromosome Deletion
Chromosomes, Human, Pair 15 - genetics
Cognition - physiology
DNA Copy Number Variations - genetics
Developmental Disabilities - genetics
Dyscalculia - genetics
Dyslexia - genetics
Female
Functional Neuroimaging - methods - standards
Heterozygote
Humans
Iceland - epidemiology
Intellectual Disability - genetics
Magnetic Resonance Imaging - methods
Male
Middle Aged
Neuropsychological Tests - standards
Phenotype
Temporal Lobe - anatomy & histology - diagnostic imaging
Young Adult
Abstract
Several copy number variants have been associated with neuropsychiatric disorders and these variants have been shown to also influence cognitive abilities in carriers unaffected by psychiatric disorders. Previously, we associated the 15q11.2(BP1-BP2) deletion with specific learning disabilities and a larger corpus callosum. Here we investigate, in a much larger sample, the effect of the 15q11.2(BP1-BP2) deletion on cognitive, structural and functional correlates of dyslexia and dyscalculia. We report that the deletion confers greatest risk of the combined phenotype of dyslexia and dyscalculia. We also show that the deletion associates with a smaller left fusiform gyrus. Moreover, tailored functional magnetic resonance imaging experiments using phonological lexical decision and multiplication verification tasks demonstrate altered activation in the left fusiform and the left angular gyri in carriers. Thus, by using convergent evidence from neuropsychological testing, and structural and functional neuroimaging, we show that the 15q11.2(BP1-BP2) deletion affects cognitive, structural and functional correlates of both dyslexia and dyscalculia.
Notes
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PubMed ID
28440815 View in PubMed
Less detail

Absence of the Asian-specific region V mitochondrial marker in Native Beringians.

https://arctichealth.org/en/permalink/ahliterature224068
Source
Am J Hum Genet. 1992 Apr;50(4):758-65
Publication Type
Article
Date
Apr-1992
Author
G F Shields
K. Hecker
M I Voevoda
J K Reed
Author Affiliation
Institute of Arctic Biology, University of Alaska, Fairbanks.
Source
Am J Hum Genet. 1992 Apr;50(4):758-65
Date
Apr-1992
Language
English
Publication Type
Article
Keywords
Alaska - ethnology
Asia, Central - ethnology
Base Sequence
Chromosome Deletion
DNA Probes - diagnostic use
DNA, Mitochondrial - analysis - genetics
Far East - ethnology
Genetic Markers - genetics
Humans
Molecular Sequence Data
Polymerase Chain Reaction
USSR - ethnology
Abstract
The Asian-specific 9-bp deletion between the genes for mitochondrial cytochrome oxidase II and lysine transfer RNA has been used to trace aboriginal human movements out of Southeast Asia and into portions of the South Pacific. Although it has been used to estimate the number of independent lineages that occur in the New World, it has not been studied in native peoples of the Beringian region. Thus, we have used PCR to amplify and compare the lengths of DNA segments surrounding this deletion in native peoples of Beringia and the adjacent regions, as well as natives of the Altai Mountains of Southwestern Siberia. Of the 176 individuals analyzed here, the deletion was found in only 3 of 25 individuals from the Ust-Kan region of the Altai Mountains. We comment on the distribution of this marker and on potential relationships between Beringians and other Native American groups in which this marker has been surveyed. One Chukchi possessed three copies of the 9-bp sequence, which suggests (1) that the number of copies of this sequence in humans may be more variable than had been believed and (2) that a mechanism of replication based on tandem duplication may be a potential explanation for the origin of this length mutation in humans.
Notes
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PubMed ID
1550120 View in PubMed
Less detail

Allelic loss on chromosome 11 is uncommon in parathyroid glands of patients with hypercalcaemic secondary hyperparathyroidism.

https://arctichealth.org/en/permalink/ahliterature34283
Source
Eur J Surg. 1997 May;163(5):331-7
Publication Type
Article
Date
May-1997
Author
F. Farnebo
L O Farnebo
J. Nordenström
C. Larsson
Author Affiliation
Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
Source
Eur J Surg. 1997 May;163(5):331-7
Date
May-1997
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Alleles
Child
Chromosome Deletion
Chromosomes, Human, Pair 11 - genetics
Disease Progression
Female
Heterozygote
Humans
Hypercalcemia - etiology - genetics
Hyperparathyroidism, Secondary - complications - genetics
Hyperplasia
Male
Middle Aged
Parathyroid Glands - pathology - physiopathology
Research Support, Non-U.S. Gov't
Abstract
OBJECTIVE: To test the hypothesis that progression of secondary hyperparathyroidism from normocalcaemia to hypercalcaemia occurs because of development of monoclonal parathyroid tumours after the inactivation of a tumour suppressor gene on chromosome 11q13. DESIGN: Experimental study. SETTING: University hospital, Sweden. SUBJECTS: 13 Patients with secondary hypercalcaemic hyperparathyroidism. INTERVENTIONS: 48 Parathyroid glands were removed, 39 of which were analysed using Southern blot hybridisation and polymerase chain reaction. MAIN OUTCOME MEASURES: Loss of heterozygosity on several loci on chromosome 11, including 11q13, which carries the presumed gene for multiple endocrine neoplasia type 1 (MEN1). RESULTS: Monosomy for chromosome 11 was found in one tumour. CONCLUSIONS: It seems unlikely that the MEN1 gene is of importance in the progression of secondary hyperparathyroidism.
PubMed ID
9195165 View in PubMed
Less detail

Angelman syndrome in Denmark. birth incidence, genetic findings, and age at diagnosis.

https://arctichealth.org/en/permalink/ahliterature108248
Source
Am J Med Genet A. 2013 Sep;161A(9):2197-203
Publication Type
Article
Date
Sep-2013
Author
Line Granild Bie Mertz
Rikke Christensen
Ida Vogel
Jens Michael Hertz
Karen Brøndum Nielsen
Karen Grønskov
John R Østergaard
Author Affiliation
Department of Pediatrics, Center for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark. linebiemertz@dadlnet.dk
Source
Am J Med Genet A. 2013 Sep;161A(9):2197-203
Date
Sep-2013
Language
English
Publication Type
Article
Keywords
Adolescent
Angelman Syndrome - diagnosis - epidemiology - genetics
Child
Child, Preschool
Chromosome Deletion
Chromosome Duplication
Chromosomes, Human, Pair 15
Denmark - epidemiology
Female
Humans
Incidence
Male
Abstract
Angelman syndrome (AS) is a neurogenetic disorder caused by loss of expression of the maternal imprinted gene UBE3A on chromosome 15q11.2-q13. Clinical features of AS include severe intellectual disability, a happy disposition, ataxia, mandibular prognatism, and epilepsy. Our objectives were to examine the birth incidence of AS in Denmark and to characterize the size of the 15q11.2-q13 deletions with 1,000K array CGH. In addition, we analyzed genotype differences in regard to age at diagnosis and investigated the occurrence of deletions/duplications outside the 15q11.2-q13 regions. We identified 51 patients with genetically verified AS, which corresponded to a birth incidence of 1:24,580 (95%CI: 1:23,727-1:25,433). Thirty-six patients showed a deletion; 13 had a Class I deletion and 20 had a Class II deletion. There was bimodal distribution of the BP3 breakpoint. Three patients had larger and atypical deletions, with distal breakpoints telomeric to BP3. Five patients had paternal uniparental disomy (pUPD) of chromosome 15, and four had a verified UBE3A mutation. Additional deletions/duplications outside the 15q11.2-q13 areas were demonstrated in half the participants. Six harbored more than one CNV. Mean age at diagnosis was 21 months (95%CI: 17-23 months) for children with a deletion and 46 months (95%CI: 36-55 months) for children with pUPD or a UBE3A mutation (P
PubMed ID
23913711 View in PubMed
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An interstitial deletion of 7.1Mb in chromosome band 6p22.3 associated with developmental delay and dysmorphic features including heart defects, short neck, and eye abnormalities.

https://arctichealth.org/en/permalink/ahliterature95191
Source
Eur J Med Genet. 2009 Sep-Oct;52(5):358-62
Publication Type
Article
Author
Bremer Anna
Schoumans Jacqueline
Nordenskjöld Magnus
Anderlid Britt-Marie
Giacobini Maibritt
Author Affiliation
Department of Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden.
Source
Eur J Med Genet. 2009 Sep-Oct;52(5):358-62
Language
English
Publication Type
Article
Keywords
Abnormalities, Multiple - genetics
Case-Control Studies
Child, Preschool
Chromosome Banding
Chromosome Breakage
Chromosome Deletion
Chromosomes, Human, Pair 6
Comparative Genomic Hybridization
DNA - genetics
Developmental Disabilities - genetics
Eye
Female
Heart Defects, Congenital - genetics
Humans
In Situ Hybridization, Fluorescence
Metaphase
Physical Chromosome Mapping
Reference Standards
Sweden
Abstract
Seven cases with an interstitial deletion of the short arm of chromosome 6 involving the 6p22 region have previously been reported. The clinical phenotype of these cases includes developmental delay, brain-, heart-, and kidney defects, eye abnormalities, short neck, craniofacial malformations, hypotonia, as well as clinodactyly or syndactyly. Here, we report a patient with a 7.1Mb interstitial deletion of chromosome band 6p22.3, detected by genome-wide screening array CGH. The patient is a 4-year-old girl with developmental delay and dysmorphic features including eye abnormalities, short neck, and a ventricular septum defect. The deleted region at 6p22.3 in our patient overlaps with six out of the seven previously reported cases with a 6p22-24 interstitial deletion. This enabled us to further narrow down the critical region for the 6p22 deletion phenotype to 2.2Mb. Twelve genes are mapped to the overlapping deleted region, among them the gene encoding the ataxin-1 protein, the ATXN1 gene. Mice with homozygous deletions in ATXN1 are phenotypically normal but show cognitive delay. Haploinsufficiency of ATXN1 may therefore contribute to the learning difficulties observed in the patients harboring a 6p22 deletion.
PubMed ID
19576304 View in PubMed
Less detail

[A simple and rapid method for determining a 32-bp deletion in the gene for the chemokine receptor CCR5].

https://arctichealth.org/en/permalink/ahliterature206499
Source
Genetika. 1997 Nov;33(11):1596-8
Publication Type
Article
Date
Nov-1997
Author
P A Slominskii
M I Shadrina
V A Spitsyn
V A Mikulich
E K Khusnutdinova
S A Limborskaia
Author Affiliation
Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia.
Source
Genetika. 1997 Nov;33(11):1596-8
Date
Nov-1997
Language
Russian
Publication Type
Article
Keywords
Alleles
Base Composition
Bashkiria
Chromosome Deletion
Ethnic Groups - genetics
Gene Frequency
Genotype
HIV-1 - pathogenicity
Humans
Receptors, Chemokine - genetics
Republic of Belarus
Russia
Time Factors
Abstract
In recent studies, a 32-bp deletion in the coding region of the chemokine receptor gene CCP5 was reported, which completely blocked penetration of the HIV-I virus into lymphocytes and macrophages. We developed a simple and rapid method for determining this deletion. The use of this method can greatly accelerate the evaluation of the frequency of the deletion allele CCP5 delta 32 in various populations and the determination of genotypes for the locus CCP5 in HIV-infected individuals. CCP5 was genotyped in three populations from Eastern Europe (Russians, Belarussians, and Bashkirs). Frequencies of the allele CCP5 delta 32 in these populations did not significantly differ from those in white Americans and Europeans from the CEPH sample. Even in Bashkiria, with its clear Turkic contribution, the frequency of CCP5 delta 32 reaches 0.10.
PubMed ID
9480225 View in PubMed
Less detail

Association between early-onset Parkinson disease and 22q11.2 deletion syndrome: identification of a novel genetic form of Parkinson disease and its clinical implications.

https://arctichealth.org/en/permalink/ahliterature107374
Source
JAMA Neurol. 2013 Nov;70(11):1359-66
Publication Type
Article
Date
Nov-2013
Author
Nancy J Butcher
Tim-Rasmus Kiehl
Lili-Naz Hazrati
Eva W C Chow
Ekaterina Rogaeva
Anthony E Lang
Anne S Bassett
Author Affiliation
Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Source
JAMA Neurol. 2013 Nov;70(11):1359-66
Date
Nov-2013
Language
English
Publication Type
Article
Keywords
Adult
Age of Onset
Aged
Brain - metabolism - pathology
Canada
Chromosome Deletion
DNA-Binding Proteins - metabolism
DiGeorge Syndrome - complications - genetics - pathology
Female
Genetic Testing
Humans
Male
Middle Aged
Mutation - genetics
Neurologic Examination
Observational Study as Topic
Parkinson Disease - complications - genetics - pathology
Protein-Serine-Threonine Kinases - genetics
Severity of Illness Index
Tyrosine 3-Monooxygenase
Young Adult
alpha-Synuclein - metabolism
Abstract
Clinical case reports of parkinsonism co-occurring with hemizygous 22q11.2 deletions and the associated multisystem syndrome, 22q11.2 deletion syndrome (22q11.2DS), suggest that 22q11.2 deletions may lead to increased risk of early-onset Parkinson disease (PD). The frequency of PD and its neuropathological presentation remain unknown in this common genetic condition.
To evaluate a possible association between 22q11.2 deletions and PD.
An observational study of the occurrence of PD in the world's largest cohort of well-characterized adults with a molecularly confirmed diagnosis of 22q11.2DS (n = 159 [6 with postmortem tissue]; age range, 18.1-68.6 years) was conducted in Toronto, Ontario, Canada. Rare postmortem brain tissue from individuals with 22q11.2DS and a clinical history of PD was investigated for neurodegenerative changes and compared with that from individuals with no history of a movement disorder.
A clinical diagnosis of PD made by a neurologist and neuropathological features of PD. RESULTS Adults with 22q11.2DS had a significantly elevated occurrence of PD compared with standard population estimates (standardized morbidity ratio = 69.7; 95% CI, 19.0-178.5). All cases showed early onset and typical PD symptom pattern, treatment response, and course. All were negative for family history of PD and known pathogenic PD-related mutations. The common use of antipsychotics in patients with 22q11.2DS to manage associated psychiatric symptoms delayed diagnosis of PD by up to 10 years. Postmortem brain tissue revealed classic loss of midbrain dopaminergic neurons in all 3 postmortem 22q11.2DS-PD cases. Typical a-synuclein-positive Lewy bodies were present in the expected distribution in 2 cases but absent in another.
These findings suggest that 22q11.2 deletions represent a novel genetic risk factor for early-onset PD with variable neuropathological presentation reminiscent of LRRK2-associated PD neuropathology. Individuals with early-onset PD and classic features of 22q11.2DS should be considered for genetic testing, and those with a known 22q11.2 deletion should be monitored for the development of parkinsonian symptoms. Molecular studies of the implicated genes, including DGCR8, may help shed light on the underlying pathophysiology of PD in 22q11.2DS and idiopathic PD.
Notes
Comment In: JAMA Neurol. 2013 Nov;70(11):1355-624018918
PubMed ID
24018986 View in PubMed
Less detail

Breakpoint characterization of a novel approximately 59 kb genomic deletion on 19q13.42 in autosomal-dominant retinitis pigmentosa with incomplete penetrance.

https://arctichealth.org/en/permalink/ahliterature153919
Source
Eur J Hum Genet. 2009 May;17(5):651-5
Publication Type
Article
Date
May-2009
Author
Linda Köhn
Sara J Bowne
Lori S Sullivan
Stephen P Daiger
Marie S I Burstedt
Konstantin Kadzhaev
Ola Sandgren
Irina Golovleva
Author Affiliation
Department of Medical Biosciences/Medical and Clinical Genetics, University of Umeå, Umeå, Sweden.
Source
Eur J Hum Genet. 2009 May;17(5):651-5
Date
May-2009
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Chromosome Breakage
Chromosome Deletion
Chromosome Mapping
Chromosomes, Human, Pair 19 - genetics
Eye Proteins - genetics
Family Health
Female
Genes, Dominant
Genotype
Haplotypes
Humans
Male
Microsatellite Repeats - genetics
Middle Aged
Pedigree
Penetrance
Polymerase Chain Reaction - methods
Retinitis Pigmentosa - genetics - pathology
Sequence Analysis, DNA
Sweden
Abstract
The aim of this study was to identify and characterize the underlying molecular mechanisms in autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance in two Swedish families. An extended genealogical study and haplotype analysis indicated a common origin. Mutation identification was carried out by multiplex ligation-dependent probe amplification (MLPA) and sequencing. Clinical examinations of adRP families including electroretinography revealed obligate gene carriers without abnormalities, which indicated incomplete penetrance. Linkage analysis resulted in mapping of the disease locus to 19q13.42 (RP11). Sequence analyses did not reveal any mutations segregating with the disease in eight genes including PRPF31. Subsequent MLPA detected a large genomic deletion of 11 exons in the PRPF31 gene and, additionally, three genes upstream of the PRPF31. Breakpoints occurred in intron 11 of PRPF31 and in LOC441864, 'similar to osteoclast-associated receptor isoform 5.' An almost 59 kb deletion segregated with the disease in all affected individuals and was present in several asymptomatic family members but not in 20 simplex RP cases or 94 healthy controls tested by allele-specific PCR. A large genomic deletion resulting in almost entire loss of PRPF31 and three additional genes identified as the cause of adRP in two Swedish families provide an additional evidence that mechanism of the disease evolvement is haploinsufficiency. Identification of the deletion breakpoints allowed development of a simple tool for molecular testing of this genetic subtype of adRP.
Notes
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PubMed ID
19050727 View in PubMed
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