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.
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.
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.
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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.
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
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.
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.
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.
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.
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