A locus for Bowen-Conradi syndrome maps to chromosome region 12p13.3

Bowen-Conradi syndrome (BCS) is a lethal autosomal recessive disorder with an estimated incidence of 1 in 355 live births in the Hutterite population. A few cases have been reported in other populations. Here, we report the results of a genome-wide scan and fine mapping of the BCS locus in Hutterite families. By linkage and haplotype analysis the BCS locus was mapped to a 3.5 cM segment (1.9 Mbp) in chromosome region 12p13.3 bounded by F8VWF and D12S397. When genealogical relationships among the families were taken into account in the linkage analysis, the evidence for linkage was stronger and the number of potentially linked regions was reduced to one. Under the assumption that all the Hutterite patients were identical by descent for a disease-causing mutation, haplotype analysis was used to infer likely historical recombinants and thereby narrow the candidate region to a chromosomal segment shared in common by all the affected children. This study also demonstrates that BCS and cerebro-oculo-facial-skeletal syndrome (COFS) are genetically distinct.     

NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review.

Nephrotic syndrome, characterized by edema, proteinuria, hyperlipidemia and low serum albumin, is a manifestation of kidney disease involving the glomeruli. Nephrotic syndrome may be caused by primary kidney disease such as focal segmental glomerulosclerosis. Mutations in the podocin gene, NPHS2, have been shown in familial and sporadic forms of steroid-resistant nephrotic syndrome, including focal segmental glomerulosclerosis. Podocin is an integral membrane protein located at the slit diaphragm of the glomerular permeability barrier. Complete information is lacking for the population frequency of some NPHS2 variants for all racial and ethnic groups. The most frequently reported variant, R229Q, is more common among European-derived populations than African-derived populations. We calculated crude odds ratios and 95% confidence intervals of childhood nephrotic syndrome and focal segmental glomerulosclerosis associated with R229Q heterozygosity using data from five studies. The R229Q variant is not associated with focal segmental glomerulosclerosis in the US population of African descent. In contrast, the R229Q variant is associated with a trend toward increased focal segmental glomerulosclerosis risk in European-derived populations, with an estimated increased risk of 20-40%. Our insight into the association between NPHS2 variants and nephrotic disease is hampered by the limitations of the existing studies, including small numbers of affected individuals and suboptimal control groups. Nevertheless, the available data suggest that large epidemiological case-control studies to examine the association between NPHS2 variants and nephrotic syndrome are warranted.     

Chromosome rearrangements in cornelia de Lange syndrome (CdLS): report of a der(3)t(3;12)(p25.3;p13.3) in two half sibs with features of CdLS and review of reported CdLS cases with chromosome rearrangements

Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited disorder characterized by multisystem involvement, cognitive delay, limb defects, and characteristic facial features. Recently, mutations in NIPBL have been found in approximately 50% of individuals with CdLS. Numerous chromosomal rearrangements have been reported in individuals with CdLS. These rearrangements may be causative of a CdLS phenotype, result in a phenocopy, or be unrelated to the observed phenotype. We describe two half siblings with a der(3)t(3;12)(p25.3;p13.3) chromosomal rearrangement, clinical features resembling CdLS, and phenotypic overlap with the del(3)(p25) phenotype. Region-specific BAC probes were used to fine-map the breakpoint region by fluorescence in situ hybridization (FISH). FISH analysis places the chromosome 3 breakpoint distal to RP11-115G3 on 3p25.3; the chromosome 12 breakpoint is distal to BAC RP11-88D16 on 12p13.3. A review of published cases of terminal 3p deletions and terminal 12p duplications indicates that the findings in these siblings are consistent with the del(3)(p25) phenotype. Given the phenotypic overlap with CdLS, we have reviewed the reported cases of chromosomal rearrangements involved in CdLS to better elucidate other potential loci that could harbor additional CdLS genes. Additionally, to identify chromosome rearrangements, genome-wide array comparative genomic hybridization (CGH) was performed on eight individuals with typical CdLS and without identifiable deletion or mutation of NIPBL. No pathologic rearrangements were identified.     

Complex karyotypic abnormality in ovarian fibroma associated with Gorlin syndrome

Nevoid basal cell carcinoma (NBCC) syndrome is an autosomal dominant disorder characterized by distinctive congenital malformations and a variety of benign and malignant neoplasms, including ovarian fibromas. We describe pathologic and cytogenetic findings in a large unilateral ovarian fibroma from a 12-year-old female with NBCC syndrome. The pathologic findings were characteristic for ovarian fibroma, but were unusual for the ovarian fibromas associated with NBCC syndrome because of the absence of calcification, the lack of bilaterality, and the presence of focal hypercellularity. The karyotype of tumor tissue showed complex numerical and structural abnormalities. Although there is frequent loss of heterozygosity of 9q22.3 and mutations in the PTCHgene in Gorlin syndrome, the ovarian fibroma in this case did not have cytogenetically detectable abnormalities of chromosome 9.     

Effect of disodium cromoglycate on antigen-evoked histamine release from human skin

The effect of disodium cromoglycate (DSCG) on antigen-evoked histamine release from IgE-sensitized human skin in vitro has been studied using breast skin from six donors. Concentrations of DSCG ranging from 10–200 μM did not produce any consistent effect on histamine release, the results ranging from moderate inhibition to moderate enhancement. With higher concentrations of DSCG (400–500 μM) enhancement of release occurred in nearly all experiments. Variation of antigen concentration did not modify the response to DSCG. These results do not support the possibility that DSCG may be effective in the treatment of immediate hypersensitivity reactions in human skin.     

Population survey of CCR5 delta32, CCR5 m303, CCR2b 64I,and SDF1 3'A allele frequencies in indigenous Chinese healthy individuals,and in HIV-1-infected and HIV-1-uninfected individuals in HIV-1 risk groups

The aim of this study is to determine in indigenous Chinese ethnic groups the frequencies of the chemokine (SDF1 3'A) and chemokine receptors (CCR5 delta32, CCR5 m303, and CCR2b 64I) HIV-1/AIDS restriction alleles. The study includes two cohorts; the first comprised 3165 indigenous healthy subjects representing eight ethnic groups: Han (n = 1406), Uygur (n = 316), Mongolia (n = 134), Hui (n = 386), Tibetan (n = 330), Zhuang (n = 378), Dai (n = 101), and Jingbo (n =114). The second cohort consisted of 330 HIV-1-infected (86 subjects infected by sexual transmission and 198 subjects infected by HIV-1-contaminated blood or by sharing injection equipment; the remaining 46 subjects said nothing about HIV-1 transmission) and 474 HIV-1-uninfected Han Chinese belonging to one of two HIV-1 high-risk groups: intravenous drug users (n = 215) and individuals with sexually transmitted diseases (n = 259). Genotypes for the four genes were obtained using PCR (CCR5 delta32) or PCR-restriction fragment length polymorphism. Randomly selected amplified PCR products were further confirmed by direct DNA sequencing. The variant allele frequencies were determined to be 0% to 3.48% for CCR5 delta32, 0% for CCR5 m303, 16.23% to 28.79% for CCR2b 64I, and 17.70% to 27.76% for SDF1 3'A in Chinese healthy individuals from eight ethnic groups. These findings show that allele frequencies differ among the eight Chinese ethnic groups for CCR5 delta32, CCR2b 64I, and SDF1 3'A and that the CCR5 m303 and CCR5 delta32 mutant alleles were absent or infrequent in Chinese, which may be helpful for studies of specific anti-HIV-1 vaccine trials and coreceptor inhibitor drug targets in Chinese populations. Furthermore, we observed no significant differences in allele or genotypic frequencies between HIV-1-infected and HIV-1-uninfected groups from the Han ethnic group. Our finding is the first reporting that there is likely no effect of the examined polymorphisms in our study on HIV-1 transmission in the Chinese Han population, However, the genetic effects of these and other AIDS-modifying polymorphisms on the pathogenesis and clinical outcome of HIV-1/AIDS diseases is under investigation in Chinese populations.     

Psychological distress among minority and low-income women living with HIV

The growing incidence of HIV infection among low-income and minority women makes it important to investigate how these women adjust to living with HIV and AIDS. Psychological distress associated with HIV infection may compound the adjustment difficulties and increase the barriers to care associated with living in poverty. The authors surveyed 100 women who were receiving HIV care at a public hospital in the southeastern United States on measures of depression, anxiety, life stress, social support, and coping; they also assessed demographic and medical characteristics of the sample. Participants' annual incomes were low (87% < $10,000), and most participants were minorities (84% African American). Their levels of depression, stress, and anxiety symptoms were elevated relative to community norms. Greater anxiety and depression symptoms were associated with women who reported higher stress, using fewer active coping strategies, and perceiving less social support (ps < .001).     

The genetic basis of Turner syndrome aortopathy

Our goal is to identify the genetic underpinnings of bicuspid aortic valve and aortopathy in Turner syndrome. We performed whole exome sequencing on 188 Turner syndrome study subjects from the GenTAC registry. A gene‐based burden test, SKAT‐O, was used to evaluate the data using bicuspid aortic valve (BAV) and aortic dimension z‐scores as covariates. This revealed that TIMP3 was associated with BAV and increased aortic dimensions at exome‐wide significance. It had been previously shown that genes on chromosome Xp contribute to aortopathy when hemizygous. Our analysis of Xp genes revealed that hemizygosity for TIMP1, a functionally redundant paralogue of TIMP3, increased the odds of having BAV aortopathy compared to individuals with more than one TIMP1 copy. The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles synergistically increased the risk for BAV aortopathy to nearly 13‐fold. TIMP1 and TIMP3 are tissue inhibitors of matrix metalloproteinases (TIMPs) which are involved in development of the aortic valve and protection from thoracic aneurysms. We propose that the combination of TIMP1 haploinsufficiency and deleterious variants in TIMP3 significantly increases the risk of BAV aortopathy in Turner syndrome, and suggest that TIMP1 hemizygosity may play a role in euploid male aortic disease.