Browsing by Subject "Homozygosity"

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Open Access
An integrated map of structural variation in 2,504 human genomes
(Nature Publishing Group, 2015) Sudmant, P. H.; Rausch, T.; Gardner, E. J.; Handsaker, R. E.; Abyzov, A.; Huddleston, J.; Zhang, Y.; Ye, K.; Jun, G.; Fritz, M. Hsi-Yang; Konkel, M. K.; Malhotra, A.; Stütz, A. M.; Shi, X.; Casale, F. P.; Chen, J.; Hormozdiari, F.; Dayama, G.; Chen, K.; Malig, M.; Chaisson, M. J. P.; Walter, K.; Meiers, S.; Kashin, S.; Garrison, E.; Auton, A.; Lam, H. Y. K.; Mu, X. J.; Alkan, C.; Antaki, D.; Bae, T.; Cerveira, E.; Chines, P.; Chong, Z.; Clarke, L.; Dal, E.; Ding, L.; Emery, S.; Fan, X.; Gujral, M.; Kahveci, F.; Kidd, J. M.; Kong, Y.; Lameijer, Eric-Wubbo; McCarthy, S.; Flicek, P.; Gibbs, R. A.; Marth, G.; Mason, C. E.; Menelaou, A.; Muzny, D. M.; Nelson, B. J.; Noor, A.; Parrish, N. F.; Pendleton, M.; Quitadamo, A.; Raeder, B.; Schadt, E. E.; Romanovitch, M.; Schlattl, A.; Sebra, R.; Shabalin, A. A.; Untergasser, A.; Walker J. A.; Wang, M.; Yu, F.; Zhang, C.; Zhang, J.; Zheng-Bradley, X.; Zhou, W.; Zichner, T.; Sebat, J.; Batzer, M. A.; McCarroll, S. A.; Mills, R. E.; Gerstein, M. B.; Bashir, A.; Stegle, O.; Devine, S. E.; Lee, C.; Eichler, E. E.; Korbel, J. O.
Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.
Open Access
Mutations in RAD21 disrupt regulation of apob in patients with chronic intestinal pseudo-obstruction
(W.B. Saunders, 2015) Bonora, E.; Bianco, F.; Cordeddu, L.; Bamshad, M.; Francescatto, L.; Dowless, D.; Stanghellini, V.; Cogliandro, R. F.; Lindberg, G.; Mungan, Z.; Cefle, K.; Ozcelik, T.; Palanduz, S.; Ozturk, S.; Gedikbasi, A.; Gori, A.; Pippucci, T.; Graziano, C.; Volta, U.; Caio, G.; Barbara, G.; D'Amato, M.; Seri, M.; Katsanis, N.; Romeo, G.; De Giorgio, R.
Background Aims Chronic intestinal pseudo-obstruction (CIPO) is characterized by severe intestinal dysmotility that mimics a mechanical subocclusion with no evidence of gut obstruction. We searched for genetic variants associated with CIPO to increase our understanding of its pathogenesis and to identify potential biomarkers. Methods We performed whole-exome sequencing of genomic DNA from patients with familial CIPO syndrome. Blood and lymphoblastoid cells were collected from patients and controls (individuals without CIPO); levels of messenger RNA (mRNA) and proteins were analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblot, and mobility shift assays. Complementary DNAs were transfected into HEK293 cells. Expression of rad21 was suppressed in zebrafish embryos using a splice-blocking morpholino (rad21a). Gut tissues were collected and analyzed. Results We identified a homozygous mutation (p.622, encodes Ala>Thr) in RAD21 in patients from a consanguineous family with CIPO. Expression of RUNX1, a target of RAD21, was reduced in cells from patients with CIPO compared with controls. In zebrafish, suppression of rad21a reduced expression of runx1; this phenotype was corrected by injection of human RAD21 mRNA, but not with the mRNA from the mutated p.622 allele. rad21a Morpholino zebrafish had delayed intestinal transit and greatly reduced numbers of enteric neurons, similar to patients with CIPO. This defect was greater in zebrafish with suppressed expression of ret and rad21, indicating their interaction in the regulation of gut neurogenesis. The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. The gut-specific isoform of APOB (APOB48) is overexpressed in sera from patients with CIPO who carry the RAD21 mutation. APOB48 also is overexpressed in sporadic CIPO in sera and gut biopsy specimens. Conclusions Some patients with CIPO carry mutations in RAD21 that disrupt the ability of its product to regulate genes such as RUNX1 and APOB. Reduced expression of rad21 in zebrafish, and dysregulation of these target genes, disrupts intestinal transit and the development of enteric neurons.
Open Access
Novel VLDLR microdeletion identified in two Turkish siblings with pachygyria and pontocerebellar atrophy
(Springer, 2010) Kolb, L. E.; Arlier, Z.; Yalcinkaya, C.; Ozturk, A. K.; Moliterno, J. A.; Erturk, O.; Bayrakli, F.; Korkmaz, B.; DiLuna, M. L.; Yasuno, K.; Bilguvar, K.; Ozcelik, T.; Tuysuz, B.; State, M. W.; Gunel, M.
Congenital ataxia with cerebellar hypoplasia is a heterogeneous group of disorders that presents with motor disability, hypotonia, incoordination, and impaired motor development. Among these, disequilibrium syndrome describes a constellation of findings including non-progressive cerebellar ataxia, mental retardation, and cerebellar hypoplasia following an autosomal recessive pattern of inheritance and can be caused by mutations in the Very Low Density Lipoprotein Receptor (VLDLR). Interestingly, while the majority of patients with VLDL-associated cerebellar hypoplasia in the literature use bipedal gait, the previously reported patients of Turkish decent have demonstrated similar neurological sequelae, but rely on quadrupedal gait. We present a consanguinous Turkish family with two siblings with cerebellar atrophy, predominantly frontal pachygyria and ataxic bipedal gait, who were found to have a novel homozygous deletion in the VLDLR gene identified by using high-density single nucleotide polymorphism microarrays for homozygosity mapping and identification of CNVs within these regions. Discovery of disease causing homozygous deletions in the present Turkish family capable of maintaining bipedal movement exemplifies the phenotypic heterogeneity of VLDLR-associated cerebellar hypoplasia and ataxia.
Open Access
Skewed X inactivation in an X linked nystagmus family resulted from a novel, p.R229G, missense mutation in the FRMD7 gene
(BMJ Group, 2008) Kaplan, Y.; Vargel, I.; Kansu, T.; Akin, B.; Rohmann, E.; Kamaci, S.; Uz, E.; Ozcelik, T.; Wollnik, B.; Akarsu, N. A.
Aims: This study aimed to identify the underlying genetic defect of a large Turkish X linked nystagmus (NYS) family. Methods: Both Xp11 and Xq26 loci were tested by linkage analysis. The 12 exons and intron-exon junctions of the FRMD7 gene were screened by direct sequencing. X chromosome inactivation analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme, followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. Results: The family contained 162 individuals, among whom 28 had NYS. Linkage analysis confirmed the Xq26 locus. A novel missense c.686C>G mutation, which causes the substitution of a conserved arginine at amino acid position 229 by glycine (p.R229G) in exon 8 of the FRMD7 gene, was observed. This change was not documented in 120 control individuals. The clinical findings in a female who was homozygous for the mutation were not different from those of affected heterozygous females. Skewed X inactivation was remarkable in the affected females of the family. Conclusions: A novel p.R229G mutation in the FRMD7 gene causes the NYS phenotype, and skewed X inactivation influences the manifestation of the disease in X linked NYS females.