The impact of 22q11.2 copy-number variants on human traits in the general population.

While extensively studied in clinical cohorts, the phenotypic consequences of 22q11.2 copy-number variants (CNVs) in the general population remain understudied. To address this gap, we performed a phenome-wide association scan in 405,324 unrelated UK Biobank (UKBB) participants by using CNV calls from genotyping array. We mapped 236 Human Phenotype Ontology terms linked to any of the 90 genes encompassed by the region to 170 UKBB traits and assessed the association between these traits and the copy-number state of 504 genotyping array probes in the region. We found significant associations for eight continuous and nine binary traits associated under different models (duplication-only, deletion-only, U-shape, and mirror models). The causal effect of the expression level of 22q11.2 genes on associated traits was assessed through transcriptome-wide Mendelian randomization (TWMR), revealing that increased expression of ARVCF increased BMI. Similarly, increased DGCR6 expression causally reduced mean platelet volume, in line with the corresponding CNV effect. Furthermore, cross-trait multivariable Mendelian randomization (MVMR) suggested a predominant role of genuine (horizontal) pleiotropy in the CNV region. Our findings show that within the general population, 22q11.2 CNVs are associated with traits previously linked to genes in the region, and duplications and deletions act upon traits in different fashions. We also showed that gain or loss of distinct segments within 22q11.2 may impact a trait under different association models. Our results have provided new insights to help further the understanding of the complex 22q11.2 region

Breakpoint mapping at nucleotide resolution in X-autosome balanced translocations associated with clinical phenotypes.

Precise breakpoint mapping of balanced chromosomal rearrangements is crucial to identify disease etiology. Ten female patients with X-autosome balanced translocations associated with phenotypic alterations were evaluated, by mapping and sequencing their breakpoints. The rearrangements' impact on the expression of disrupted genes, and inferred mechanisms of formation in each case were assessed. For four patients that presented one of the chromosomal breaks in heterochromatic and highly repetitive segments, we combined cytogenomic methods and short-read sequencing to characterize, at nucleotide resolution, breakpoints that occurred in reference genome gaps. Most of rearrangements were possibly formed by non-homologous end joining and have breakpoints at repeat elements. Seven genes were found to be disrupted in six patients. Six of the affected genes showed altered expression, and the functional impairment of three of them were considered pathogenic. One gene disruption was considered potentially pathogenic, and three had uncertain clinical significance. Four patients presented no gene disruptions, suggesting other pathogenic mechanisms. Four genes were considered potentially affected by position effect and the expression abrogation of one of them was confirmed. This study emphasizes the importance of breakpoint-junction characterization at nucleotide resolution in balanced rearrangements to reveal genetic mechanisms associated with the patients' phenotypes, mechanisms of formation that originated the rearrangements, and genomic nature of disrupted DNA sequences

Clinical, Cytogenetic, And Molecular Characterization Of Six Patients With Ring Chromosomes 22, Including One With Concomitant 22q11.2 Deletion

We report here on six patients with a ring chromosome 22 and the range of cytogenetic and phenotypic features presented by them. Genomic analysis was carried out using classical and molecular cytogenetics, MLPA (Multiplex Ligation-dependent Probe Amplification) and genome-wide SNP-array analysis. The ring was found in all patients, but Patient 6 displayed constitutional mosaicism with a normal cell line. Five patients had deletions in the ring chromosome 22, and in four of them the breakpoints-unique for each patient-could be identified by genome-wide SNP-array analysis. One patient presented with a 22q11.2 deletion concomitant with the deletion caused by the ring formation. Common phenotypic features included autism, speech delay and seizures, as previously reported for individuals with r(22) and/or 22q13.3 deletions. Investigation of the genes within the deletions revealed multiple genes related to development of the central nervous system, psychomotor delay, severe language impairment, hypotonia, and autistic symptoms. There was no clear correlation between the severity of clinical features and the size of the deleted segment. This study underscores the variability in ring structure and clinical presentation of the r(22) and adds information to the limited literature on this rare disorder. © 2014 Wiley Periodicals, Inc.164716591665Anderlid, B.M., Schoumans, J., Anneren, G., Tapia-Paez, I., Dumanski, J., Blennow, E., Nordenskjold, M., FISH-mapping of a 100-kb terminal 22q13 deletion (2002) Hum Genet, 110, pp. 439-443Assumpcao Jr., F.B., Brief report: A case of chromosome 22 alteration associated with autistic syndrome (1998) J Autism Dev Disord, 28, pp. 253-256Baumer, A., Dutly, F., Balmer, D., Riegel, M., Tukel, T., Krajewska-Walasek, M., Schinzel, A.A., High level of unequal meiotic crossovers at the origin of the 22q11. 2 and 7q11.23 deletions (1998) Hum Mol Genet, 7, pp. 887-894Cusmano-Ozog, K., Manning, M.A., Hoyme, H.E., 22q13.3 deletion syndrome: A recognizable malformation syndrome associated with marked speech and language delay (2007) Am J Med Genet C Semin Med Genet, 145 C, pp. 393-398De Mas, P., Chassaing, N., Chaix, Y., Vincent, M.C., Julia, S., Bourrouillou, G., Calvas, P., Bieth, E., Molecular characterisation of a ring chromosome 22 in a patient with severe language delay: A contribution to the refinement of the subtelomeric 22q deletion syndrome (2002) J Med Genet, 39, pp. e17Delahaye, A., Toutain, A., Aboura, A., Dupont, C., Tabet, A.C., Benzacken, B., Elion, J., Drunat, S., Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3 (2009) Eur J Med Genet, 52, pp. 328-332Devriendt, K., Fryns, J.P., Mortier, G., van Thienen, M.N., Keymolen, K., The annual incidence of DiGeorge/velocardiofacial syndrome (1998) J Med Genet, 35, pp. 789-790Dhar, S.U., del Gaudio, D., German, J.R., Peters, S.U., Ou, Z., Bader, P.I., Berg, J.S., Sahoo, T., 22q13.3 deletion syndrome: Clinical and molecular analysis using array CGH (2010) Am J Med Genet A, 152 A, pp. 573-581Funderburk, S.J., Sparkes, R.S., Klisak, I., Phenotypic variation in two patients with a ring chromosome 22 (1979) Clin Genet, 16, pp. 305-310Giza, J., Urbanski, M.J., Prestori, F., Bandyopadhyay, B., Yam, A., Friedrich, V., Kelley, K., Goldfarb, M., Behavioral and cerebellar transmission deficits in mice lacking the autism-linked gene islet brain-2 (2010) J Neurosci, 30, pp. 14805-14816Goizet, C., Excoffier, E., Taine, L., Taupiac, E., El Moneim, A.A., Arveiler, B., Bouvard, M., Lacombe, D., Case with autistic syndrome and chromosome 22q13.3 deletion detected by FISH (2000) Am J Med Genet, 96, pp. 839-844Guilherme, R.S., de Freitas Ayres Meloni, V., Sodre, C.P., Christofolini, D.M., Pellegrino, R., de Mello, C.B., Conlin, L.K., Melaragno, M.I., Cytogenetic and molecular evaluation and 20-year follow-up of a patient with ring chromosome 14 (2010) Am J Med Genet A, 152 A, pp. 2865-2869Guilherme, R.S., Meloni, V.F., Kim, C.A., Pellegrino, R., Takeno, S.S., Spinner, N.B., Conlin, L.K., Melaragno, M.I., Mechanisms of ring chromosome formation, ring instability and clinical consequences (2011) BMC Med Genet, 12, p. 171Hunter, A.G., Ray, M., Wang, H.S., Thompson, D.R., Phenotypic correlations in patients with ring chromosome 22 (1977) Clin Genet, 12, pp. 239-249Ishmael, H.A., Cataldi, D., Begleiter, M.L., Pasztor, L.M., Dasouki, M.J., Butler, M.G., Five new subjects with ring chromosome 22 (2003) Clin Genet, 63, pp. 410-414Jacquemont, M.L., Sanlaville, D., Redon, R., Raoul, O., Cormier-Daire, V., Lyonnet, S., Amiel, J., Philippe, A., Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders (2006) J Med Genet, 43, pp. 843-849Jeffries, A.R., Curran, S., Elmslie, F., Sharma, A., Wenger, S., Hummel, M., Powell, J., Molecular and phenotypic characterization of ring chromosome 22 (2005) Am J Med Genet A, 137 A, pp. 139-147Kosho, T., Matsushima, K., Sahashi, T., Mitsui, N., Fukushima, Y., Sobajima, H., Ohashi, H., Ring syndrome" involving chromosome 2 confirmed by FISH analysis using chromosome-specific subtelomeric probes (2005) Genet Couns, 16, pp. 65-70Le Caignec, C., Boceno, M., Jacquemont, S., Nguyen, T., Tich, S., Rival, J.M., David, A., Inherited ring chromosome 8 without loss of subtelomeric sequences (2004) Ann Genet, 47, pp. 289-296Lejeune, J., On the duplication of circular structures (1968) Ann Genet, 11, pp. 71-77Luciani, J.J., de Mas, P., Depetris, D., Mignon-Ravix, C., Bottani, A., Prieur, M., Jonveaux, P., Mattei, M.G., Telomeric 22q13 deletions resulting from rings, simple deletions, and translocations: Cytogenetic, molecular, and clinical analyses of 32 new observations (2003) J Med Genet, 40, pp. 690-696MacLean, J.E., Teshima, I.E., Szatmari, P., Nowaczyk, M.J., Ring chromosome 22 and autism: Report and review (2000) Am J Med Genet, 90, pp. 382-385Nesslinger, N.J., Gorski, J.L., Kurczynski, T.W., Shapira, S.K., Siegel-Bartelt, J., Dumanski, J.P., Cullen Jr., R.F., McDermid, H.E., Clinical, cytogenetic, and molecular characterization of seven patients with deletions of chromosome 22q13.3 (1994) Am J Hum Genet, 54, pp. 464-472Phelan, K., McDermid, H.E., The 22q13.3 deletion syndrome (Phelan-McDermid Syndrome) (2012) Mol Syndromol, 2, pp. 186-201Prasad, C., Prasad, A.N., Chodirker, B.N., Lee, C., Dawson, A.K., Jocelyn, L.J., Chudley, A.E., Genetic evaluation of pervasive developmental disorders: The terminal 22q13 deletion syndrome may represent a recognizable phenotype (2000) Clin Genet, 57, pp. 103-109Precht, K.S., Lese, C.M., Spiro, R.P., Huttenlocher, P.R., Johnston, K.M., Baker, J.C., Christian, S.L., Ledbetter, D.H., Two 22q telomere deletions serendipitously detected by FISH (1998) J Med Genet, 35, pp. 939-942Ritter, C.L., Steele, M.W., Wenger, S.L., Cohen, B.A., Chromosome mosaicism in hypomelanosis of Ito (1990) Am J Med Genet, 35, pp. 14-17Saitta, S.C., Harris, S.E., Gaeth, A.P., Driscoll, D.A., McDonald-McGinn, D.M., Maisenbacher, M.K., Yersak, J.M., Emanuel, 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Inactivation of AMMECR1 is associated with growth, bone, and heart alterations.

We report five individuals with loss-of-function of the X-linked AMMECR1: a girl with a balanced X-autosome translocation and inactivation of the normal X-chromosome; two boys with maternally inherited and de novo nonsense variants; and two half-brothers with maternally inherited microdeletion variants. They present with short stature, cardiac and skeletal abnormalities, and hearing loss. Variants of unknown significance in AMMECR1 in four male patients from two families with partially overlapping phenotypes were previously reported. AMMECR1 is coexpressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alterations. Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients' features. The increased transcript and encoded protein levels of AMMECR1L, an AMMECR1 paralog, in the t(X;9) patient's cells indicate a possible partial compensatory mechanism. AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid-binding RAGNYA folds. Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart, and kidney alterations with or without elliptocytosis