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Advances in Non-Invasive Diagnosis of Single-Gene Disorders and Fetal Exome Sequencing
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Liesbeth Vossaert, Roni Zemet, Ignatia B. Van den Veyver
NGS cannot cover all sequence variants.57,65,74 It performs well for single-nucleotide variants and small insertion/deletions, but regions with high CG content are more difficult to capture. Because the consensus sequence is built from the alignment of overlapping short fragments, regions with high homology to other sequences within the genome are challenging. These include duplicated genes or exons, repetitive sequences, short repeat expansions, pseudogenes, and highly homologous gene families. Structural chromosomal abnormalities or aneuploidy can be detected by genome sequencing (GS), but not currently as effectively by ES. Low-level mosaic variants are also challenging, but can be identified provided that the sequencing depth is adequate. Haplotype information can aid in detecting uniparental disomy.
Mosaicism Mechanisms in Preimplantation Embryos
Published in Darren K. Griffin, Gary L. Harton, Preimplantation Genetic Testing, 2020
Maurizio Poli, Antonio Capalbo
Provided that mosaicism is reported only for embryos with a ratio of aneuploid cells not lower than 30%, careful consideration should be given to the chromosomes involved in the alteration. In a recent study, Grati and colleagues analyzed over 70,000 CVS and over 3800 POCs in order to assess incidence and risk of adverse outcome in the case of mosaicism for each chromosome [4]. Taking into consideration (i) the risk of a certain aneuploidy to result in full-term pregnancy; (ii) the likelihood that a mosaic aneuploidy present in the villi would involve the fetus (and not only the placenta); (iii) the incidence that a uniparental disomy present in the villi would involve a clinically significant condition in the fetus, and (iv) the chance that a specific chromosomal mosaicism would result in miscarriage, they have produced a mosaicism risk score to help in the selection of which mosaic embryos might be eligible for transfer (Figure 8.7). This information can help clinicians and embryologists in counseling patients regarding the risks of transferring a mosaic embryo. Based on these data, the transfer of embryos showing certain types of mosaicism should be avoided because of the increased life-threating risks associated. These cases involve aneuploidies that are (i) compatible with life (i.e., mosaic trisomies for chromosomes, 21; 18; 13, and 45,X), (ii) compatible with late fetal development (i.e., mosaic trisomies for chromosome 16), (iii) associated with a high chance of deriving from uniparental disomy (i.e., mosaic trisomies for chromosome 14), and (iv) highly likely to involve the fetus (i.e., 47,XXY).
Genetics
Published in Rachel U Sidwell, Mike A Thomson, Concise Paediatrics, 2020
Rachel U Sidwell, Mike A Thomson
The absence of the active gene may result from: New mutation. Normal parental chromosomes. Gene deletion from one parentUniparental disomy. Normal parental chromosomes. The child inherits both copies from one parent. Thus the normal number of copies is present but there is an effective deletion of the copy from one of the parents. The resulting syndrome depends on which copy is missing
Near-Haploid B-Cell Acute Lymphoblastic Leukemia in a Patient with Rubinstein-Taybi Syndrome
Published in Pediatric Hematology and Oncology, 2022
Kristen J. Kurtz, Eran Tallis, Andrea N. Marcogliese, Rao H. Pulivarthi, Lorraine Potocki, Alexandra M. Stevens
Genetics was consulted to evaluate for a unifying cause of the patient’s developmental delay, short stature, and hematologic malignancy. We specifically sought to rule out TP53 pathogenic variants considering her near-haploid clone because of the association between low-hypodiploid B-ALL (32–39 chromosomes) and Li Fraumeni syndrome.11,12 On examination, dysmorphic facial features (Figure 2A) and short broad digits (Figure 2B), were noted. Chest X-ray showed a bifid first rib. No central nervous system (CNS), cardiac, or renal malformations were identified on diagnostic imaging. Family history was overall noncontributory with no history of genetic diagnoses, birth defects, intellectual disability, or cancers diagnosed before the age of 50 in the extended family. Genetic testing with chromosomal microarray analysis (CMA) and exome sequencing was recommended. CMA performed on peripheral blood identified a small 0.002 Mb copy number loss within chromosome band 15q22.31, as well as a small 0.019 Mb copy number gain within chromosome band 15q25.2. Neither change was interpreted as contributing to the patient’s phenotype. No increased blocks of absence of heterozygosity suggestive of uniparental disomy or consanguinity were identified. Exome sequencing of fibroblasts cultured from a skin biopsy uncovered a likely pathogenic heterozygous missense variant (c.4442A > G; p.D1481G) within exon 27, in the critical HAT domain of CREBBP, confirming a diagnosis of Rubinstein-Taybi syndrome. No other molecular changes were reported.
Analysis of an NGS retinopathy panel detects chromosome 1 uniparental isodisomy in a patient with RPE65-related leber congenital amaurosis
Published in Ophthalmic Genetics, 2021
Fabiana Louise Motta, Rafael Filippelli-Silva, Joao Paulo Kitajima, Denise A. Batista, Elizabeth S. Wohler, Nara L. Sobreira, Renan Paulo Martin, Juliana Maria Ferraz Sallum
Uniparental disomy (UPD) is characterized by the inheritance of a pair of homologous chromosomes from only one parent. This genetic event may entirely or partially affect the chromosome (complete or segmental uniparental disomy, respectively) and may result in identical copies of a chromosome (isodisomy) or different copies of the same chromosome (heterodisomy) from one parent (5,6). Some mechanisms may lead to UPD, such as monosomy rescue, postfertilization errors, trisomy rescue, or gamete complementation (5). Despite being a non-Mendelian event, uniparental disomy can lead to a recessive monogenic disease by the formation of a homozygous allele derived from a heterozygous parent (7). The identification of UPD is extremely important because it impacts family genetic counseling and the risk of disease recurrence.
Further Characterization of Hb Bronovo [α103(G10)His→Leu; HBA2: c.311A>T] and First Report of the Homozygous State
Published in Hemoglobin, 2020
Nikita Mehta, J. Martin Johnston, Molly Hein, Benjamin R. Kipp, Lea Coon, Michelle E. Savedra, James D. Hoyer, Rong He, Aruna Rangan, Min Shi, Jennifer L. Oliveira
Uniparental disomy (UPD) analysis of chromosomes 11 and 16 were also performed for the proband and his parents. Uniparental disomy studies were performed by a previously described technique [7,8]. In brief, samples were genotyped using PCR of chromosome-specific microsatellite markers (dinucleotide repeats). The markers used for chromosome 16 were D16S521, D16S418, D16S500, D16S3041, D16S3100, D16S3034, D16S3057, D16S503, D16S515, D16S516, D16S505 and D16S520; the markers used for chromosome 11 were D11S1363, D11S4046, D11S4146, D11S1760, D11S1338, D11S4116, D11S935, D11S987, D11S1314, D11S937, D11S901, D11S898, D11S4151, D11S1320 and D11S968. Diagnosis of UPD required that the proband carries at least two informative markers representing uniparental inheritance of chromosome 16, in addition to all informative markers for chromosome 11 showing biparental inheritance [9].