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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
In a euploid-aneuploid mosaic embryo, both normal and abnormal cells are present. This scenario derives from either (i) a euploid zygote undergoing an aberrant mitotic division that generates one or more defective chromosomal sets in the embryo, or (ii) a chromosomally abnormal zygote where a mitotic event corrects the original aneuploidy, rebalancing chromosomal copies and generating a euploid cell lineage. In this latter case, uniparental disomy (UPD) can ensue.
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.
Improvement of Planning Abilities in Adults with Prader-Willi Syndrome: A Randomized Controlled Trial
Published in Developmental Neurorehabilitation, 2021
Séverine Estival, Virginie Laurier, Fabien Mourre, Virginie Postal
The experimental group comprised 27 adults with PWS, 16 women and 11 men. Eighteen patients had a paternal deletion, three had uniparental maternal disomy and six had other forms of genetic defect (imprinting center mutations or translocations). The control group comprised 26 adults with PWS, 16 women and 10 men. Twenty-three patients had a paternal deletion, one patient had uniparental maternal disomy and two other forms of genetic defect (translocations). Characteristics of the two groups relative to age, gender, FSIQ, VIQ and PIQ can be found in Table 2. Intergroup difference was found for age, t (51) = 2.10, p = .03 and was later controlled for in between-group comparisons. No differences were found between the groups for FSIQ, t (39) = −.23, p = .82, VIQ, t (39) = −.15, p = .88, or PIQ, t (39) = .07, p = .94. An assessment of the overall cognitive efficiency of the participants was done with the MoCA (Montreal Cognitive Assessment).49 The MoCA is an assessment tool that allows to quickly evaluate several cognitive functions such as visuospatial skills, attention, concentration, EF, memory, language, abstraction, calculation and orientation. The maximum score is 30 points with a threshold of detection of mild cognitive impairment at 26/30. There was no difference between the groups for the MoCA score, t (51) = .81, p = .42.
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.