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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
Clinical genetics
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Any change in DNA sequence that affects the processes of transcription, splicing, or translation will affect the production of protein. A disease-causing mutation may be a deletion of the entire gene, deletion of a part of the gene, or a change of a single base. When considering the effect of a mutation, it is important to work out how it will affect the processes of transcription, splicing, translation, and post-translational modification of a protein (Table 5.1).
The eye
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Choroideraemia is a specific X-linked disorder that may be confused with retinitis pigmentosa, especially in its early stages. It is infrequently associated with more generalised, and often severe, developmental problems as part of a contiguous gene deletion syndrome. Norrie disease is the severe end of a spectrum associated with mutation in the NDP gene, which also causes the milder X-linked familial exudative retinopathy. It is associated with progressive deafness and more generalised developmental difficulties in 30%–50% of those affected. Retinoschisis is yet another X-linked disorder, with retinal degeneration associated with a characteristic splitting of the retina, where specific molecular analysis is possible.
Therapeutic approach to neurological manifestations of Angelman syndrome
Published in Expert Review of Clinical Pharmacology, 2022
Michele Ascoli, Maurizio Elia, Sara Gasparini, Paolo Bonanni, Giovanni Mastroianni, Vittoria Cianci, Sabrina Neri, Angelo Pascarella, Domenico Santangelo, Umberto Aguglia, Edoardo Ferlazzo
Severe cognitive disability is described in AS subjects. Cognitive assessment, using psychometric tests and instruments that give a qualitative evaluation of cognitive competencies, can demonstrate this finding in almost all AS patients [8]. Cognitive skills appear to be much lower in subjects with gene deletion than in subjects without deletion. Regarding language abilities, a severe impairment of expressive and receptive skills was found at all ages in AS. Some children showed gestural skills such as referential gestures, and none of them revealed pretending play skills, which involve the use of language use and take place in social settings [46]. Speech disorder in AS has a typical evolution; approximatively before 10 months, infants show decreased cooing and babbling; around 10–18 months they are typically able to pronounce a single word, such as ‘mom’ or ‘dad’ (often used infrequently and indiscriminately without symbolic meaning). At the age of 2 to 3 years, the speech delay is quite evident; children with higher levels of mental function generally initiate some type of nonverbal language at this age.
Detection of a Large Novel α-Thalassemia Deletion in an Autochthonous Belgian Family
Published in Hemoglobin, 2019
Laura Heireman, Ariane Luyckx, Katrien De Schynkel, Annelies Dheedene, Mélanie Delaunoy, Anne-Sophie Adam, Béatrice Gulbis, Johan Dierick
As the deletion was extended in the ATR-16 syndrome locus, at first diagnosis of this rare contiguous gene deletion syndrome was presumed. The ATR-16 syndrome results from a deletion (1-2 Mb) at the telomeric short arm of chromosome 16p13.3 removing both α-globin genes and genes involved in central nervous system development and function nearby the α-globin locus [1,2,4,8]. The ATR-16 syndrome is characterized by mild intellectual disability, facial and skeletal abnormalities and developmental delay [1,3,8,9]. Harteveld [10] narrowed the region for which haploinsufficiency leads to mental retardation and dysmorphic features typical for ATR-16 down to a ∼800 kb region localized between 0.9 and 1.7 Mb from the telomere of 16p. About 14 known genes or gene families are located in this locus [10]. Pfeifer [8] identified a deletion of the SOX8 gene as a possible contributor to the mental impairment seen in the ATR-16 syndrome. In contrast, Bezerra et al. [11] described a Brazilian family characterized by haploinsufficiency of SOX8 but without intellectual disability or dysmorphic features. The deleted region observed in the current family is very small compared to deletions described in ATR-16 syndrome and does not contain the ∼800 kb region associated with intellectual disability and dysmorphic features, thereby excluding a full-blown ATR-16 syndrome [9].
The clinical management of factor XI deficiency in pregnant women
Published in Expert Review of Hematology, 2020
Allison P. Wheeler, Celeste Hemingway, David Gailani
Unlike plasma levels of factor VIII and von Willebrand factor [22,23], FXI levels do not rise significantly during pregnancy. Indeed, FXI activity has been reported to remain stable [24] or decrease [25] during pregnancy in healthy women without FXI deficiency. Data for women with partial or severe FXI deficiency are conflicting. Several studies indicate that FXI activity does not change significantly over the course of pregnancy [26–28], while others reported modest increases or decreases [29,30]. Regardless, the magnitude of changes in FXI levels during pregnancy is unlikely to have an appreciable impact on hemostasis. Furthermore, as discussed, obstetrical bleeding in women with FXI deficiency does not correlate well with plasma factor activity [7,15,16,31,32]. Two groups have commented on obstetrical bleeding and the molecular genotype responsible for FXI deficiency. Salomon et al. did not find a correlation between specific mutations and bleeding tendency in a group of pregnant FXI-deficient women, primarily of Jewish background, in Israel. Specifically, patients homozygous for the type II mutation who have no circulating FXI did not appear to have more severe bleeding than patients with other genotypes [7]. Myers et al. identified four patients from one family with a rare whole gene deletion (obligate). All had bleeding histories and developed pregnancy-associated complications, but other contributors to bleeding were not ruled out [28]. As most FXI-deficient patients have reductions in FXI protein in their plasmas (cross-reactive material negative deficiency), genetic assessment probably does not provide much information on which to base management beyond that provided by the plasma FXI level.