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Sotos Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Although Sotos syndrome often occurs in people with no history of the disorder in their family, cases showing family links suggest its autosomal dominant inheritance. The identification of the NSD1 gene located on chromosome 5q35.3 in 2002 further confirmed the familial nature of Sotos syndrome [2]. Subsequent evolutionary studies suggested that Sotos syndrome could be traced to the duplication of low-copy repeats (LCRs) flanking NSD1 in the primate genome about 23.3–47.6 million years ago, before the divergence of Old World monkeys, likely predisposing to deletions mediated by non-allelic homologous recombination [3].
Velo-cario-Facial Syndrome
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Wendy R. Kates, Kevin Antshel, Wanda Fremont, Nancy Roizen, Robert J. Shprintzen
The loss of DNA that causes VCFS is an interstitial deletion from the long arm of chromosome 22 that resides within a region of the genome that is highly susceptible to mutation. This region of chromosome 22 seems to be one of the most mutable regions in the entire human genome, thus accounting for the high rate of spontaneous mutation and the large number of nonfamilial cases. The mechanism for the deletion has been determined to occur during gametogenesis (34). The rearrangement happens as a result of a recombinant event in the first meiotic prophase (Prophase I) during synapsis. There is an unusual arrangement of chromosome 22 in the region that marks the normal breakpoint for the proximal end of the deletion and the region at the distal end. In both of these regions, there occurs a series of low copy repeats (LCRs) of DNA that are largely homologous (Fig. 4).
Clinical genomics and contextualizing genome variation in the diagnostic laboratory
Published in Expert Review of Molecular Diagnostics, 2020
James R. Lupski, Pengfei Liu, Pawel Stankiewicz, Claudia M. B. Carvalho, Jennifer E. Posey
Variation of the haploid reference human genome, which is 3 × 109 base pairs of DNA (A, C, G, or T), can consist of changes of a single nucleotide in a uniquely defined coding or non-coding nucleotide sequence that can vary into any one of the other three bases at that particular W-C base pair position. Variation of nucleotides mapping within repetitive sequences (Alu, LINE) and low-copy repeats (LCRs) or segmental duplications provides a particular challenge to detecting individual locus variation – the ‘non-unique’ map position of the DNA sequence that is varying within the repeat. Each personal genome has an abundance of rare variation, but through systematic computational filtering one can narrow the potential disease contributing clinically impactful variation to a small number of rare variants that can potentially constitute medically actionable variation and thus, formulate a molecular diagnosis in a locus or gene-specific manner. Some types of rare variation, e.g. copy-number neutral inversions, balanced translocations, and repeat expansions are not detectable by current clinical genomics assays.
Atypical presentation of Cat Eye Syndrome in an infant with Peters anomaly and microphthalmia with cyst
Published in Ophthalmic Genetics, 2020
Benjamin Katz, Jennifer Enright, Steven Couch, George Harocopos, Andrew R. Lee
Because CES has a wide phenotypic variability with the potential to affect many organ systems, the overall prognosis varies from individuals who present with only mild abnormalities to those with fatal presentations(6). While the molecular size of the duplicated region can vary depending on which low-copy repeat is the site for rearrangement, there has been no correlation between the various phenotypes and size of chromosome 22 duplications (3).
Copy number variation analysis using next-generation sequencing identifies the CFHR3/CFHR1 deletion in atypical hemolytic uremic syndrome: a case report
Published in Hematology, 2022
Joonhong Park, Ho-Young Yhim, Kyung Pyo Kang, Tae Won Bae, Yong Gon Cho
Atypical hemolytic uremic syndrome (aHUS) is characterized by a triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure that results from platelet thrombi in the microcirculation of the kidney and other organs, in the absence of a preceding diarrheal illness [1]. Several large cohort studies in different ethnic populations have reported complement gene mutations in up to 60% of aHUS patients [2,3]. The most commonly mutated gene in aHUS is CFH, which encodes the complement regulator of complement factor H–related proteins (CFHR1 to 5) residing in a centromeric 355 kb segment on chromosome 1q32. Disease-causing mutations are detected in up to 40% of familial and 25% of sporadic cases [2,3]. It is likely that mutation of CFH, CFI, CFB, C3, CD46, or THBD confers a predisposition to developing aHUS rather than directly leading to the disease. Particularly, a hybrid CFH/CFHR3 gene resulting from a microhomology-mediated deletion in familial aHUS has been reported [4]. Molecular analysis of this region provides evidence of multiple independent large genomic duplications, also known as low-copy repeats, resulting in a high degree of sequence identity between CFH and CFHR1 to CFHR5 [5]. In addition, non-enteric bacterial (Streptococcus pneumoniae accounts for 40% of aHUS) and viral infections, malignancies (∼6%), drugs, pregnancy, and transplantation that trigger complement activation can precipitate an acute occurrence in those with predisposing genetic evidence [6]. In patients in whom the pathogenic mutation(s) related to aHUS has been identified, monitoring of laboratory findings such as hemoglobin, platelet count, and serum concentrations of C3, C4, LDH, haptoglobin, and creatinine is required after exposure to potential triggering events [7]. Eculizumab, a first-in-class humanized monoclonal anti-C5 antibody is recommended to treat aHUS and to induce remission of aHUS refractory to plasma manipulation [8]. While plasma exchange or infusion can decrease mortality, plasma dependence or resistance also can occur [9].