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The Case for Single Gene Effects on Human Obesity
Published in Claude Bouchard, The Genetics of Obesity, 2020
There are several genetic syndromes in humans for which obesity is a prominent symptom. These include the Prader-Willi, Borjeson-Forssman-Lehmann, Bardet-Biedl, Biemond, Pickwickian, and Cohen syndromes.3 Prader-Willi syndrome is one of the best understood in terms of its genetic causes. It is commonly due to deletions in chromosome region 15ql1— 12, although in some cases no deletions may be detected cytogenetically. Deletions visible under a light microscope probably involve the loss of at least 2 to 5 million base pairs of DNA. Disorders caused by such deletions are called contiguous gene syndromes because their phenotypes are probably due to the deletion of three to ten genes and regulatory sequences. Deletions associated with Prader-Willi syndrome suggest that genes in chromosome region 15q 11-12 may affect appetite and/or satiety cues that mediate food intake. A variety of other genes involved in carbohydrate metabolism, lipid metabolism and storage, and endocrine function may be deleted in other human syndromes. The existence of genetic obesity syndromes is important because it indicates that altering one or a few genes can cause obesity in humans. Once the obesity-relevant genes from these syndromes are identified, it will be possible to determine whether normal variation in the same genes causes obesity in people with a normal chromosome complement.
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
It is now well established that VCFS is a contiguous gene syndrome and, in fact, is the most common contiguous gene syndrome in humans (10). A contiguous gene syndrome is typically referred to as a disorder that is caused by a deletion of a submicroscopic segment of DNA from one of the nuclear chromosomes with that deletion encompassing a region that normally contains more than one gene. In the case of VCFS, one copy of chromosome 22 has the deletion of the long arm at the q11.2 band (Fig. 1). Approximately 90% of affected individuals have a deletion that spans 3 million base pairs of DNA and another 7% have a smaller deletion spanning 1.5 million base pairs so that 25–30 genes are deleted in the large majority of cases. The remaining cases have unique, smaller deletions.
Basic genetics and patterns of inheritance
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Many other microdeletion syndromes have been identified (24). Many of these conditions were well recognized by clinical geneticists for years before the microdeletion could be detected. With the improvement of cytogenetic technology, smaller fragments of missing chromosome material can be identified using FISH. Studies in this area have been aided by the use of chromosome microarray analysis. Microdeletion syndromes have also been referred to as contiguous gene syndromes because of the loss of multiple adjacent genes. It is understandable that the phenotypes of these patients may vary depending on the size of the deletion and the number and importance of the deleted genes. One good example of this is Williams syndrome, which is readily diagnosed by FISH (Fig. 4). Williams syndrome is a well-recognized multiple anomaly syndrome characterized by moderate mental retardation, craniofacial dysmorphic features, hypercalcemia, and cardiovascular abnormalities. Facial features include epicanthal folds with periorbital fullness, stellate iris pattern, long philtrum, and wide mouth with prominent lips (Fig. 13). The cardiovascular abnormalities typically involve supravalvular aortic stenosis, but other blood vessels, such as pulmonary and renal arteries, may be affected. Most cases are sporadic, but there is autosomal dominant inheritance in some families. There is a separate, clearly autosomal dominant disorder of isolated supravalvular aortic stenosis, which is not associated with the other features of Williams syndrome. It has been discovered that the supravalvular aortic stenosis and other vascular abnormalities in both of these disorders are due to abnormalities in the gene for elastin, which is located on chromosome 7 at 7q11.23 (26). In the case of Williams syndrome, one copy of the elastin gene is deleted, along with other genes in the surrounding regions. Williams syndrome patients without deletion of the elastin gene do not have arterial disease. Thus, variable expression of contiguous gene or microdeletion syndromes can be directly related to the extent of the deleted genes, but all patients share an overlapping area of involvement.
Extending Phenotypic Spectrum of 17q22 Microdeletion: Growth Hormone Deficiency
Published in Fetal and Pediatric Pathology, 2021
Ceren Damla Durmaz, Şule Altıner, Elifcan Taşdelen, Halil Gürhan Karabulut, Hatice Ilgın Ruhi
17q22 microdeletion syndrome is a contiguous gene syndrome recently described by Laurell et al. [1]. Characteristic features of the syndrome are intellectual disability (ID), attention deficit hyperactivity disorder, facial dysmorphism (microcephaly, narrow long face, maxillary hypoplasia, short philtrum, thin border of upper lip, micrognathia, large bulbous nose, hypoplastic alae nasi, prominent columella, large dysplastic ears, upslanting palpebral fissures, epicantal folds and hypertelorism), conductive hearing loss, visual impairment like astigmatism, hyperopia, strabismus and limb anomalies such as symphalangism, brachydactyly, clinodactyly, short first metacarpal, proximally placed thumbs, coxa valga, genu valgum, and broad halluces [1]. Affected individuals have variable clinical manifestations depending on the deletion sizes.
Novel Intragenic PAX6 Deletion in a Pedigree with Aniridia, Morbid Obesity, and Diabetes
Published in Current Eye Research, 2020
Erin A. Boese, Mallory R. Tollefson, Michael J. Schnieders, Benjamin W. Darbro, Wallace L.M. Alward, John H. Fingert
The index patient of our pedigree (Patient III-1) has a complex set of systemic medical conditions including aniridia, morbid obesity, diabetes mellitus, and cardiomyopathy, which suggested to us that he might have a contiguous-gene syndrome involving a deletion or rearrangement of genes on chromosome 11p that includes PAX6 and neighboring genes to explain some or all of these features. There is evidence to support our hypothesis for a contiguous-gene syndrome in this patient. Several of his clinical features have been previously associated with genes in the region. While some reports suggest that PAX6 mutations may cause glucose intolerance and promote diabetes,23 there is also evidence that defects in another gene in the region may stimulate the development of diabetes mellitus.24 Moreover, there are cardiomyopathy genes on chromosome 11.21,22 Coupled with his aniridia, these observations suggested to us that Patient III-1 might have a novel contiguous-gene syndrome involving PAX6.
Centronuclear myopathy: advances in genetic understanding and potential for future treatments
Published in Expert Opinion on Orphan Drugs, 2018
Mutations are found in the entire coding sequence of the MTM1 gene, but most mutations are clustered in exons 4, 8, 9, 11, and 12 [15,16,18–33,35–37]. To date, more than 400 mutations have been described. There is no evident correlation between phenotype and genotype. However, mutations leading to truncation tend to produce more severe clinical pictures. Rearrangement, duplication, and deletion of one exon or of the whole MTM1 gene have been described in some cases [38,39]. A contiguous gene syndrome with the deletion of MTM1 and a gene implicated in sexual development has been described (OMIM *300219) [40,41]. The genital abnormalities that were reported include micropenis, enlarged clitoris, bifid scrotum, impalpable testes, vaginal pouch, and perineum–scrotum hypospadias.