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Microdeletion Syndromes
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Gopalrao V. N. Velagaleti, Nancy J. Carpenter
For a long time, the etiology of Sotos syndrome was not known. Several patients with chromosome abnormalities involving chromosomes 2, 3, 6, and 12 have been reported, although the majority of the patients showed normal karyotypes. Recent studies have shown that haploinsufficiency for NSD1 (nuclear receptor binding Su-var, enhancer of zeste, and trithorax domain protein 1) gene, cloned from the 5q35 breakpoint in a patient with a chromosomal translocation (128) is one of the genes responsible for Sotos syndrome. NSD1 consists of 23 exons and encodes at least six functional domains that are thought to be related to chromatin regulation in addition to 10 putative nuclear localization signals. NSD1 is expressed in several tissues including fetal and adult brain, kidney, skeletal muscle, spleen, and thymus. Analysis of the NSD1 gene in sporadic cases of Sotos syndrome showed that the majority of the patients had submicroscopic deletions (Fig. 15), while a small number of patients showed frame shift and nonsense mutations (128). As a common ~2.2 Mb deletion accounts for the majority of the NSD1 deletions in Sotos syndrome patients, it is hypothesized that unequal crossing over or intrachromosomal recombination between low copy repeats is responsible for the deletions (129).
Clinical Theory and Skills EMIs
Published in Michael Reilly, Bangaru Raju, Extended Matching Items for the MRCPsych Part 1, 2018
Chromosome 2.Chromosome 6.Chromosome 9.Cognitive impairment.Generalised anxiety disorder.Major depressive episode.Manic episode.Rapidly progressive dementia.Sensorimotor impairment.Slowly progressive dementia.
Blood and immune system disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Gilbert syndrome is a disorder that results in impairment of the removal of bile pigment (bilirubin) from the liver. It is characterised by jaundice that is most evident on the face, the palms of the hands and the soles of the feet. This is a result of an abnormal increase in bilirubin levels in the blood. This disorder is thought to be caused by decreased activity of an enzyme system known as bilirubin-uridine diphosphate glucuronyl transferase (bilirubin-UGT). The gene responsible for this disorder is located on the long arm of chromosome 2.
SCN1A as a therapeutic target for Dravet syndrome
Published in Expert Opinion on Therapeutic Targets, 2023
From a molecular perspective, 80–90% of cases of Dravet syndrome are attributed to pathogenic variants in SCN1A (OMIM 182389), which encodes the NaV1.1 subunit of the voltage-gated sodium channel [7,8]. Approximately half the SCN1A pathogenic variants in Dravet syndrome result in protein truncation, while the other half are missense, usually leading to loss of function [7]. The SCN1A gene is located on the long arm of chromosome 2 and has 26 exons [9]. The protein product is comprised of 2009 amino acids, with a structure that includes four domains, each comprised of six transmembrane helices (Figure 1). In each domain, helices 5 and 6 form the ion channel pore, while helix 4 is the voltage sensor. Hyperexcitability in the brain is believed to result because loss of NaV1.1 function leads to decreased sodium current primarily in inhibitory GABAergic interneurons, while excitatory cells are relatively unaffected [10].
Nitric oxide pathway as a plausible therapeutic target in autism spectrum disorders
Published in Expert Opinion on Therapeutic Targets, 2022
Rishab Mehta, Anurag Kuhad, Ranjana Bhandari
The human leukocyte antigen (HLA) gene on chromosome 6 and killer cell immunoglobulin-like receptor (KIR) gene on chromosome 19 are reported to be associated with an enhanced risk of developing ASD [40]. A chromosome 15 phenotype has been identified having an altered sequence of the 15q11-15q13 region thus, causing cytogenetic abnormalities characterized by dysmorphic facial features, mental retardation, epilepsy, language delay, and repetitive movements [41,42]. The RELN gene found in the 7q22 region of chromosome 7 is suspected to be associated with neuronal migration and prenatal neuronal development [43]. The polymorphism of the MET gene found in 7q31 is known to affect the development of the cerebellum and cerebral cortex [44]. Various evidence-based studies suggest that disrupted MET signaling also leads to gastrointestinal dysfunction [45]. Alterations in chromosome 16 and chromosome 2 are also predicted to play a part in the occurrence of mental retardation, gastrointestinal alterations, and CNS disorders in patients with ASDs [6].
Copy-number variation of the NPHP1 gene in patients with juvenile Nephronophthisis
Published in Acta Clinica Belgica, 2021
Mayssa Abdelwahed, Ines Maaloul, Valerie Benoit, Pascale Hilbert, Mongia Hachicha, Hassen Kamoun, Leila Keskes-Ammar, Neila Belguith
The NPHP1, responsible for Juvenile nephronophthisis, has been located on chromosome 2 (2q13) [15]. Chromosome 2 appeared after the telomere-telomere fusion of two ancestral chromosomes located in band 2q13 [15]. The telomeric regions contain several repetition sequences which make this region susceptible to rearrangements (deletions or duplications). In addition, the NPHP1 has been shown to be located between two large inverted repeats of 330 kb and a second sequence of 45 kb. These repeats are extremely unstable and fragile, which could have a negative effect on the stability of the NPHP1 region, and lead to the deletion of the whole gene. In order to better understand the mechanisms of CNV formation in juvenile nephronopthisis, Saunier et al. made two hypotheses. They suggest that CNVs could result either in interchromic rearrangement, leading to the replacement of a short genomic sequence containing STS 804H10R by a repeat sequence of 45 or by intra-chromosomal rearrangement by unequal crossing-over, leading to the inversion of the entire NPHP1 kb region [15]. Nevertheless, no study has validated any of these hypotheses.