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Genetic Disorders
Published in Jeremy R. Jass, Understanding Pathology, 2020
Genomic imprinting may be suspected on clinical grounds when an inherited disease occurs in both males and females but is transmitted only by parents of a particular gender. Genomic imprinting may also be suspected when a disease arises do novo and is associated with parental disomy (in which an individual has two identical chromosomes derived from the same parent). Interestingly, both scenarios have been observed in the case of the Beckwith-Wiedemann syndrome, an inherited disorder associated with organomegaly, hemihypertrophy, gigantism and a propensity to tumours of childhood, notably nephroblastoma or Wilms’ tumour. Underlying this syndrome is the phenomenon of imprinting of the insulin-like growth factor 2 (IGF2)gene in female germ cells. A paternal disomy involving the locus 11p15.5 leads to a double dose of IGF2. This in turn accounts for the organ enlargement. Conversely, mutations or cytogenetic abnormalities involving the 1 lpl5.5 locus are thought to block the process of imprinting in the female germline. Females and their offspring may therefore possess two functioning copies of IGF2 and so express a double dose of the growth factor (Tycko, 1997).
Genetics
Published in Rachel U Sidwell, Mike A Thomson, Concise Paediatrics, 2020
Rachel U Sidwell, Mike A Thomson
Genomic imprinting is the differential activation of genes depending on which parent they were inherited from. Examples are Prader–Willi, Angelman syndrome and Beckwith–Wiedemann syndromes.
Methylome and epigenetic markers
Published in Moshe Hod, Vincenzo Berghella, Mary E. D'Alton, Gian Carlo Di Renzo, Eduard Gratacós, Vassilios Fanos, New Technologies and Perinatal Medicine, 2019
Skevi Kyriakou, Marios Ioannides, George Koumbaris, Philippos Patsalis
Genomic imprinting is an epigenetic phenomenon that controls gene expression in a parent-of-origin–specific manner. Genomic imprinting is inherited independent of Mendelian inheritance and takes place during embryonic development. Thus, loss of imprinting as a result of deletions, mutations, or uniparental disomy (UPD) can lead to a number of disorders such as Prader–Willi syndrome, Angelman syndrome, and Beckwith-Wiedemann syndrome (18).
Establishing perinatal and neonatal features of Prader-Willi syndrome for efficient diagnosis and outcomes
Published in Expert Opinion on Orphan Drugs, 2020
Lili Yang, Bo Ma, Shujiong Mao, Qiong Zhou, Chaochun Zou
Prader-Willi syndrome (PWS, OMIM 176270) is a rare multisystem genetic disorder caused by genomic imprinting errors and firstly reported in 1956 [1]. PWS is characterized by severe hypotonia, poor sucking, and feeding difficulties in early infancy, followed by excessive eating and gradual development of morbid obesity in early childhood, short stature, typical facial dysmorphism, psychomotor delay, behavioral abnormalities, and cognitive disability [2,3]. The prevalence of PWS is about 1 in 10,000–30,000 independent of gender and ethnicity [2,4,5]. PWS has several genetic subtypes: 1) deletion of the paternal copy of 15q11–13 (in 65%-70% of the cases), which including type I (BPI-BPIII), type II (BPII-BPIII), type III (BPI-BPIV), and type IV (BPI-BPV) at least according to the breakpoints. Type III and IV deletions are very rare and not typical; 2) maternal uniparental disomy (UPD) for chromosome 15 (in 20–30%), 3) imprinting center defect or epimutation in less than 5%, and 4) very rare cases of translocation in the region of chromosome 15q11-q13 [2,3] or small deletions in the key gene of PWS (e.g. Snord116 gene cluster) [6–11].
Corpus Callosum Abnormalities and Short Femurs in Beckwith–Wiedemann Syndrome: A Report of Two Fetal Cases
Published in Fetal and Pediatric Pathology, 2018
Aurélie Beaufrère, Maryse Bonnière, Julia Tantau, Philippe Roth, Elodie Schaerer, Fréderic Brioude, Irène Netchine, Bettina Bessières, Antoinette Gelot, Michel Vekemans, Ferechté Razavi, Delphine Heron, Tania Attié-Bitach
Beckwith–Wiedemann syndrome (BWS) (OMIM #130650) is the most common overgrowth syndrome [1–3]. Molecular heterogeneity is observed in BWS with several genetic and/or epigenetic alterations in imprinted growth regulatory genes at 11p15.5 [1–5]. Approximately 85% of reported BWS cases are sporadic, while the remaining 15% are familial [5]. Clinical features are highly variable, including neonatal macrosomia, post-natal overgrowth, abdominal wall defects (omphalocele, umbilical hernia, diastasis recti), macroglossia, organomegaly, nephro-ureteral malformations, ear anomalies, capillary malformations (hemangioma and nevus flammeus), hypoglycemia, and predisposition to develop embryonic tumors in infancy [1,3,6]. Placenta anomalies are also observed [7,8]. Possible patterns include autosomal dominant inheritance with variable expressivity, contiguous gene duplication at 11p15, and genomic imprinting resulting from a defective or absent copy of the maternally derived gene. Specific phenotype–epigenotype correlations have been reported and recurrence risk estimation is guided by the molecular etiology [5]. Brains malformations were occasionally reported, mainly posterior fossa abnormalities [9–14].
An emerging new concept for the management of type 2 diabetes with a paradigm shift from the glucose-centric to beta cell-centric concept of diabetes - an Asian perspective
Published in Expert Opinion on Pharmacotherapy, 2020
Recent evidence has shown that beta cell function and mass, referred to as functional BCM, are already reduced in patients with prediabetes [8,9,16]. Although the mechanisms by which functional BCM decreases before the development of T2DM remain unclear, various mechanisms have been proposed such as oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, autophagy dysfunction, amyloid toxicity, inflammatory cytokines, and glucolipotoxicity [8]. Rather than a single mechanism, several mechanisms may be involved in this process. However, recent studies have shown that the change in BCM in response to insulin resistance is only modest in humans, indicating that the workload of individual beta cells secreting insulin is easily increased by the condition of insulin resistance in humans (Figure 4)[8]. This leads to the hypothesis that beta cell overwork is the cause of beta cell dysfunction in T2DM [18]. Asians are known to be at risk of T2DM with lower BMI compared with other ethnicities [92,93]. This may be explained by the smaller increase in BCM in response to obesity in Asians compared with Caucasians [94–96]. Intrauterine environment as well as genetic imprinting may also affect inter-individual difference in BCM [97,98]. It has also been reported that Asians show abdominal fat accumulation with lower BMI compared with Caucasians [99–101], suggesting that insulin resistance is already present with low BMI in Asians, and contributes to increasing beta cell workload [102], although insulin sensitivity is generally higher in Asians when directly compared with Caucasians [103,104].