Browsing by Subject "Phenotypic variability"

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    Influence of allelic differences in Down syndrome
    (Elsevier, 2020) Roper, Randall J.; Hawley, Laura; Goodlett, Charles R.; Biology, School of Science
    Both trisomic and non-trisomic genes may affect the incidence and severity of phenotypes associated with Down syndrome (DS). The importance of extra (trisomic) genetic material is emphasized in DS, with less emphasis to the allelic composition of candidate trisomic genes in defining the trisomic gene-phenotype relationship in DS. Allelic differences in non-trisomic genes have been shown to be important moderators of cardiac, leukemia, and developmental phenotypes associated with DS. Trisomic mouse models provide an in vivo genetic platform for examining the gene-phenotype relationship, including the influence of allelic variants, on DS-like phenotypes. DS mouse models have differing trisomic genetic makeup, and optimal development, viability and translational value of these mouse models may require a non-inbred genetic background with heterogeneity at many loci. Additionally, understanding the contribution of specific genes or regions to DS phenotypes often requires the utilization of genetically manipulated mice that may be established on a different inbred background than the trisomic mice. The impact of allelic differences of trisomic and background genes in human and model systems may offer insight into the variability in occurrence and severity of trisomic phenotypes.
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    Phenotypic Variability in Phelan-McDermid Syndrome and Its Putative Link to Environmental Factors
    (MDPI, 2022-03-17) Boccuto, Luigi; Mitz, Andrew; Abenavoli, Ludovico; Sarasua, Sara M.; Bennett, William; Rogers, Curtis; DuPont, Barbara; Phelan, Katy; Pediatrics, School of Medicine
    Phelan-McDermid syndrome (PMS) is a multi-systemic disorder characterized by both genetic and phenotypic variability. Genetic abnormalities causing PMS span from pathogenic variants of the SHANK3 gene to chromosomal rearrangements affecting the 22q13 region and leading to the loss of up to over nine megabases. The clinical presentation of individuals with PMS includes intellectual disability, neonatal hypotonia, delayed or absent speech, developmental delay, and minor dysmorphic facial features. Several other features may present with differences in age of onset and/or severity: seizures, autism, regression, sleep disorders, gastrointestinal problems, renal disorders, dysplastic toenails, and disrupted thermoregulation. Among the causes of this phenotypic variability, the size of the 22q13 deletion has effects that may be influenced by environmental factors interacting with haploinsufficiency or hemizygous variants of certain genes. Another mechanism linking environmental factors and phenotypic variability in PMS involves the loss of one copy of genes like BRD1 or CYP2D6, located at 22q13 and involved in the regulation of genomic methylation or pharmacokinetics, which are also influenced by external agents, such as diet and drugs. Overall, several non-mutually exclusive genetic and epigenetic mechanisms interact with environmental factors and may contribute to the clinical variability observed in individuals with PMS. Characterization of such factors will help to better manage this disorder.