Clinical genetics
C. Simon Herrington in Muir's Textbook of Pathology, 2020
In autosomal dominant diseases, loss of function of one allele may reduce protein production, but will not abolish it because there is a second, functioning, allele. In this case there are two possible mechanisms by which mutation may cause disease: Haploinsufficiency: The level of a protein is important, either in absolute terms or in relation to another protein. Loss of a single copy of the gene reduces the amount of protein produced sufficiently to cause a disease phenotype. This mechanism is more likely to be the case for signalling molecules where the exact level of a protein may be critical for normal cell function. Haploinsufficiency is also the mechanism whereby mutations in one of the collagen genes, COL1A1 or COL1A2, cause the milder form of osteogenesis imperfecta, osteogenesis imperfecta type I. Loss of one copy of the collagen gene leads to reduced collagen levels in bone and a tendency to fractures in childhood (see Chapter 13).Loss of function of the second copy of the gene during somatic cell division, leading to a cell that has no functioning copy of the gene: This is a common mechanism in inherited cancer syndromes, such as in Lynch syndrome, described in Case History 5.1, Chapters 6 and 10.
Multiple endocrine neoplasia type 2
J. K. Cowell in Molecular Genetics of Cancer, 2003
A broad spectrum of mutations in a proto-oncogene are capable of causing loss-of-function. Indeed, in HSCR, germline loss-of-function mutations in RET include gross deletions and chromosomal aberrations, nonsense mutations, frameshift mutations, splice site mutations and missense mutations (section 4.1) (Angrist et al., 1993, 1995; Attié et al., 1994, 1995; Edery et al., 1994; Luo et al., 1994; Mulligan et al., 1994a). Thus, it would seem obvious that haploinsufficiency, whether structural or functional, plays a large role in causing HSCR. Whole gene deletions and truncated protein secondary to nonsense, frameshift and nonsense mutations result in such haploinsufficiency. Even missense mutations which cause loss-of-function, e.g. in the catalytic core of the tyrosine kinase, would be predicted to cause functional haploinsufficiency. Missense mutations in the extracellular domain of RET have been shown to result in lack of maturation of the mutant receptor and hence, lack of receptor at the cell surface with consequent haploinsufficiency surface (Carlomagno et al., 1997; Ito et al., 1997).
Microdeletion Syndromes
Merlin G. Butler, F. John Meaney in Genetics of Developmental Disabilities, 2019
Comparative analysis of clinical features between patients with intragenic mutations and submicroscopic deletions suggested that certain clinical features are more or less associated with the type of abnormality. For example, features like overgrowth, advanced maturation, performance disturbance, slowing of growth, and amelioration of mental development in later stages are ascribed to NSD1 haploinsufficiency due to submicroscopic deletions (129). Development of large ventricles, brain atrophy, neonatal asphyxia, and hypoglycemia may also be due to deletions. Features like agenesis or hypoplasia of the corpus callosum, cardiovascular and urinary anomalies, neonatal jaundice, and recurrent convulsions are thought to be due to some other genes and are not related to NSD1 haploinsufficiency, because patients with NSD1mutations do not manifest these features. In addition, the body size tends to be smaller and mental development tends to be more retarded in patients with deletions than those with point mutations.
Ocular findings of albinism in DYRK1A-related intellectual disability syndrome
Published in Ophthalmic Genetics, 2020
Julia Ernst, Michelle L. Alabek, Amgad Eldib, Suneeta Madan-Khetarpal, Jessica Sebastian, Aashim Bhatia, Alkiviades Liasis, Ken K. Nischal
The highly conserved dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) plays an important role in many biological pathways (1). Most notably it is essential for the development of the central nervous system including neurogenesis, neural proliferation and differentiation, cell cycle regulation, and synaptic plasticity (2). The DYRK1A gene is located on chromosome 21q22.13 within the Down syndrome critical region (3). It is a dosage-sensitive locus, and its abnormal increase in Down syndrome affects neural progenitor cells (4). Conversely, heterozygous mutations in DYRK1A leading to haploinsufficiency are associated with DYRK1A-related intellectual disability syndrome (5–7). The constellation of features most commonly reported in this syndrome includes congenital microcephaly, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. Less frequently, seizures, structural brain abnormalities, eye defects, ataxia, intrauterine growth retardation, minor skeletal abnormalities and feeding difficulties can manifest, as well (8,9). Since the first description of DYRK1A haploinsufficiency in 2008, the clinical features of numerous patients carrying a mutation in this gene have been reported in the literature; however, given the recent recognition of this diagnosis, the full phenotypic spectrum of DYRK1A-related intellectual disability syndrome is yet to be established (10).
CTLA4 haploinsufficiency as a predisposition to classical Hodgkin lymphoma
Published in Pediatric Hematology and Oncology, 2020
Upendra Mahat, Meryem K. Terzioglu, Ilia Buhtoiarov
Given the rare nature of this disorder, no consensus exits for the treatment of CTLA4 haploinsufficiency. General medical management revolves around controlling immune dysregulation and autoimmunity. Immunoglobulin replacement has been used for CTLA4 haploinsufficiency-related secondary hypogammaglobulinemia. Corticosteroids and non-steroidal immunosuppressive agents (sirolimus, rituximab, mycophenolate mofetil, cyclosporin, antithymocyte globulin and tumor necrotic factor-alpha inhibitors) have been tried to control T cell hyperactivation.7 A soluble version of biologically engineered CTLA4 mimetic, Abatacept, is currently approved to treat various forms of immune mediated arthritis in adults (such as rheumatoid arthritis, psoriatic arthritis and juvenile idiopathic arthritis). Although its role in treating patients with CTLA4 haploinsufficiency currently is not established, mechanistically it appears as an attractive replacement therapy. Apropos, its role in patients with active EBV viremia is unclear, and needs further investigation. A phase 1/2 double blind randomized intra-patient dose escalation placebo controlled trial (NCT03733067) is currently open, and aims to evaluate the safety and efficacy of abatacept in patients with CTLA4 haploinsufficiency and cytopenia. Hematopoietic stem cell transplantation (HSCT) is usually offered to patients with life-threatening, treatment-resistant immune dysregulation secondary to CTLA4 haploinsufficiency.22
KFL1 Gene Variants in α-Thalassemia Individuals with Increased Fetal Hemoglobin in a Chinese Population
Published in Hemoglobin, 2018
Fan Jiang, Yan-Xia Qu, Gui-Lan Chen, Jian Li, Jian-Ying Zhou, Lian-Dong Zuo, Can Liao, Dong-Zhi Li
Krüppel-like factor 1 (KLF1) is a pleiotropic erythroid transcription factor that is a master regulator of definitive erythropoiesis. The KLF1–/– mice develop fatal anemia during fetal liver erythropoiesis, due to a defect in the maturation of red blood cells (RBCs), and die by embryonic day 16 [1–3]. Similarly, KLF1-null fetuses or neonates can display hydrops fetalis and a deranged erythroid transcriptome [4,5]. However, heterozygous mutations in the KLF1 gene alone are not pathologically relevant, although there are a number of scenarios in which KLF1 can interact with other conditions and lead to a broad spectrum of human RBC phenotypes. For example, KLF1 haploinsufficiency has been associated with hereditary persistence of fetal hemoglobin (Hb) (HPFH), borderline elevated levels of Hb A2, and marginal microcytosis and/or hypochromia [6].