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Currarino Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Mutations (including frameshift [45%], missense [25%], nonsense [12%], and splice site variants) in the MNX1 gene causing haploinsufficiency have been found in almost all familial cases and 30% of sporadic cases. In addition, large deletion or complex rearrangement involving the 7q36 region may also occur in Currarino syndrome. To date, at least 82 MNX1 heterozygous pathogenic variants have been reported. Most missense variants are located in the homeobox domain, and only a few (p.Met1Ile, p.Pro-27Leu, and p.Arg243Trp) are outside of this region. Interestingly, patients with missense variant may show milder phenotypes (anorectal stenosis, cystic formation, and anterior angulation of coccyx) than those with other null variants [6–8].
Clinical genetics
Published in C. Simon Herrington, 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.
Microdeletion Syndromes
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Gopalrao V. N. Velagaleti, Nancy J. Carpenter
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.
De novo frameshift mutation in YAP1 associated with bilateral uveal coloboma and microphthalmia
Published in Ophthalmic Genetics, 2022
Charles DeYoung, Bin Guan, Ehsan Ullah, Delphine Blain, Robert B. Hufnagel, Brian P. Brooks
The observation that both nonsense and frameshift mutations result in similar ocular phenotypes suggests that loss-of-function and, presumably, haploinsufficiency is the primary mechanism of disease. The reasons for the incomplete penetrance with variable expressivity remain unclear, although it has been suggested that a second transcription start site in the gene (Figure 4) is a plausible mechanism (9). Indeed, our proband’s frameshift mutation would be predicted to allow for this shorter transcript to continue to be expressed. Another potential explanation may be variable levels of YAP1 expressed from the remaining normal allele in ocular/non-ocular tissues; these differences could be due to sequence changes and/or epigenetic differences in control elements such as enhancers/super-enhancers. This hypothesis awaits further experimental testing.
Pathogenic variants in the CYP21A2 gene cause isolated autosomal dominant congenital posterior polar cataracts
Published in Ophthalmic Genetics, 2022
Vanita Berry, Nikolas Pontikos, Alex Ionides, Angelos Kalitzeos, Roy A. Quinlan, Michel Michaelides
In the families reported herein, the p.Q319X and p.M257T variants cause isolated congenital autosomal dominant congenital cataracts (ADCC) in European and Indian Asian ethnicities, further extending the genetic basis of congenital cataracts. It is possible that haploinsufficiency accounts for the autosomal dominant nature of the cataract caused by these variants—although other genetic modifying factors and/or environmental influences may be involved. It is commonplace in the inherited retinal disease group of disorders that specific alleles can be associated with a huge range of differing phenotypes both within and between families, as well as causing both syndromic and non-syndromic manifestations. Moreover, the p.Q319X variant association with both syndromic recessive disease and isolated ADCC is in keeping with the phenotypes reported for certain WFS1 variants (35).
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).