In Autosomal Dominant Inheritance Jsp Section

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In Autosomal Dominant Inheritance Jsp Section
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The autosomal dominant inheritance is apparently due to the accumulation of the nonfunctional receptor on the cell surface, perhaps due to the failure in recycling of the receptor containing one or two copies of the kinase negative receptor subunit.
Robert M. Kliegman MD , in Nelson Textbook of Pediatrics , 2020
Autosomal dominant inheritance is determined by the presence of one abnormal gene on one of the autosomes (chromosomes 1-22). Autosomal genes exist in pairs, with each parent contributing 1 copy. In an autosomal dominant trait, a change in 1 of the paired genes affects the phenotype of an individual, even though the other copy of the gene is functioning correctly. A phenotype can refer to a physical manifestation, a behavioral characteristic, or a difference detectable only through laboratory tests.
The pedigree for autosomal dominant disorders demonstrates certain characteristics. These disorders show a vertical transmission (parent-to-child) pattern and can appear in multiple generations. In Fig. 97.5 , this is illustrated by individual I.1 passing on the changed gene to II.2 and II.5. An affected individual has a 50% (1 in 2) chance of passing on the deleterious gene in each pregnancy and, therefore, of having a child affected by the disorder. This is referred to as the recurrence risk for the disorder. Unaffected individuals (family members who do not manifest the trait and do not harbor a copy of the deleterious gene) do not pass the disorder to their children. Males and females are equally affected.
Although not a characteristic per se, the finding of male-to-male transmission essentially confirms autosomal dominant inheritance. Vertical transmission can also be seen with X-linked traits. However, because a father passes on his Y chromosome to a son, male-to-male transmission cannot be seen with an X-linked trait. Therefore, male-to-male transmission eliminates X-linked inheritance as a possible explanation. Although male-to-male transmission can occur with Y-linked genes as well, there are very few Y-linked disorders, compared with thousands having the autosomal dominant inheritance pattern.
Although parent-to-child transmission is a characteristic of autosomal dominant inheritance, many patients with an autosomal dominant disorder have no history of an affected family member, for several possible reasons. First, the patient may have the disorder due to a de novo (new) mutation that occurred in the DNA of the egg or sperm that formed that individual. Second, many autosomal dominant conditions demonstrate incomplete penetrance , meaning that not all individuals who carry the mutation have phenotypic manifestations. In a pedigree this can appear as a skipped generation , in which an unaffected individual links 2 affected persons ( Fig. 97.6 ). There are many potential reasons that a disorder might exhibit incomplete penetrance, including the effect of modifier genes, environmental factors, gender, and age. Third, individuals with the same autosomal dominant variant can manifest the disorder to different degrees. This is termed variable expression and is a characteristic of many autosomal dominant disorders. Fourth, some spontaneous genetic mutations occur not in the egg or sperm that forms a child, but rather in a cell in the developing embryo. Such events are referred to as somatic mutations , and because not all cells are affected, the change is said to be mosaic . The phenotype caused by a somatic mutation can vary but is usually milder than if all cells were affected by the mutation. In germline mosaicism the mutation occurs in cells that populate the germline that produces eggs or sperm. An individual who is germline mosaic might not have any manifestations of the disorder but may produce multiple eggs or sperm that are affected by the mutation.
Alan Lap-Yin Pang , Wai-Yee Chan , in Essential Concepts in Molecular Pathology , 2010
ADH is a familial form of isolated hypoparathyroidism characterized by hypocalcemia, hyperphosphatemia, and normal to hypoparathyroidism. Inheritance of the disorder follows an autosomal dominant mode. The patients are generally asymptomatic. A significant fraction of cases of idiopathic hypoparathyroidism may in fact be ADH.
More than 80% of the reported ADH kindreds have CaSR mutations. There are 44 activating mutations of CaSR reported that produce a gain of CaSR function when expressed in in vitro systems. The majority of the ADH mutations are missense mutations within the extracellular domain and transmembrane domain of CaSR. The mechanism of CaSR activation by these mutations is not known. Interestingly, almost every ADH family has its own unique missense heterozygous CaSR mutation. Most ADH patients are heterozygous. The only deletion-activating mutation occurs in a homozygous patient in an ADH family. However, there is no apparent difference in the severity of the phenotype between heterozygous and homozygous patients.
Andrew P. Schachat MD , in Ryan's Retina , 2018
Autosomal dominant inheritance occurs when a single copy of a mutation on an autosomal chromosome is sufficient to cause disease. That is, an affected individual is heterozygous for the mutation. Diseases caused by dominant mutations pass from generation to generation, i.e., most families have affected individuals in multiple generations. Males are as likely to be affected as females, and approximately 50% of children of an affected individual will be affected. Forms of retinal disease that are often autosomal dominant include maculopathies such as Best disease.
Two phenomena that can confuse the picture of autosomal dominant disease are variable expression and incomplete penetrance.
Variable clinical expression means that individuals with the same mutation may vary in onset, progression, or severity of disease or, in some cases, may have distinctly different clinical findings. Autosomal dominant RP is notoriously variable in expression. For example, mutations in one autosomal gene, PRPH2 (also known as RDS ), can cause dominant RP, dominant macular degeneration, or dominant panretinal maculopathy, even among members of the same family. 7–11
Variable expression is a problem in determining mode of inheritance because some individuals may not show symptoms until late in life, and individuals with different symptoms may be diagnosed with different diseases even if the underlying cause is the same.
Incomplete penetrance, or nonpenetrance, means that some individuals with a disease-causing mutation will not be affected. For instance, 20% of individuals with a dominant-acting mutation in PRPF31 will have normal vision by age 60 even though relatives with the same mutation may have RP by age 20. 12–15 One indicator of nonpenetrance in a multigenerational family is a “skipped generation,” that is, an unaffected individual with an affected parent and an affected child. This is often seen in families with PRPF31 mutations. 16,17
Although variable expression and incomplete penetrance are seen as distinct phenomena, they are actually part of a continuum, with nonpenetrance just the extreme. The difference between late onset and no onset may simply be the age of the patient when examined. Whatever the terminology, the underlying finding is that dominant retinal disease mutations may have highly variable consequences, confounding diagnosis.
An additional rare but confounding possibility has been observed in large, multigenerational families with inherited retinal disease: mutations in more than one gene may be segregating independently in the family. This occurs because families with late onset, nonlethal diseases are likely to meet and socialize with similar families. Descendants of these families are at risk of inheriting mutations in more than one gene. This is “assortative mating.”
Alan Lap-Yin Pang , ... Wai-Yee Chan , in Molecular Pathology , 2009
ADH is a familial form of isolated hypoparathyroidism characterized by hypocalcemia, hyperphosphatemia, and normal to hypoparathyroidism. Inheritance of the disorder follows an autosomal dominant mode. The patients are generally asymptomatic. A significant fraction of cases of idiopathic hypoparathyroidism may in fact be ADH.
More than 80% of the reported ADH kindreds have CaSR mutations. There are 44 activating mutations of CaSR reported in the literature. These mutations produce a gain of CaSR function when expressed in in vitro systems [ 13 , 117 ]. The majority of the ADH mutations are missense mutations within the extracellular domain and transmembrane domain of CaSR. In addition, a deletion in the intracellular domain, p.S895_V1075del, has also been described in an ADH family. The mechanism of CaSR activation by these mutations is not known. Worthwhile noting is that almost every ADH family has its own unique missense heterozygous CaSR mutation [ 117 ]. Most ADH patients are heterozygous. The only deletion-activating mutation occurs in a homozygous patient in an ADH family. However, there is no apparent difference in the severity of the phenotype between heterozygous and homozygous patients.
Elaine S. Jaffe MD , in Hematopathology , 2017
This disease has been recently characterized. 71,72 Heterozygous mutations in CTLA-4 lead to T-cell impairment with immune dysregulation with later onset compared to IPEX and incomplete penetrance. Several of these patients had a diagnosis of CVID due to hypogammaglobulinemia, deficit in antibody production, and expansion of autoreactive B cells. Tregs constitutively express the inhibitory receptor CTLA-4, which is an essential part of their suppressive functions. Upon antigen presentation by dendritic cells (or other specialized AP cells) in the presence of T-cell receptor, costimulatory molecule CD28 mediates T-cell effector function, T-cell activation, and generation of memory T cells, and provides helper function to B cells and antibody production. The inhibitory signals of these events are mediated by CTLA-4. Both receptors share the same ligands CD80/CD86; it has been recently shown that CTLA-4 not only recycles from the surface to the cytoplasm of T cells, where it can either be recycled to the surface or digested, but also has the ability to remove the ligands (CD80 and CD86) from the antigen-presenting cells via transendocytosis. 73 Both mechanisms offer a way to regulate the availability of ligands and subsequently enhance or reduce T-cell activation, and proliferation.
Patients present with recurrent respiratory tract infections, hypogammaglobulinemia, autoimmune cytopenias (thrombocytopenia, autoimmune hemolytic anemia), autoimmune enteropathy, and CNS lesions. Lymphadenopathy is present in about one third of patients. Histologically, there are lymphocytic infiltrates involving the gastrointestinal tract with evidence of enterocolitis consistent with lymphocytic and/or neutrophilic (cryptitis) colitis as well as lymphoid hyperplasia with a mixture of B cells and T cells; a full clinical spectrum of severity corresponding to underlying histology (not infectious) similar to the enterocolitis in patients treated with anti-CTLA4 antibody, is observed. 74 Another distinguishing feature in these patients is the inflammatory infiltrate involving the CNS with supratentorial and infratentorial lesions, occasionally involving brain stem and spine ( Fig. 54-4 ). It is of interest that the degree of involvement by MRI did not correlate with the severity of the clinical symptoms. Histologically, the infiltrate was either lymphohistiocytic with scattered plasma cells or mostly lymphoplasmacytic. There was no necrosis, granulomata, or tissue destruction; by immunophenotype, the majority of lymphocytes were T cells with a predominance of CD4-positive cells, the plasma cells were often polyclonal, and in only one patient there was light chain restriction. Histology of the lymph node was more varied; in some cases follicular hyperplasia was present, and only one case showed an atypical T-cell proliferation not clonal in nature, but composed predominantly of CD8-positive T cells. One patient has been described with classical Hodgkin's, EBV-positive lymphoma. 71
Guy Helman , ... Adeline Vanderver , in Handbook of Clinical Neurology , 2018
ADLD is caused by heterozygous duplications in the gene encoding Lamin B1 ( LMNB1 ) ( 150340 ) ( Padiath et al., 2006 ; Giorgio et al., 2015 ). Inheritance is autosomal dominant. Apparent sporadic cases are reported in addition to cases of autosomal-dominant inheritance. Deletion/duplication analysis of LMNB1 should be performed by gene sequencing, either by single-gene testing or as part of a multigene panel, or can be tested by chromosomal microarray or polymerase chain reaction-based methods ( Nahhas et al., 1993 ).
Stefan Somlo , ... Michael J. Caplan , in Seldin and Giebisch's The Kidney (Fourth Edition) , 2008
Isolated autosomal dominant PLD (ADPLD) (MIM 174050) also occurs as a genetically distinct disease in the absence of renal cysts ( 274 , 281 , 328 ). Like ADPKD, ADPLD is genetically heterogeneous, with two genes identified ( PRKCSH and SEC63 ) accounting for approximately one third of isolated ADPLD cases ( 49 , 57 , 166 ). ADPLD often goes undetected even in first-degree relatives of patients with highly symptomatic polycystic liver disease. As in the case of polycystic liver disease associated with ADPKD, isolated ADPLD is more severe in women than in men. Liver function tests remain normal and when symptoms develop, these are related to mass effects or complications such as cyst hemorrhage or infection. Patients with isolated ADPLD may also be at increased risk for intracranial aneurysms and valvular heart disease ( 274 ).
ADH1 is characterized by mild-to-moderate hypocalcemia and inappropriately low or normal PTH concentrations ( Pearce et al., 1996b ). Other biochemical features of ADH1 include hyperphosphatemia, hypomagnesemia and hypercalciuria ( Roszko et al., 2016 ). ADH1 is symptomatic in 72% of patients and these patients present with hypocalcemic symptoms including carpopedal spasms, tetany, paraesthesia and seizures ( Raue et al., 2011 ). Additionally, some patients present with associated features including basal ganglia calcifications and nephrocalcinosis. The severity of hypocalcemia correlates with the observance of symptomatic ADH1 with such individuals presenting with a significantly lower serum calcium concentration than those without symptoms ( Gorvin, 2019 ).
The majority of ADH1 cases are caused by heterozygous missense mutations (96%). The ECD missense mutations are clustered in three key sites: the hinge region between lobes 1 and 2; the homodimer interface, and loop 2, which stretches across the inter-protomer region to stabilize dimerization ( Geng et al., 2016 ; Zhang et al., 2016 ; Gorvin, 2019 ). It has been hypothesized that these mutant residues, many of which lie in ligand binding sites, favor a partially active state that is fully activated at a lower concentration of ligand than WT receptor ( Geng et al., 2016 ; Zhang et al., 2016, 2014 ). Almost half of the ADH1 mutations within the CaSR TMD are located in the TM6–TM7 region. Mutagenesis studies have shown these residues are important for maintaining the receptor in its inactive conformation, consistent with that observed for other class C GPCRs ( Binet et al., 2007 ; Xue et al., 2015 ). This understanding of the specific residues involved in CaSR activation could facilitate the rational design of allosteric modulators.
Occasionally, ADH1 patients present with features of Bartter's syndrome including hypokalemia, hypomagnesemia, metabolic alkalosis and hyperaldosteronemia ( Watanabe et al., 2002 ). Bartter's syndrome is a heterogeneous disorder caused by defects in several proteins involved in transepithelial NaCl transport across the thick ascending limb of the loop of Henle ( Watanabe et al., 2002 ; Hu et al., 2002 ).
Patients with ADH1 need to be distinguished from individuals with other forms of hypoparathyroidism as treatment with vitamin D or its metabolites to correct hypocalcemia may exacerbate hypercalciuria and nephrocalcinosis in ADH1 patients ( Roszko et al., 2016 ). In ADH1 patients with symptomatic hypocalcemia alternative treatments include thiazide diuretics, which lower urinary calcium, or recombinant human PTH ( Roszko et al., 2016 ). Future treatments of symptomatic ADH1 may include negative allosteric modulators of the CaSR (calcilytics), which demonstrate efficacy in mouse models of ADH1 by increasing serum PTH and calcium, while reducing urinary calcium excretion ( Dong et al., 2015 ).
Autosomal dominant epilepsy with auditory features (ADEAF), also known as autosomal dominant lateral temporal lobe epilepsy (ADLTLE), is a rare epilepsy syndrome that confers focal seizures that often secondarily generalize. 91 The seizures can begin at any age, but usually start in the second or third decade of life. As the syndrome’s name suggests, the majority of the patients (64%) have focal seizures that begin with an auditory component. Some have simple auditory hallucinations, such as ringing that changes in volume, 92 or a “buzzing, or humming like a machine.” 93 In other patients, auditory hallucinations are formed, such as voices or singing. 92 Some patients have visual, autonomic, psychic or vertiginous focal seizures. In some pedigrees, the seizures are accompanied by a sensory aphasia with or without auditory hallucinations. 94 In most patients, the seizures are infrequent (only several times per year before starting medication) and can usually be controlled with anticonvulsant drugs.
Interictal EEG abnormalities, if present, are usually left temporal spike and sharp wave complexes. ADEAF patients do not have causative brain lesions on conventional MRI imaging. However, one diffusion tensor imaging study suggested that some patients may have subtle malformations in the left temporal cortex. 95 Finally, although their neurological exams are normal, functional imaging and magnetoencephalography studies of members of four ADEAF families were consistent with impaired language processing. 96
At the time of its first description, ADEAF was linked to a 10-cM region on chromosome 10q with a 71% penetrance. 97 Linkage studies in another family narrowed the region to approximately 3 cM. 93 Kalachikov et al. sequenced all exons and intron/exon junctions from one affected patient form three different ADEAF pedigrees and then genotyped all family members from five different ADEAF pedigrees. 98 They found that all affected family members and obligate carriers possessed mutations (four frameshift/intron retention truncation mutations and one missense mutation) in the leucine-rich, glioma-inactivated 1 gene ( LGI1 ). Some unaffected family members also possessed the mutations, a finding consistent with the reduced penetrance found in the gene linkage studies. There are now 27 LGI1 mutations associated with ADEAF ( Table 84.4 ).
Less than 50% of ADEAF families and less than 2% of sporadic ADEAF patients have LGI1 mutations. Recently, a new ADEAF locus was found in a large Brazilian family. The DNA from 11 affected and 14 unaffected family and performed genotyping found linkage to region 19q13.11–q13.31 with incomplete penetrance. 99
Elliott H. Soh
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