WordNet

create by mixing or combining
(chemistry) a substance formed by chemical union of two or more elements or ingredients in definite proportion by weight (同)chemical_compound
put or add together; "combine resources" (同)combine
an enclosure of residences and other building (especially in the Orient)
a whole formed by a union of two or more elements or parts
combine so as to form a whole; mix; "compound the ingredients" (同)combine
calculate principal and interest
composed of more than one part; "compound leaves are composed of several lobes; "compound flower heads"
consisting of two or more substances or ingredients or elements or parts; "soap is a compound substance"; "housetop is a compound word"; "a blackberry is a compound fruit"
(genetics) an organism having two different alleles of a particular gene and so giving rise to varying offspring
combined into or constituting a chemical compound

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(…になるように)〈要素・成分など〉'を'混ぜ合わせる《+『名』+『into』+『名』》;(…から)〈薬など〉'を'調合する,混ぜ合わせて作る《+『名』+『from』(『of』)+『名』》 / 《しばしば受動態で》〈めんどうな事・損害など〉'を'もっとひどくする / 〈利子〉'を'複利で計算する / (…と)話し合いをつける,妥協する《+『with』+『名』》 / 複合の,合成の / 『合成物』,混合物,調合物;化合物 / 複合語,合成語(classroom, heart-to-heartなどをいう)
(異民族の家屋・商館などがある)囲み地区,構内

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/09/30 12:25:00」(JST)

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Compound heterozygosity in medical genetics is the condition of having two heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state. That is, an organism is a compound heterozygote if it has two recessive alleles for the same gene, but with those two alleles being different from each other (for example, both alleles might be mutated but at different locations). Compound heterozygosity reflects the diversity of the mutation base for many autosomal recessive genetic disorders; mutations in most disease-causing genes have arisen many times. This means that many cases of disease arise in individuals who have two unrelated alleles, who technically are heterozygotes, but both the alleles are defective.

These disorders are often best known in some classic form, such as the homozygous recessive case of a particular mutation that is widespread in some population. In its compound heterozygous forms, the disease may have lower penetrance, because the mutations involved are often less deleterious in combination than for a homozygous individual with the classic symptoms of the disease. As a result, compound heterozygotes often become ill later in life, with less severe symptoms. Although compound heterozygosity as a cause of genetic disease had been suspected much earlier, widespread confirmation of the phenomenon was not feasible until the 1980s, when polymerase chain reaction techniques for amplification of DNA made it cost-effective to sequence genes and identify polymorphic alleles.

Etiology of genetic disease[edit]

Compound heterozygosity is one of the causes of variation in genetic disease. The diagnosis and nomenclature for such disorders sometimes reflects history, because most diseases were first observed and classified based on biochemistry and pathophysiology before genetic diagnosis was available. Some genetic disorders are really a family of related disorders that occur in the same metabolic pathway, or in related pathways. Naming conventions for the disease became established before precise molecular diagnosis was possible. (The mutation makes it 'as if' fraternal twins have fused and became one person).

For example, hemochromatosis is the name given to several different heritable diseases with the same outcome, excess absorption of iron. These variants all reflect a failure in a metabolic pathway associated with iron metabolism, however mutations that cause hemochromatosis can occur at different gene loci. Mutations have occurred at each locus many times, and a few such mutations have become widespread in some population. The fact that multiple loci are involved is the primary cause for the variant forms of hemochromatosis and its outcome. This variation is caused not by compound heterozygosity, but rather by the fact that several different enzyme defects can cause the disease. Clinically, most cases of hemochromatosis are found in homozygotes for the most common mutation in the HFE gene.^[1] But at each gene locus associated with the disease, there is the possibility of compound heterozygosity, often caused by inheritance of two unrelated alleles, of which one is a common or classic mutation, while the other is a rare or even novel one.^[2]

For some genetic diseases, environmental cofactors are an important determinant of variation and outcome. In the case of hemochromatosis, penetrance is incomplete, even for the classic HFE mutation, and is affected by gender, diet, and behaviors such as alcohol consumption. Compound heterozygotes are often observed only through subclinical symptoms such as excess iron. Disease is rarely observed in such compound heterozygotes unless other causal factors (such as alcoholism) are present. As a result, compound heterozygosity for hemochromatosis may be more common than diagnosis based on pathology would suggest.^[3]

Some genetic diseases are named more precisely, and represent a single point of failure on a metabolic pathway. For example, Tay-Sachs disease, GM2-gangliosidosis, AB variant, and Sandhoff disease might easily have been defined together as a single disease, because the three disorders are associated with failure of the same enzyme and have the same outcome. However, the three were discovered and named separately, and each represents a distinct molecular point of failure in a subunit that is required for activation of the enzyme. For all three disorders, compound heterozygosity is responsible for variant forms. For example, both TSD and Sandhoff disease have a more common infantile form and several late-onset variants. Post-infantile forms, which are rare, are generally caused by the inheritance of two unrelated alleles, of which one is usually a classic mutation, while the other is a rare or even novel one.

Examples[edit]

Phenylketonuria. Because phenylketonuria was the first genetic disorder for which mass post-natal genetic screening was available, beginning in the early 1960s, atypical cases were detected almost immediately. Molecular analysis of the genome was not yet possible, but protein sequencing revealed cases caused by compound heterozygosity.^[4] As molecular genomic techniques became available in the 1980s and 1990s, it became possible to explain a range of disorders in heterozygotes carrying one copy of one of the classic mutations for phenylketonuria.^[5]

Tay-Sachs disease. In addition to its classic infantile form, Tay Sachs disease may present in juvenile or adult onset forms, often as the result of compound heterozygosity between two alleles, one which would cause the classic infantile disease in homozygotes and another that allows some residual HEXA enzyme activity.^[6]

Sickle cell syndromes. A variety of sickle cell disorders result from inheritance of the sickle cell gene in a compound heterozygous manner with other mutant beta globin genes. These disorders include sickle cell-beta thalassemia.^[7] In the case of sickle cell anemia, an individual with one allele for hemoglobin S and one allele for hemoglobin C would still develop the disease, despite being heterozygous for both genes.^[8]

References[edit]

^ KJ Allen, LC Gurrin, CC Constantine, et al. (2008-01-17). "Iron-Overload–Related Disease in HFE Hereditary Hemochromatosis". New England Journal of Medicine 358 (3): 221–230. doi:10.1056/NEJMoa073286. PMID 18199861.
^ Rossi E, Olynyk JK, Cullen DJ, Papadopoulos G, Bulsara M, Summerville L, Powell LW (Feb 2000). "Compound heterozygous hemochromatosis genotype predicts increased iron and erythrocyte indices in women". Clinical Chemistry 46 (2): 162–166. PMID 10657371.
^ Deugnier Y, Mosser J (Aug 2008). "Modifying factors of the HFE hemochromatosis phenotype". Expert Reviews in Gastroenterology and Hepatology 2 (4): 531–540. doi:10.1586/17474124.2.4.531. PMID 19072401.
^ Anderson JA, Fisch R, Miller E, Doeden D (Mar 1966). "Atypical phenylketonuric heterozygote. Deficiency in phenylalanine hydroxylase and transaminase activity". Journal of Pediatrics 68 (3): 351–360. PMID 4379218.
^ Avigad S, Kleiman S, Weinstein M, Cohen BE, Schwartz G, Woo SL, and Shiloh Y (Aug 1991). "Compound heterozygosity in nonphenylketonuria hyperphenylalanemia: The contribution of mutations for classical phenylketonuria". American Journal of Human Genetics 49 (2): 393–399. PMC 1683284. PMID 1867197.
^ Ohno, Kousaku and Suzuki, Kunihiko (1988-12-05). "Multiple Abnormal beta-Hexosaminidase alpha-Chain mRNAs in a Compound-Heterozygous Ashkenazi Jewish Patient with Tay-Sachs Disease" (PDF). Journal of Biological Chemistry 263 (34): 18563–7. PMID 2973464. Retrieved 2007-05-11.
^ Gonzalez-Redondo JM, Stoming, TA, Lanclos, KD, et al. (1988). "Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States". Blood 72 (3): 1007–1014. PMID 2458145.
^ Witkowska HE; Lubin BH; Beuzard Y; Baruchel S; Esseltine DW; Vichinsky EP; Kleman KM; Bardakdjian-Michau J; Pinkoski L; Cahn S; et al. (1991-10-17). "Sickle cell disease in a patient with sickle cell trait and compound heterozygosity for hemoglobin S and hemoglobin Quebec-Chori". New England Journal of Medicine (Massachusetts Medical Society) 325 (16): 1150–1154. doi:10.1056/NEJM199110173251607. PMID 1891024.

UpToDate Contents

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1. 遺伝学用語集 glossary of genetic terms
2. 鉄過剰が疑われる患者に対するアプローチ approach to the patient with suspected iron overload
3. ヘモグロビン変異の概要 introduction to hemoglobin mutations
4. ゴーシェ病：病因、臨床症状、および診断 gaucher disease pathogenesis clinical manifestations and diagnosis
5. 遺伝性ヘモクロマトーシスの臨床症状および診断 clinical manifestations and diagnosis of hereditary hemochromatosis

English Journal

Liver cirrhosis treated by living donor liver transplantation in a patient with AGL mutation c.2607-2610delATTC and c.1672dupA.

Kondo Y, Usui H, Ishige-Wada M, Murase T, Owada M, Okubo M.SourceOkinaka Memorial Institute for Medical Research, Tokyo, Japan.
Clinica chimica acta; international journal of clinical chemistry.Clin Chim Acta.2013 Sep 23;424:19-21. doi: 10.1016/j.cca.2013.05.007. Epub 2013 May 13.
Glycogen storage disease type III (GSD III) is an inherited disorder characterized by the accumulation of abnormal glycogen in the liver. Hepatic manifestations were considered as improving with age; however, patients live longer and liver cirrhosis is being recognized. We report a patient of GSD II
PMID 23688858

Complexities of gender assignment in 17beta-hydroxysteroid dehydrogenase type 3 deficiency: is there a role for early orchiectomy?

Chuang J, Vallerie A, Breech L, Saal HM, Alam S, Crawford P, Rutter MM.AbstractBACKGROUND: 17beta-Hydroxysteroid dehydrogenase type-3 (17betaHSD-3) deficiency is a rare cause of 46,XY disorders of sex development. The enzyme converts androstenedione to testosterone, necessary for masculinization of male genitalia in utero. 17betaHSD-3 deficiency is frequently diagnosed late, at puberty, following virilization, with consequent female-to-male gender reassignment in 39-64%. The decision for sex of rearing is difficult, especially if diagnosed in early childhood. Consensus guidelines are equivocal or support male gender assignment. Long-term outcomes data to guide decisions are also lacking; however, in the few cases of early diagnosis and orchiectomy, female gender retention appears more likely.We report two patients with 17betaHSD-3 deficiency, who presented at unusual ages, in whom female gender was chosen. We performed a focused literature review and summary of gender outcomes in 17betaHSD-3 deficiency following early orchiectomy.CasesPatient A was a phenotypic female who presented at one year of age with bilateral inguinal hernias and external female genitalia. Testes were identified at surgery. The karyotype was 46,XY. She was initially diagnosed with complete androgen insensitivity syndrome; however, androgen receptor mutation analysis was negative. Human chorionic gonadotropin stimulation yielded a low testosterone: androstenedione ratio (0.6, normal >0.8). Genetic testing demonstrated compound heterozygosity for two known mutations of the HSD17B3 gene. She underwent bilateral orchiectomy at two years of age.Patient B was born with female genitalia and virilized at 13 years of age. She did not seek evaluation until 22 years of age. Her karyotype was 46,XY. She had bilateral inguinal testes and low testosterone: androstenedione ratio (0.3). HSD17B3 gene sequencing showed her to be a compound heterozygote for two known mutations. She identified herself as female and underwent bilateral orchiectomy and estrogen replacement therapy.
International journal of pediatric endocrinology.Int J Pediatr Endocrinol.2013 Sep 12;2013(1):15. [Epub ahead of print]
BACKGROUND: 17beta-Hydroxysteroid dehydrogenase type-3 (17betaHSD-3) deficiency is a rare cause of 46,XY disorders of sex development. The enzyme converts androstenedione to testosterone, necessary for masculinization of male genitalia in utero. 17betaHSD-3 deficiency is frequently diagnosed late, a
PMID 24025597

Variant ataxia telangiectasia: clinical and molecular findings and evaluation of radiosensitive phenotypes in a patient and relatives.

Claes K, Depuydt J, Taylor AM, Last JI, Baert A, Schietecatte P, Vandersickel V, Poppe B, De Leeneer K, D'Hooghe M, Vral A.SourceCenter for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium, kathleen.claes@ugent.be.
Neuromolecular medicine.Neuromolecular Med.2013 Sep;15(3):447-57. doi: 10.1007/s12017-013-8231-4. Epub 2013 Apr 30.
Variant ataxia telangiectasia (A-T) may be an underdiagnosed entity. We correlate data from radiosensitivity and kinase assays with clinical and molecular data from a patient with variant A-T and relatives. The coding region of ATM was sequenced. To evaluate the functional effect of the mutations, w
PMID 23632773

Japanese Journal

骨格筋型塩化物イオンチャネル遺伝子(CLCN1)の複合ヘテロ接合体変異で重症化したThomsen病

佐々木良元,高橋正紀,穀内洋介 [他]
臨床神経学 53(4), 316-319, 2013-04
NAID 40019663429

Molecular analysis of afibrinogenemic mutations caused by a homozygous FGA1238 bp deletion, and a compound heterozygous FGA1238 bp deletion and novel FGA c.54+3A>C substitution

TAKEZAWA Yuka,TERASAWA Fumiko,MATSUDA Kazuyuki,SUGANO Mitsutoshi,TANAKA Aiko,FUJIWARA Mitsuhiro,KAINUMA Keigo,OKUMURA Nobuo
International journal of hematology 96(1), 39-46, 2012-07-01
NAID 10030954472