PMC:1852721 / 56221-59534 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/1852721","sourcedb":"PMC","sourceid":"1852721","source_url":"https://www.ncbi.nlm.nih.gov/pmc/1852721","text":"Oligogenic Inheritance\nOMIM describes \u003e14 instances of possible digenic inheritance. The first molecular documentation of digenic inheritance, reported by Kajiwara et al.,64 concerned retinitis pigmentosa caused by a heterozygous mutation in the gene encoding peripherin (RDS [MIM *179605.0004]) in combination with a heterozygous null mutation in the unlinked gene (ROM1 [MIM *180721.0001]) encoding rod outer segment protein-1. Retinitis pigmentosa did not occur with either mutation alone in the heterozygous state. Nadeau65 suggested that this is an example of modification rather than digenic inheritance, ROM1 being the modifier. He cited classic examples of dominance modification in mouse models.\nKatsanis et al.66 reported several families in which Bardet-Biedl syndrome (BBS [MIM #209900]) showed what they termed “triallelic inheritance”—for example, patients with BBS who are homozygous for a missense mutation in the MKKS gene (MIM *604896.0003) and heterozygous for a mutation in the BBS2 gene (MIM *606151.0013). Katsanis et al.66 estimated that 40% of patients with BBS-2 (see MIM #209900) have homozygosity or compound heterozygosity for mutations in the BBS2 gene in combination with heterozygosity for a third mutation in another BBS gene.\nBartter syndrome type 4 (MIM #602522)—renal salt wasting and deafness—is most often caused by mutation in the BSND gene (MIM *606412). In a child with this disorder whose parents were consanguineous, Schlingmann et al.67 found no mutation in the BSND gene but found homozygous deletion of the CLCNKB gene (MIM *602023.0008) and a homozygous missense mutation of the linked CLCNKA gene (MIM *602024.0001).\nIn some cases, the nature of the interaction of the gene products in a triallelic digenic inheritance pattern can be deduced—for example, in the case of cortisone reductase deficiency (MIM #604931) due to an intronic mutation in HSD11B1 (MIM *600713.0001) and exonic mutations in H6PD (MIM *138090.0001 –*138090.0002).68 The long QT syndromes, in which the interaction of mutations in two different ion-channel genes appear to occur, provide other examples. OMIM records two examples of the LQT syndrome resulting from double heterozygosity for mutations in two LQT genes—that is, biallelic digenic inheritance. LQT 1/2 results from heterozygous mutations in the KCNQ1 (MIM *607542.0009) and KCNH2 (MIM +152427.0019) genes, and LQT3/6 results from heterozygous mutations in the SCN5A (MIM +600163.0007) and KCNE2 (MIM +603796.0005) genes. LQT 2/5 can result from a heterozygous mutation in the KCNH2 (MIM +152427.0021) gene and a homozygous mutation in the KCNE1 (MIM *176261.0005) gene, another example of triallelic digenic inheritance.\nAs more is learned about Mendelian disorders, complexities come to light that indicate that most of these also must be viewed as multifactorial or at least as complex traits.38 Modifier genes/loci implicated in Mendelian disorders are being identified—for example, the cystic fibrosis modifier-1 locus (CFM1 [MIM 603855]) in cystic fibrosis. Imprinting is an important factor contributing to the complexity of inheritance in a number of genetic disorders. In the instance of the many Mendelian disorders that are caused by expanded repeats, the random loss and gain in number of repeats introduce complexities.","divisions":[{"label":"title","span":{"begin":0,"end":22}},{"label":"p","span":{"begin":23,"end":704}},{"label":"p","span":{"begin":705,"end":1258}},{"label":"p","span":{"begin":1259,"end":1663}},{"label":"p","span":{"begin":1664,"end":2702}}],"tracks":[{"project":"2_test","denotations":[{"id":"17357067-8202715-2054077","span":{"begin":171,"end":173},"obj":"8202715"},{"id":"17357067-11256068-2054078","span":{"begin":525,"end":527},"obj":"11256068"},{"id":"17357067-11567139-2054079","span":{"begin":720,"end":722},"obj":"11567139"},{"id":"17357067-11567139-2054080","span":{"begin":1043,"end":1045},"obj":"11567139"},{"id":"17357067-15044642-2054081","span":{"begin":1477,"end":1479},"obj":"15044642"},{"id":"17357067-12858176-2054082","span":{"begin":1982,"end":1984},"obj":"12858176"},{"id":"17357067-11479736-2054083","span":{"begin":2877,"end":2879},"obj":"11479736"}],"attributes":[{"subj":"17357067-8202715-2054077","pred":"source","obj":"2_test"},{"subj":"17357067-11256068-2054078","pred":"source","obj":"2_test"},{"subj":"17357067-11567139-2054079","pred":"source","obj":"2_test"},{"subj":"17357067-11567139-2054080","pred":"source","obj":"2_test"},{"subj":"17357067-15044642-2054081","pred":"source","obj":"2_test"},{"subj":"17357067-12858176-2054082","pred":"source","obj":"2_test"},{"subj":"17357067-11479736-2054083","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#bd93ec","default":true}]}]}}