Genetic Heterogeneity

Author: Marco Seri
Submitted: Thursday 11th of November 2010 08:10:30 AM
Submitted by: marco.seri
Language: English
Content type: Learning resource
Educational levels: expert, qc3

Abstract

The term “Genetic Heterogeneity” is used when the same condition can be caused by mutations in different genes. This can some times be a difficult situation in Genetic Counseling; for instance, two parents affected with an autosomal recessive form of deafness could have 100% affected children if they carry mutations at the same locus, or 100% healthy children if their deafness is due to mutations in different genes. The determination of identical or similar phenotypes by different genetic mechanisms is an emerging problem in Medical Genetics. Several monogenic disorders are caused by mutations in more than one gene, and for some disorders, the degree of genetic heterogeneity is such that more than 100 genes can be responsible for the same phenotype. As an example, Retinitis Pigmentosa (RP) is a heterogeneous group of inherited disorders characterized by constriction of the visual field, night blindness, and fundus changes, responsible for progression of visual impairment. Every kind of inheritance pattern is possible in nonsyndromic RP, with autosomal recessive trait being the most frequent. The extensive genetic heterogeneity in RP is complicated by additional patterns of inheritance described in nonsyndromic or syndromic RP. In sporadic cases of RP, a digenic inheritance has been reported, while triallelic inheritance has been recently demonstrated for Bardet-Biedl syndrome, characterized by retinal dystrophy, polydactyly, mental retardation, obesity, hypogonadism and renal anomalies. So far 12 different genes have been identified as responsible for this autosomal recessive disorder and the presence of a third mutated allele (“triallelic inheritance”), could suggest a “modifier of penetrance”. An extreme case of reduced penetrance and/or variable clinical expression can be observed in Holoprosencephaly (HPE), with some families in which patients carrying the mutated allele show only a single central incisor. This situation is probably due to the presence of a second mutation in a different gene with a modifier effect. Also HPE shows genetic and clinical heterogeneity and so far 8 different causative genes have been identified, acting at different points in the same biochemical or regulatory pathway. Genetic heterogeneity is also present in several syndromes that present dysmorphic features (Noonan Syndrome, CHARGE, Sotos Syndrome, FG Syndrome, etc.) For instance, about half of patients affected with Noonan Syndrome (NS) present mutations in the PTPN11 gene, while de novo germline mutations of the KRAS gene have been identified in less than 5% of NS cases. Among patients with NS without mutation in PTPN11 or KRAS, missense SOS1 mutations account for approximately 20% of cases. Thus, mutations in these three genes cause approximately 60% of NS cases. Recently, mutations in RAF1 have been reported in about 3% of all affected NS individuals. Nevertheless, in a large portion of NS patients the genetic defect remains to be identified and in these cases the risk of recurrence can not be clarified completely. Genetic heterogeneity is a feature of some neurodegenerative disorders as well, such as Spinocerebellar Ataxia (SCA) or Hereditary Spastic Paraplegia (HSP). We have studied a large Sardinian pedigree with recurrence of HSP, where the analysis of the Spastin gene, responsible for about 40% of autosomal dominant HSP, revealed a deletion in most of the patients but not in four affected members, suggesting the presence of intrafamilial genetic or allelic heterogeneity. In our experience, this is the first time that a similar observation has been made, but intrafamilial genetic or allelic heterogeneity is something to keep in mind during counseling of families with disorders characterized by extensive genetic heterogeneity.

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abstract Eterogeneita_Genetica_5092.ppt

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Marco Seri. Genetic Heterogeneity. EUROGENE portal. November 2010. online: http://eurogene.open.ac.uk/content/genetic-heterogeneity

UMLS keywords

10q22, 10q24, 11p13, 11q12, 11q13, 11q23, 12q13, 12q14, 13q14, 14q22, 16q21, 16q24, 1p21, 1q21, 1q23, 20p12, 2B, 2p12, 2q31, 2q35, 2q37, 3q27, 4q12, 7p13, 7q35, 8p12, Aa, ABDOMINAL DISTENTION, Abnormalities, absence, Achondrogenesis, show more...Achondroplasia, Activated protein C, Activation, Additional, adenomatous polyposis coli, Adrenal Medulla, Affecting, Albright syndrome 1, Allele, Alveolar, Anal, Androgen, APOA1, Approximate, ARL6, Arrest, ART, Assembly, Associated, autophosphorylation, Autosomal recessive inheritance, Based, BB, BBS1, BBS10, BBS11, BBS12, BBS2, BBS3, BBS4, BBS5, BBS6, BBS7, BBS8, BBS9, Becker Muscular Dystrophy, Bilateral, Binding, Bony, BSCL2, cadherin, Cardiomyopathy, Case, Caudal, Causing, Cell Lineages, Cells, Cellular, Central, Central Core Disease, CFTR gene, Change, Characteristics, Characterization, Charge, CHARGE SYNDROME, Cholesteryl Ester Storage Disease, Chromosome 2, Classical, CLCN1, Clinical, Clinical heterogeneity, Cofactor, COL2A1, Complex, Complicated, Concept, Condition, CONGENITAL HEARING LOSS, Congenital hypertrophy, Counseling NOS, Course, Cystic Fibrosis, CYTO, Cytogenetics, Defect, Deficiency, Deleted, Deletion, Derived, described, determination, Development, Difference, Difficult, Dimerization, disease cause, disease course, Disease susceptibility, Diseases, Disruption, Diversity, Domain, Dominant, Downstream, Dysmorphic features, ECE1, EDN, EDN3, EDNRB, Effect, Elliptocytosis, EMERGENT, End, Erythrocytosis, Etiology, Euro, European, Example, Exons, Experience, Extensive, eyebrows, Facial Features, FACTOR V DEFICIENCY, Familial, Familial fatal insomnia, Families, Fibrous Dysplasia, First, Flare, Form, FOXH1, Frequencies, Frequent, Fundus, Further, Ganglion Cells, GDNF, Genes, Genetic, Genetic Counseling, Genetic Disorders, Genetic Heterogeneity, Genetic Medicine, genetics, Genome Assembly, GFRA1, GFRA2, GFRA3, Glioma, GNAS1, Green, Greig cephalopolysyndactyly syndrome, Growth failure, HAD, HAEMORRHAGIC DISORDER, Hb Osler, Heritable, Heterogeneity, Hindgut, Hirschsprung, Holoprosencephaly, HSAS1, HSP60, HT2A, Hughes, Human, HYDROCEPHALUS, Hyperkalaemic periodic paralysis, Hypertriglyceridemia, Hypochondrogenesis, Hypochondroplasia, Hypogonadism, I 102, I NOS, Ia, Identical, Identified, III, incidence, Incidences, Individual, Induce, Infantile, Inheritance, Insensitivity, Insertion, Interaction, Internal, Intestinal occlusion, Introns, Involved, Isoform, Issue, Italy, Kennedy Syndrome, KIAA1279, KIF5A, Kinase, Kit, Kniest dysplasia, KRAS, L1CAM, Large, Leading, Level, ligand, Lineage, LIPA, Live Births, Loc, Location, Locus, Main, Major, Make, MAL, Malignant Hyperthermia, Map, MARCO, MASA SYNDROME, MAST, Mean, Mechanism, Medial, Medicine, MEDITERRANEAN, Medullary thyroid carcinoma, MEN 2a, Mental Retardation, Microcephaly, Migration, Million, MIM, Mind, MKKS, Modifier, Molecular, Mutation, Myenteric plexus, Myotonia Congenita, Nature, Nephropathic amyloidosis, Neural Crest, Neurodegenerative Disorders, Neurofibromatosis, Neuropathy, neurturin, NF1, Night Blindness, NODAL, Noonan Syndrome, NORRIE DISEASE, Not, NPD, O NOS, Obese, observation, Oncogene, Order, p11, P12, Palsies, Paramyotonia Congenita, Parasympathetic ganglion, Part, Pathway, Patterns, PAX3, Penetrance, Permutation, PGN, Phenotype, Piebaldism, Pigmentation, PLP, PMP22, Polydactyly, Population, Pre, Pregnancy, Premature, Presence, Present, PRNP gene, Pro, Proaccelerin, Promoter, Protein, Protein NOS, PSPS, PurE, Q13, Q15, RAF1, RAS, Rearrangement, Recently, Recession, Rectum, Red, Reduced penetrance, Reference, Remaining, Renal anomalies, Renal cell cancer, Repeat, Repeats, Reports, Represent, Responsible, Results, RET Protein, Retina, Retinal dystrophy, Retinal Pigment Epithelium, Retinitis Pigmentosa, Rhabdomyosarcoma, Rich, RP, RYR1 gene, Same, SAP, Scheie, School, SCN4A, Series, Severe constipation, Shape, SHH, Show, SHP2, Sickle Cell Anemia, Signaling, Silver syndrome, Similar, Single, Situation, SIX3, size, SLC30A6, SOS1, SOX10, Span, SPG10, SPG11, SPG12, SPG13, SPG14, SPG15, SPG16, SPG19, SPG2, SPG20, SPG21, SPG23, SPG24, SPG25, SPG26, SPG27, SPG28, SPG29, SPG30, SPG31, SPG33, SPG3A, SPG4, SPG5A, SPG6, SPG8, SPG9, Spherocytosis, Spinocerebellar Ataxias, Sporadic, SPTA1, Stenoses, Stickler syndrome, STRUMPELLIN, Submucosal, Suggest, Susceptibility, symbol, Syndromes, TCC, TDGF1, TGF, TGIF, Third, Thrombotic, Thyroid carcinoma, Time, Times, Transfection, Tumor Suppressors, Tumorigenesis, Tumors, Two, TYPE, Type 5, Type 6, Type I, Type II, Type III, Type IV, Tyrosine Kinase Domain, TYROSINE KINASE RECEPTOR, V A, Variable expression, Variable expressivity, Vas deferens, VHL, Visual field, Visual loss NOS, Waardenburg, Watson Syndrome, Wilms Tumor, Wolman, WT1, Xq28, Yellow, ZFHX1B, ZFYVE27, ZIC2

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