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


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:

UMLS keywords

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