Oct 01, 2004 Abstract. Single gene disorders with Mendelian inheritance patterns have contributed greatly to the identification of genes and pathways implicated in genetic.
Abstract Single gene disorders with Mendelian inheritance patterns have contributed greatly to the identification of genes and pathways implicated in genetic disease. Teamviewer. In these cases, molecular analysis predicts disease status relatively directly. However, there are many abnormalities which show familial recurrence and have a clear genetic component, but do not show regular Mendelian segregation patterns. Defining the causative gene for non-Mendelian diseases is more difficult, and even when the underlying gene is known, there is uncertainty for prenatal prediction.
However, detailed examination of the different mechanisms that underlie non-Mendelian segregation provides insight into the types of interaction that regulate more complex disease genetics. Mendelian inheritance patterns are well-established, and readily recognizable as ‘textbook’ examples, for many single gene diseases (), and a few digenic cases (–). However, in most clinical genetics settings many cases are seen where the disease diagnosed is well known to have a strong genetic component, and show some familial recurrence, but no clear Mendelian inheritance.
Such cases clearly pose additional problems in counselling and the estimation of recurrence risk. Here, we review some of the different molecular mechanisms that lead to such irregular inheritance patterns, focussing mostly on diseases where at least one implicated gene and some underlying mutations have been identified. It is useful to attempt to categorize the different ways in which the observed inheritance patterns are generated (Table ) and then to consider in more detail some examples in each category. Some detailed molecular mechanisms underlying non-Mendelian inheritance patterns will be unfolded below, but first some general concepts need to be clarified. Incomplete penetrance (), where not all mutation carriers present with the expected phenotype, is commonly observed in human family studies.
This forms a continuum with variable expressivity, which can be so extreme that subtle manifestations of carrier status are sometimes only identified with hindsight (). Even some of the most classical Mendelian traits, like cystic fibrosis (CF), show complex variation (,).
A significant proportion of variability can be ascribed to allelic differences (,), some of which will be cryptic regulatory variation, influencing gene expression levels (,). The existence of widespread variation is not surprising, as gene products fulfil their function through finely tuned interactions with other cellular components, often showing some degree of threshold requirement (). Each component is subject to regulation, and variation, at every stage: transcription, splicing, translation (), protein folding, oligomerization, translocation and compartmentalization within the cell or export from it (). Subsequently, there is controlled turnover, through well-policed pathways of destruction (,). When focussing on gene products, we mostly think of proteins, but should increasingly remember that many cellular processes are regulated by RNA molecules, or at the RNA level (). The complexity of the proteome is strongly affected by controlled alternative splicing, a mechanism often altered or damaged through sequence variation or mutation. Protein folding, association and sub-cellular localization, also require some helper systems, such as molecular chaperones, which often double as stress response proteins (), and these are very likely implicated in extreme phenotypic variability, and hence segregation pattern variability (,).
SPORADIC OCCURRENCE OF GENETICALLY LETHAL SINGLE GENE ANOMALIES An apparently sporadic pattern of disease incidence is observed if virtually all cases arise as a result of new mutation. No parent to child inheritance of the phenotype is seen, generally because the affected individuals are consistently unable to reproduce through infertility or for physical or social reasons. Occasionally sibling recurrence is seen in such cases, if the parent in whom the new mutation arose has gonadal mosaicism, which is sometimes accompanied by somatic mosaicism.
Such recurrent new mutations are seen in Apert syndrome, with craniosynostosis and severe syndactyly caused by gain-of-function paternal mutations () at specific sites in the FGFR2 gene (). A significant proportion of severe bilateral anophthalmias is caused by de novo loss-of-function mutations in the early neural and eye development gene SOX2 (). Predicted loss of function mutations were recently identified in another developmental anomaly with no vertical transmission, Cornelia de Lange syndrome, in the human orthologue, NIPBL, of the Drososphila Nipped-B protein, with homology to sister chromatid cohesion protein SCC2 and a possible role in promoter-enhancer interactions (,). Most early onset severe cases of congenital central hypoventilation syndrome (CCHS) are associated with polyalanine expansion mutations in the paired-like homeobox gene PHOX2B ().