For a summary of non-Mendelian inheritance patterns, see Table 4-3.
Chromosome abnormalities can occur sporadically or can be caused by familial transmission of duplications,deletions, or rearrangements that can result in imbalance of genetic material in the offspring.12 Due to the presence of many genes along the segment of chromosome involved, multiple phenotypic effects usually are seen. Risks to offspring of familial cases depend on parent of origin and size and location of the involved chromosomal segment, and vary depending on loss or gain of material in a particular region. In apparently sporadic cases, parental status with respect to the chromosomal abnormality should be assessed for all cases of offspring with chromosomal rearrangements. Absence of a parental chromosomal abnormality significantly reduces the risk to future offspring.
Contiguous Gene Disorders/ Microdeletion Syndromes
Contiguous gene disorders are the result of loss of several adjacent genes along a segment of chromosome and may consist of symptoms of one known hereditary disorder, more than one closely linked group of hereditary disorders, or either of these in conjunction with mental retardation, dysmorphic features, or both.13 The condition results from loss of one copy of a group of closely linked genes (haploinsufficiency) that may be detectable by highresolution chromosome analysis or fluorescence in situ hybridization (FISH) using region-specific probes. Approximately 5% to 10% of monogenic diseases are associated with gene deletions that cannot be detected through routine cytogenetic analysis.10 The microdeletions occur in regions of repeated genomic sequences that lead to rearrangements (recombination), resulting in loss or gain of genetic material during transmission, both of which have been documented.
Individuals inherit essentially all their mitochondrial DNA from their mothers; thus, any disease associated with a mitochondrial DNA mutation is transmitted from the mother to the offspring. In each cell, including egg cell progenitors, there may be up to 1000 mitochondria. If a mutation occurs in one of these mitochondria, as the mitochondrion divides over time, the mutation becomes present in a percentage of the overall mitochondrial population in the cell. When the cell divides, the mitochondria are distributed stochastically to the daughter cells. The
Table 4-3. Features of Non-Mendelian Patterns of Inheritance Chromosomal Disorders
Increased frequency in individuals with 2 or more major birth defects, 3 or more minor birth defects, or 1 major and 2 minor birth defects
Occurrence of multiple pregnancy losses or infertility Occurrence of mental retardation with dysmorphism Occurrence of mental retardation with multiple congenital anomalies
Many occur as sporadic conditions with negative family history Contiguous Gene Disorders/Microdeletion Syndromes
Involvement of multiple organ systems Negative family history; frequent/isolated or sporadic cases May appear as recognized single-gene disorder May involve occurrence of mental retardation with an otherwise recognized hereditary or medical disorder typically lacking mental retardation May involve occurrence of dysmorphism with an otherwise recognized hereditary or medical disorder typically lacking dysmorphism
Maternal transmission (fathers do not transmit disease) Males and females affected
Extreme variability of clinical symptoms; multiple organ systems involved
Multiple generations affected (matrilineal) Degenerative/neuromuscular disorders predominate Gender can influence variability of symptoms Environmental factors may influence symptoms (pseudomultifactorial)
Gender of transmitting parent modifies gene/disease expression
(parent-of-origin effects) May appear to skip generations
Documentation of only one carrier parent Single/isolated case in a family
Trinucleotide Repeat Disorders
Increasing severity with subsequent generations Gender of transmitting parent may influence disease severity Disorders may have variable age at onset, degree of severity May see skipping of generations (transmission of premutation)
Described in inborn errors of metabolism Variability in severity of symptoms among affected family members
Complex phenotypes, multisystem involvement Multiple partial enzyme deficiencies in affected individuals Environmental factors may influence severity of disease
Gender of affected individual influences recurrence risk Classically, few affected family members, but now also implicated in common adult-onset disorders Degree of relationship to affected individual influences recurrence risk Recurrence risk correlates with number of affected family members daughter cells may inherit only mutant mitochondrial DNA (homoplasmy), a percentage of mutant mitochondrial DNA (heteroplasmy), or no mutant mitochondrial DNA. The degree of heteroplasmy affects the overall function of the cell or population of cells and thus correlates with disease severity. It is not possible to predict for any given cell what the degree of heteroplasmy will be; thus, it is extremely difficult to predict recurrence risk or severity of disease. Furthermore, different cell populations in different organs can have different degrees of heteroplasmy, yielding a variable multisystem disease (pleiotropy).
Imprinting refers to differential expression of genes depending on the parent of origin. The process is reversible, as it affects the action of the gene but not the gene structure; genes that are passed from a male (imprinted as male) to a female and then passed by the female are reimprinted as female, and so on. This is thought to occur early in development, most likely in the germ cells.14 A number of disorders have been described that are caused by imprinting. Depending on the underlying mechanism and assuming transmission from the critical parent of origin, recurrence risks could be as high as 50%, particularly if a mutation exists in an imprinting control center that regulates methy-lation status and, thus, gene expression.
Uniparental disomy is defined as both copies of all or part of a chromosome in a cell or individual being derived from only one parent. This can appear as heterodisomy (the presence of copies of both of one parent's chromosomes) or homodisomy (a single chromosome or chromosome segment present in two identical copies). This becomes clinically relevant when males and females differentially imprint the chromosomal segment in question, or when the parent who transmits the disomic region carries a mutation in that region.14 This process has been seen in cystic fibrosis, Prader-Willi and Angelman syndromes and other disorders, and may need to be considered for any autosomal recessive disorder when only one parent is a confirmed carrier, and for X-linked recessive disorders occurring in 46, XX females. The frequency of this phenomenon is unknown.
Most classic hereditary disorders are caused by static or stable mutations in one or a few genes. For trinucleotide repeat disorders, alterations in the causative gene are unstable, called dynamic mutations, and characterized by a variable number of copies of a tandemly repeated three-nucleotide sequence within the gene.14 These trinucleotide repeats are normal, do not generally cause disease, and can be inherited stably within certain, usually small, tandem repeat size ranges that are gene specific.
Due to the structure of the repeated gene sequence, however, miscopying during DNA replication can occur, leading to expansion (creation of additional tandem copies of the trinucleotide sequence) or, rarely, contraction (loss of one to five copies of the trinucleotide sequence) of the gene segment. With expansion, the gene segment becomes less stable and thus more likely to expand further. Intermediate lengths of expanded gene segment are called pre-mutations, which are extremely unstable and highly likely to undergo further expansion. Individuals who carry pre-mutations typically do not have symptoms of the associated disorder but may show mild signs or develop associated problems at later ages.
Once the gene segment has expanded into the disease-associated repeat size range, disease symptoms occur in the individual. Degree of disease severity typically correlates with the size of the repeated segment, with earlier age of onset and more severe symptoms with increasing repeat size. The clinical phenomenon of anticipation (earlier onset of disease in subsequent generations) is explained mechanistically by the progressive expansion of the trinu-cleotide repeat region from one generation to the next, with earlier and more severe disease for each generation. Gender of transmitting parent also influences likelihood and degree of expansion, and is gene specific (the significant parent of origin varies by disease).
A phenomenon described primarily to date in inborn errors of metabolism, synergistic heterozygosity results from relative decreases in function in several components of a complex biological pathway.15 Effects of mutations in a single copy of each of multiple genes encoding components of a pathway accumulate and lead to an overall decrease in function of the pathway. This is much more akin to multi-factorial or at least polygenic inheritance than classical Mendelian inheritance typical of the majority of inborn errors of metabolism. Recurrence risks depend on the degree of decreased function of each of the components, which components are involved,genetic linkage of the components, or the potential for environmental influences on the pathway, or some combination of these factors.
Multifactorial disorders are the result of interactions among multiple genetic and environmental factors. A threshold effect defines the likelihood of disease based on the relative contributions of each of the factors involved. With a relatively low concentration of contributing factors, no effect will be seen. However, above a critical cutoff of accumulated factors, the condition occurs. Risk to relatives of affected individuals increases as more family members are affected, presumably reflecting the presence of a higher "dose" of critical factors in the family or shared environmental factors. The threshold for affected status may, however, be different in males and females. In classic conditions, such as pyloric stenosis or neural tube defects, a higher dose of risk factors is needed to push the less-fre-quently affected gender above the critical threshold; close relatives are therefore more likely to have a similar clustering of risk factors and be above the threshold, particularly if they are of the more commonly affected gender and thus are presumed to have a lower threshold.
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