| Factor | Definition | Effect on Pedigree Analysis |
|---|---|---|
| Incomplete Penetrance (不完全外显) | Proportion of individuals with a pathogenic genotype who show clinical symptoms is less than 100%. | Causes skipped generations, mimicking recessive inheritance or new mutations; unaffected carriers may be misclassified as non-carriers. |
| Variable Expressivity (变异性表现度) | Variation in phenotype severity among individuals with the same genotype. | Mildly affected individuals may be overlooked or considered unaffected, distorting segregation ratios. |
| New (De Novo) Mutation (新突变) | Mutation arising in germline or zygote without prior family history. | Isolated affected individual in a family; for dominant disorders, may appear as a sporadic case; recurrence risk is low but not zero (germline mosaicism in parent). |
| Phenocopy (拟表型) | Environmental or acquired condition mimicking a genetic disease. | Sporadic cases without family history may be mistaken for inherited disease; overestimation of genetic contribution; incorrect inheritance pattern assignment. |
| Nonpaternity (非父权) | Legal father is not the biological father. | Breaks expected genetic links; can falsely exclude or confirm genetic transmission patterns; linkage analysis becomes invalid. |
| Consanguinity (近亲婚配) | Mating between individuals sharing a common ancestor. | Increases probability of recessive disorders; presence of multiple affected siblings with healthy parents points to recessive inheritance; may cause pseudodominance. |
| Genetic Heterogeneity (遗传异质性) | Mutations in different genes producing similar phenotypes (locus heterogeneity) or different mutations in same gene (allelic heterogeneity). | Affected individuals from different families may not share the same gene; within a family, atypical segregation can occur; pooling families for linkage analysis may fail. |
| X-inactivation (X染色体失活) | Random inactivation of one X chromosome in female cells (Lyonization). | Skewed inactivation can cause variable expression in females with X‑linked disorders, mimicking autosomal dominant or recessive patterns; female carriers may be symptomatic. |
| Pleiotropy (基因多效性) | One gene influencing multiple seemingly unrelated phenotypic traits. | Multiple system involvement may be misattributed to separate diseases; affected individuals with only one manifestation may be missed. |
| Onset Age (发病年龄) | Age at which disease symptoms first appear. | Late‑onset diseases lead to young carriers being recorded as healthy; early‑onset lethal diseases may eliminate affected individuals before ascertainment, reducing observed affected count. |
| Sex‑influenced (性别影响) | Autosomal gene whose expression is modulated by sex hormones; one sex more severely or more frequently affected. | Imbalance between sexes may be mistaken for X‑linked inheritance; correct pattern only revealed by family data across both sexes. |
| Sex‑limited (性别限制) | Autosomal gene expressed only in one sex (e.g., uterus, prostate). | The non‑expressing sex carries the gene without showing symptoms, creating apparent skipping of generations; transmission appears “through” unaffected individuals. |
| Mitochondrial Inheritance (线粒体遗传) | Transmission of mitochondrial DNA (mtDNA) mutations exclusively through the mother. | Affected females transmit to all offspring; affected males never transmit; pattern is non‑Mendelian and may be mistaken for dominant or recessive without maternal link. |
| Genomic Imprinting (遗传印记) | Gene expression depends on parent‑of‑origin (maternal vs. paternal allele). | Disease appears only when inherited from a specific parent; non‑Mendelian transmission; can mimic dominant or recessive depending on imprinting status. |
| Mosaicism (嵌合体) | Presence of ≥2 genetically distinct cell lines in one individual (somatic or germline). | |
| Anticipation (遗传早现) | Increasing severity and/or earlier onset in successive generations. | Observed in trinucleotide repeat disorders (e.g., Huntington, myotonic dystrophy); may be misinterpreted as different diseases if not recognized; suggests dynamic mutation. |
| Pseudodominance (假性显性) | Apparent dominant transmission of a recessive disorder due to consanguinity or high population carrier frequency. | Pedigree shows affected individuals in consecutive generations, mimicking autosomal dominant inheritance; correct interpretation requires knowledge of consanguinity. |
| Uniparental Disomy (UPD) (单亲二体) | Both homologues of a chromosome inherited from the same parent. | Can cause recessive disease in non‑consanguineous families (parent heterozygous, child homozygous); unexpected segregation ratios; some UPD forms cause imprinting disorders. |
| Polygenic / Multifactorial Inheritance (多基因/多因素遗传) | Interaction of multiple genes + environmental factors causing disease (threshold model). | No clear Mendelian segregation; familial aggregation without typical patterns; recurrence risk <10% for first-degree relatives; cannot be traced with single gene analysis. |
| Age‑dependent Penetrance (年龄依赖性外显) | Penetrance increases progressively with age (e.g., BRCA1, Huntington). | Young individuals are classified as unaffected but may develop disease later; requires life‑table correction and follow‑up; static pedigree analysis underestimates risk. |
| Reduced Reproductive Fitness (生殖适合度降低) | Decreased ability of affected individuals to have children due to disease severity or infertility. | Fewer affected individuals in later generations; may mimic low penetrance or recessive inheritance; ascertainment bias toward milder cases. |
| Somatic Mosaicism (体细胞嵌合体) | Mutation acquired post‑zygotically, present only in a subset of somatic cells (not in germline). | Affected individual may have patchy or mild disease; offspring risk is zero unless germline also involved; can mimic acquired/environmental conditions. |
| Germline Mosaicism (生殖系嵌合体) | Mutation present only in a fraction of germ cells, not in somatic cells. | Unaffected parents have multiple affected children with a dominant disorder; recurrence risk is >0 but <50% (depends on proportion of affected germ cells). |
| Balanced Chromosomal Rearrangement (e.g., translocation) (染色体平衡重排) | Structural rearrangement without net gain/loss of DNA; carrier is phenotypically normal. | Carrier parents have increased risk of unbalanced offspring (deletion/duplication) causing disease; can mimic dominant inheritance with reduced penetrance or new mutations. |
| Heteroplasmy (mitochondrial) (异质性（线粒体异质性）) | Mixture of wild‑type and mutant mtDNA within an individual. | Variable expressivity; threshold effect; transmission patterns less predictable than homoplasmy; offspring can inherit different mutation loads. |
| Digenic Inheritance (double heterozygosity) (双基因遗传) | Mutations in two different genes required for disease expression (each inherited separately). | Resembles recessive but may show complex segregation; can mimic incomplete penetrance; family members with one mutation are unaffected. |
| Incomplete Family History (不完全家系信息) | Missing medical or demographic information on family members (e.g., deceased, adopted, lost follow‑up). | May lead to under‑ascertainment of affected individuals and incorrect inheritance assignment; false-negative family history. |
| Diagnostic Error / Misclassification (诊断错误/分类错误) | Incorrect assignment of disease status (affected vs. unaffected) due to clinical overlap or testing error. | False‑positive or false‑negative cases distort segregation ratios and linkage analysis; may suggest wrong inheritance pattern. |
| Adoption / Unknown Biological Relationships (收养/未知生物学关系) | Lack of biological relationship information; individual may not be genetically related to the recorded family. | Pedigree structure is incorrect; genetic analysis invalid without correction; nonpaternity is a subset. |
| Small Family Size (小家庭规模) | Few siblings or generations available for analysis (e.g., only child, one generation). | Cannot distinguish between recessive and dominant patterns; statistical power very low; impossible to confirm segregation. |
| Ascertainment Bias (确认偏倚) | Non‑random selection of families for study (e.g., through affected probands, large families only). | Overestimation of recurrence risks; segregation ratios deviate from Mendelian expectations; linkage distances may be overestimated. |
| Imprinting + UPD (e.g., Prader‑Willi / Angelman) (印记合并单亲二体) | Combined effect of imprinting and uniparental disomy leading to disease. | Requires both parent‑of‑origin effect and UPD; not explainable by standard Mendelian or simple imprinting models; specific molecular testing needed. |
| Epigenetic Modifications (non‑imprinting) (表观遗传修饰（非印记）) | Heritable changes in gene expression without DNA sequence change (e.g., DNA methylation, histone modification). | Can alter disease expression and transmission patterns across generations; complicates genotype‑phenotype correlation; may cause discordance in monozygotic twins. |
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