2.3 Mendelian & Non-Mendelian Inheritance

[!NOTE] MRCP Part 1 Blueprint Focus: The clinical genetics curriculum emphasizes pedigree recognition, recurrence risk calculations, non-Mendelian inheritance nuances (imprinting, uniparental disomy, mitochondrial heteroplasmy), trinucleotide repeat expansion dynamics, and the clinical features of constitutional chromosomal aneuploidies.

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Classical Mendelian Inheritance Patterns

Mendelian disorders follow predictable transmission patterns based on whether the mutant allele resides on an autosome or sex chromosome, and whether a single allele (dominant) or both alleles (recessive) are required to manifest the phenotype.

Mendelian Inheritance Modes
├── Autosomal Dominant (vertical transmission, 50% risk, structural proteins, variable expressivity)
├── Autosomal Recessive (horizontal transmission, 25% risk, enzymatic defects, consanguinity)
├── X-Linked Recessive (male-predominant, carrier mothers, no male-to-male transmission)
└── X-Linked Dominant (all daughters of affected males affected, no sons affected, lethal in males)

Autosomal Dominant (AD) Inheritance

• Transmission: Vertical transmission across generations without skipped generations (unless incomplete penetrance occurs). Each child of an affected parent has a 50% (1 in 2) probability of inheriting the pathogenic allele, irrespective of biological sex. Male-to-male transmission excludes X-linked inheritance.
• Molecular Pathology: Typically involves mutations in structural proteins (collagen, fibrillin), cell surface receptors (LDLR), or proteins participating in complex regulatory pathways.
• Crucial Genetic Concepts:
  • Incomplete (Reduced) Penetrance: An individual who inherits the disease-causing genotype fails to express the clinical phenotype. Expressed quantitatively as a percentage (e.g., 80% penetrance means 80% of individuals with the mutation develop clinical signs). Examples: BRCA1/2 hereditary breast and ovarian cancer, hereditary haemochromatosis (HFE C282Y homozygosity has ~10-20% penetrance).
  • Variable Expressivity: Individuals carrying identical genetic mutations exhibit differences in the severity and spectrum of clinical manifestations. Example: Neurofibromatosis type 1 (NF1), where one individual may have isolated café-au-lait macules and Lisch nodules, while their affected sibling develops severe disfiguring plexiform neurofibromas, optic gliomas, and malignant peripheral nerve sheath tumors.
  • Pleiotropy: A single gene defect produces multiple, seemingly unrelated phenotypic abnormalities across multiple organ systems. Example: Marfan syndrome (FBN1 mutation on chromosome 15q21 encoding fibrillin-1) manifests with ectopia lentis, aortic root aneurysm and dissection, and tall stature with arachnodactyly.
  • Dominant Negative Effect: A mutant protein disrupts or "poisons" the function of the normal wild-type protein synthesized from the normal allele in a heterozygote. Example: Osteogenesis imperfecta type II (COL1A1/COL1A2 missense mutations disrupting triple-helix assembly).
  • De Novo Mutation Rate: High in disorders that compromise reproductive fitness. Achondroplasia (FGFR3 gain-of-function mutation on chromosome 4p16) occurs de novo in ~80% of cases, strongly associated with advanced paternal age due to selective clonal expansion of mutant spermatogonia.

Autosomal Recessive (AR) Inheritance

• Transmission: Typically presents "horizontally" within a single sibling generation; parents are asymptomatic obligate heterozygous carriers. For carrier parents, each conception has a 25% (1 in 4) chance of an affected child, a 50% chance of an asymptomatic carrier child, and a 25% chance of an unaffected non-carrier child. Among healthy siblings of an affected child, the probability of being a carrier is 2/3 (67%).
• Consanguinity: Significantly increases the probability that both parents share a rare ancestral mutant allele.
• Molecular Pathology: Involves loss-of-function mutations in enzymes (inborn errors of metabolism) or transport channels where a 50% reduction in gene product remains functionally sufficient for baseline homeostasis.
• High-Yield AR Conditions: Cystic fibrosis (CFTR), Hereditary haemochromatosis (HFE), Sickle cell disease (HBB), Wilson disease (ATP7B), Alpha-1 antitrypsin deficiency (SERPINA1), Friedreich ataxia (FXN).

X-Linked Recessive (XLR) Inheritance

• Transmission: Males are hemizygous for the X chromosome; inheriting a single mutant allele results in full clinical manifestation. Heterozygous females are typically asymptomatic carriers.
• Transmission Rules: No male-to-male transmission (an affected male transmits his Y chromosome to all sons and his mutant X chromosome to all daughters). All daughters of an affected male are obligate carriers. A carrier female transmits the pathogenic allele to 50% of sons (who will be affected) and 50% of daughters (who will be carriers).
• Manifesting Female Carriers: Females may manifest mild to severe features due to skewed (non-random) X-inactivation (lyonisation), Turner syndrome (45,X), or rare biallelic mutations (consanguineous parents).
• High-Yield XLR Conditions: Haemophilia A (Factor VIII) and B (Factor IX), Duchenne and Becker muscular dystrophies (DMD gene on Xp21), G6PD deficiency, Fabry disease (GLA), Lesch-Nyhan syndrome (HGPRT), Wiskott-Aldrich syndrome (WAS).

X-Linked Dominant (XLD) Inheritance

• Transmission: Expressed in both hemizygous males and heterozygous females. An affected male passes the disease to 100% of his daughters and 0% of his sons. An affected heterozygous female passes the disease to 50% of her sons and 50% of her daughters.
• Sex Ratios: Females are affected approximately twice as frequently as males, but males typically demonstrate much more severe or lethal phenotypes.
• High-Yield XLD Conditions:
  • X-Linked Hypophosphataemic Rickets: Inactivating mutation in the PHEX gene on Xp22.1, causing impaired degradation of FGF23. Elevated circulating FGF23 suppresses renal proximal tubular sodium-phosphate cotransporters (NaPi-IIa/c) and inhibits 1-alpha-hydroxylase, causing severe renal phosphate wasting, rachitic skeletal deformities, and osteomalacia resistant to standard vitamin D.
  • Rett Syndrome: Loss-of-function mutations in the MECP2 gene on Xq28 (methyl-CpG-binding protein 2). Almost exclusively observed in females due to hemizygous male lethality in utero. Girls exhibit normal initial development for 6-18 months, followed by rapid developmental regression, loss of purposeful hand skills, stereotyped midline hand-wringing movements, deceleration of head growth (microcephaly), seizures, and autonomic breathing abnormalities.

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Non-Mendelian Inheritance Mechanisms

Mitochondrial Inheritance & Heteroplasmy

Mitochondrial DNA (mtDNA) is a circular, double-stranded molecule of 16,569 base pairs encoding 13 polypeptides of the oxidative phosphorylation electron transport chain, 22 tRNAs, and 2 rRNAs. The mitochondrial genetic code differs slightly from the nuclear code (e.g., UGA encodes tryptophan rather than stop).

• Strict Maternal Transmission: The ovum contains over 100,000 mitochondria, whereas the spermatozoon contributes negligible mitochondria upon fertilisation (paternal mitochondria entering the zygote are tagged with ubiquitin and selectively degraded by autophagy). Therefore, all offspring of an affected mother inherit the mutation, whereas no offspring of an affected father inherit the disease.
• Heteroplasmy and Replicative Segregation: A single cell contains hundreds of mitochondria and thousands of copies of mtDNA. Heteroplasmy describes the coexistence of wild-type and mutant mtDNA within the same cell or tissue. During cytokinesis, mitochondria distribute stochastically to daughter cells.
• Threshold Effect: Tissues require a minimum level of ATP generation to maintain normal physiological function. A clinical phenotype manifests only when the proportion of mutant mtDNA exceeds that tissue's critical energetic threshold (typically 60-90%). Tissues with the highest metabolic and oxidative demands—the central nervous system, retina, cochlea, myocardium, and skeletal muscle—are selectively vulnerable.
• Muscle Biopsy: Subsarcolemmal accumulation of abnormal proliferated mitochondria produces classic ragged red fibres on Gömöri trichrome staining.

Genomic Imprinting and Chromosome 15q11-13

Genomic imprinting is an epigenetic process whereby gene expression is monoallelic and governed strictly by the parent of origin. Differential DNA methylation of cytosine residues at CpG islands within Imprinting Control Regions (ICRs) silences one parental allele during gametogenesis.

                    Chromosome 15q11-13 Imprinting Cluster
  Paternal Allele: [Active: SNRPN, snoRNAs, NDN] ──> [Imprinted / Silent: UBE3A]
  Maternal Allele: [Imprinted / Silent: SNRPN]   ──> [Active: UBE3A]

  Loss of Paternal 15q11-13 (70% Del, 25% Mat UPD) ──> Prader-Willi Syndrome (PWS)
  Loss of Maternal 15q11-13 (70% Del, 5% Pat UPD)   ──> Angelman Syndrome (AS)

• Prader-Willi Syndrome (PWS): Loss of expression of paternally derived genes within the 15q11-13 locus (SNRPN, necdin, snoRNAs):
  • Mechanisms: 70% paternal microdeletion (detected by FISH or chromosomal microarray); 25% maternal uniparental disomy (UPD) where the child inherits two maternal copies of chromosome 15 and zero paternal copies; 5% imprinting centre defects.
  • Clinical Features: Severe neonatal hypotonia with poor suck and failure to thrive; hypoplastic external genitalia and cryptorchidism; bitemporal narrowing and almond-shaped eyes; progression at age 2-4 to insatiable appetite (hyperphagia due to elevated ghrelin), morbid hypothalamic obesity, type 2 diabetes, short stature, and behavioral problems.
• Angelman Syndrome (AS): Loss of expression of maternally derived genes at 15q11-13, specifically the UBE3A gene encoding ubiquitin-protein ligase E3A (critical for proteasome-mediated degradation in neurons):
  • Mechanisms: 70% maternal microdeletion; 10% UBE3A intragenic inactivating point mutations; 5% paternal uniparental disomy (UPD); 5% imprinting centre defects.
  • Clinical Features: Severe intellectual disability with virtually absent speech; microcephaly; refractory epilepsy; severe ataxia with jerky, puppet-like limb movements; paroxysmal outbursts of unprovoked laughter and a permanently cheerful disposition ("happy puppet").
• Uniparental Disomy (UPD) Mechanics: Arises via meiotic nondisjunction producing a trisomic zygote, followed by mitotic loss of one supernumerary chromosome (trisomy rescue). If the lost chromosome is from the single parent, the embryo retains two chromosomes from the other parent. Heterodisomy (inheritance of two non-identical homologous chromosomes) reflects an error in Meiosis I. Isodisomy (inheritance of two identical sister chromatids) reflects an error in Meiosis II and carries the additional hazard of duplicating a recessive mutation.

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