Single Gene Disorders

Slide 1 · Single-Gene Disorders

Mutational mechanisms • allelic effects • inheritance • phenotypes

Mutations → proteins → tissues → clinical phenotype

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · What this lecture explains

INTRODUCTION

Recognize the molecular classes of mutations that alter gene function.

Relate mutant-allele dosage and protein function to dominant or recessive phenotypes.

Differentiate pleiotropism, genetic heterogeneity and codominance.

Apply genotype–phenotype reasoning to representative Mendelian conditions.

Slide 3 · Where monogenic disease fits

INTRODUCTION

Monogenic

Complex multigenic

Chromosomal

A major defect in one gene

Multiple variants plus environment

Numerical or structural chromosome change

Frequently Mendelian segregation

Often multifactorial susceptibility

May affect many genes

Examples: sickle cell disease, CF

Examples: common hypertension, diabetes

Examples: large deletions, trisomies

Slide 4 · Germline versus somatic mutation

INTRODUCTION

Germline / inherited

Somatic / acquired

May be transmitted to offspring

Not transmitted through germ cells

May be present in many tissues

Restricted to a cell lineage

Relevant to inherited disease

Relevant to tumors and mosaicism

Slide 5 · Hereditary, familial and congenital are not synonyms

INTRODUCTION

Term

Meaning

Teaching implication

Hereditary

Transmitted via germ cells

May become symptomatic late in life

Familial

Occurs within relatives

Not sufficient alone to prove inheritance

Congenital

Present at birth

Can be non-genetic

Slide 6 · Congenital does not necessarily mean genetic

INTRODUCTION

Congenital refers to timing of presence, not the underlying cause.

A hereditary variant can produce symptoms only in adult life.

Huntington disease illustrates delayed onset of a genetic condition.

Conception

Birth

Adulthood

Genetic origin and clinical onset may occur at different times.

Slide 7 · A single gene can influence multiple levels of function

INTRODUCTION

DNA sequence

RNA quantity / processing

Protein quantity / function

Cellular and tissue phenotype

A mutation becomes clinically relevant through its effect on a gene product.

Slide 8 · Mutation: The basic definition

INTRODUCTION

A mutation is a permanent change in DNA sequence.

A germline mutation can be passed to descendants.

A somatic mutation is acquired within the individual.

The functional consequence depends on the location and nature of the change.

Slide 9 · Mutation classes: Orient the problem

INTRODUCTION

Coding substitution

Missense or nonsense

Regulatory region

Altered transcription

Splice region

Abnormal RNA processing

Insertion or deletion

In-frame change or frameshift

Gene rearrangement

Altered copy number or structure

Repeat expansion

Dynamic repeat-length change

Slide 10 · Missense mutation changes an encoded amino acid

MUTATION MECHANISMS

Single-nucleotide substitution

Altered codon

Different amino acid

Variable protein effect

The severity is determined by the biochemical and structural role of the substitution.

Slide 11 · Conservative and nonconservative missense changes

MUTATION MECHANISMS

Conservative

Nonconservative

Biochemically similar amino acid

Biochemically dissimilar amino acid

May have little functional effect

More likely to perturb structure or function

Context still matters

Context still matters

Slide 12 · Sickle cell disease: A coding substitution

MUTATION MECHANISMS

Normal β-globin mRNA

GAG → glutamate

Mutant β-globin mRNA

GUG → valine

Result

Hemoglobin S (HbS)

The single amino acid change is glutamate → valine in the β-globin chain.

Slide 13 · Why HbS changes red-cell behavior

MUTATION MECHANISMS

β-globin Glu → Val

HbS polymerization under deoxygenating conditions

Red-cell injury and hemolysis

Red-cell sickling and vascular obstruction

Anemia and ischemic tissue injury

Slide 14 · Nonsense mutation creates a premature stop

MUTATION MECHANISMS

Original codon

CAG → glutamine

Mutant codon

UAG → STOP

Translation

Premature termination

Truncated proteins are frequently unstable or nonfunctional.

Slide 15 · β-thalassemia: The nonsense example

MUTATION MECHANISMS

Nonsense change in β-globin gene

Premature termination

Deficiency of β-globin chains

Hereditary anemia

The phenotype results from reduced chain production, not an altered mature chain.

Slide 16 · Missense and nonsense are not equivalent

MUTATION MECHANISMS

Missense

Nonsense

Codon specifies a different amino acid

Codon becomes a premature stop

Full-length protein may be produced

Protein may be truncated or absent

Sickle hemoglobin: altered behavior

Some β-thalassemias: deficient globin production

Slide 17 · Regulatory mutations alter transcription

MUTATION MECHANISMS

Promoter / enhancer mutation

Impaired regulatory-protein binding

Reduced transcription

Reduced gene product

Coding sequence can remain intact while protein production declines.

Slide 18 · Splice-region mutations alter RNA maturation

MUTATION MECHANISMS

Intronic / splice-site sequence change

Abnormal pre-mRNA splicing

Aberrant transcript / RNA degradation

Reduced or abnormal protein

A gene can fail despite an apparently preserved coding exon sequence.

Slide 19 · Insertions and deletions depend on their length

MUTATION MECHANISMS

A coding insertion or deletion can preserve or disrupt the reading frame.

A multiple of three nucleotides preserves triplet grouping.

Other lengths shift downstream codons, usually with extensive effects.

ABC | DEF | GHI

ABC | GHI

ABD | EFG | HI…

Simplified triplet schematic; Letters denote bases, not actual sequence.

Slide 20 · In-frame deletion preserves the reading frame

MUTATION MECHANISMS

Deletion of 3 coding bases

One amino acid absent

Downstream codons remain aligned

Altered protein function possible

Loss of one amino acid is not synonymous with a frameshift.

Slide 21 · CFTR ΔF508 illustrates an in-frame deletion

MUTATION MECHANISMS

A three-base deletion removes phenylalanine at position 508.

The reading frame remains intact.

The CFTR protein lacks this residue.

The specific molecular defect is distinct from a frameshift mutation.

Slide 22 · Frameshift changes downstream codons

MUTATION MECHANISMS

Indel not divisible by 3

Reading frame displaced

Abnormal amino-acid sequence

Often premature termination

The downstream consequence can be substantially larger than the original DNA change.

Slide 23 · Tay–Sachs: An example of frameshift mutation

MUTATION MECHANISMS

Four-base insertion in HEXA

Reading-frame disruption

Abnormal hexosaminidase A protein

Enzyme deficiency and disease

A particular four-base insertion associated with Tay–Sachs disease.

Slide 24 · In-frame versus frameshift: Clinical reasoning

MUTATION MECHANISMS

In-frame indel

Frameshift indel

Length divisible by 3

Length not divisible by 3

Triplet grouping preserved

Triplet grouping altered

Selected residues added/removed

Downstream residues changed

May preserve substantial protein

Often introduces premature stop

Slide 25 · Copy-number change can alter gene dosage

MUTATION MECHANISMS

Deletion / amplification

Changed number of gene copies

Changed abundance or activity

Phenotypic consequence

Gene copy-number abnormalities may be germline or acquired in somatic tissues.

Slide 26 · Gene rearrangements can create abnormal function

MUTATION MECHANISMS

DNA breakage and rearrangement

Altered gene structure / fusion

Abnormal protein activity

Disease phenotype

BCR–ABL rearrangement in chronic myeloid leukemia is a somatic example.

Slide 27 · Repeat expansions behave differently

MUTATION MECHANISMS

Tandem trinucleotide sequences can expand markedly.

Repeat length may be unstable between generations.

The size and site of the expansion influence gene expression and phenotype.

CGG CGG CGG

CGG × many repeats

Gene expression impaired

Schematic repeat units; Not a patient sequence.

Slide 28 · Fragile X: Expanded FMR1 CGG repeats

MUTATION MECHANISMS

Expanded CGG repeat tract

Abnormal regulation of FMR1

Reduced gene expression

Fragile X phenotype

FMR1 expansion as an example of a dynamic mutation.

Slide 29 · One pathway, multiple points of disruption

MUTATION MECHANISMS

DNA

Coding mutation • promoter variant • deletion

RNA

Transcription loss • splice defect • premature-stop transcript

Protein

Reduced amount • truncated form • abnormal activity

Phenotype

Cellular failure • tissue pathology • clinical disease

Slide 30 · What defines a monogenic disorder?

MONOGENIC DISEASE

A pathogenic mutation in one gene has a large functional effect.

Disease often follows a recognizable Mendelian segregation pattern.

Expression reflects both the mutant allele and the function of its gene product.

A monogenic cause can still produce diverse clinical findings.

Slide 31 · A single allele may or may not be enough

MONOGENIC DISEASE

Heterozygote

Homozygote / biallelic

One mutant copy, one functional copy

Both gene copies affected

May be asymptomatic for recessive traits

Typically manifests recessive loss of function

May manifest dominant traits

Severity depends on specific variants

Slide 32 · Wild-type allele can compensate for loss of function

MONOGENIC DISEASE

One allele loses function

Other allele remains functional

Sufficient product persists

No major phenotype in carrier

This is a common explanation for asymptomatic heterozygous carriers.

Slide 33 · Recessive loss of function: Two hits in trans

MONOGENIC DISEASE

Two independently inherited alleles

Each allele lacks sufficient function

Maternal pathogenic variant

Paternal pathogenic variant

Biallelic defect produces phenotype

Slide 34 · Haploinsufficiency: One normal copy is insufficient

MONOGENIC DISEASE

One allele loses function

Functional dosage decreases

Remaining copy cannot compensate

Disease in a heterozygote

This is one mechanism of autosomal dominant disease.

Slide 35 · Familial hypercholesterolemia: Gene dosage matters

MONOGENIC DISEASE

Reduced LDL receptor function

Impaired LDL uptake

Elevated circulating cholesterol

Accelerated atherosclerotic disease

LDL receptor haploinsufficiency in affected heterozygotes.

Slide 36 · Dominant-negative proteins disrupt complexes

MONOGENIC DISEASE

Mutant structural subunit

Abnormal multimer assembly

Functional complexes reduced

Dominant phenotype

Some collagen disorders exemplify this mechanism.

Slide 37 · Gain of function creates excessive or new activity

MONOGENIC DISEASE

Hyperactive normal activity

New (neomorphic) activity

Protein performs its usual function excessively

Protein acquires a novel activity

Can cause disease in heterozygotes

Can cause disease in heterozygotes

Distinct from insufficient protein quantity

Distinct from classic loss of function

Slide 38 · Huntington disease illustrates toxic protein gain

MONOGENIC DISEASE

Trinucleotide-repeat expansion

Abnormal huntingtin protein

Toxic effect on neurons

Adult-onset neurologic syndrome

This is not explained by simple loss of half the gene product.

Slide 39 · Mechanism predicts more than mutation size

MONOGENIC DISEASE

Mechanism

Functional consequence

Typical pattern

Recessive loss

One normal copy sufficient

Autosomal recessive

Haploinsufficiency

One normal copy insufficient

Autosomal dominant

Dominant negative

Mutant protein impairs wild type

Often autosomal dominant

Gain of function

Abnormal or excessive activity

Often autosomal dominant

Slide 40 · Classic transmission patterns

INHERITANCE

Autosomal dominant

Heterozygote phenotype

Autosomal recessive

Biallelic variants required

X-linked recessive

Hemizygous males often manifest

Slide 41 · Autosomal dominant transmission

INHERITANCE

A

a

a

Aa

aa

a

Aa

aa

An affected heterozygote × unaffected homozygote: Each child has a 1-in-2 chance of inheriting the variant.

Slide 42 · Autosomal dominant: The phenotype may skip recognition

INHERITANCE

A de novo variant can occur without a previously affected parent.

Incomplete penetrance may obscure vertical transmission.

Some conditions manifest only after years of apparently normal health.

Slide 43 · Autosomal recessive transmission

INHERITANCE

A

a

A

AA

Aa

a

Aa

aa

Two heterozygous carriers: 1-in-4 affected, 1-in-2 carrier, 1-in-4 unaffected noncarrier per conception.

Slide 44 · Compound heterozygosity is still biallelic disease

INHERITANCE

A person can inherit two different pathogenic variants in the same gene.

The variants reside on opposite copies (in trans).

Neither allele supplies adequate functional product.

Maternal allele: Variant A

Paternal allele: Variant B

Two different pathogenic variants may produce recessive disease.

Slide 45 · Autosomal recessive disorders often affect siblings

INHERITANCE

Parents may be healthy heterozygotes.

Brothers and sisters can be affected despite unaffected parents.

Recurrence probability applies independently to each conception.

Enzyme defects often exhibit this inheritance pattern.

Slide 46 · X-linked recessive inheritance

INHERITANCE

Xᴺ (father)

Y (father)

Xᴺ (mother)

XᴺXᴺ

XᴺY

Xᵐ (mother)

XᴺXᵐ

XᵐY

Carrier mother × unaffected father: Half of sons inherit the affected X; Half of daughters become carriers.

Slide 47 · Why there is no father-to-son X-linked transmission

INHERITANCE

Father transmits X or Y

Sons inherit paternal Y

Sons receive their X from mother

No paternal X → son transmission

A father with an X-linked recessive variant passes his X chromosome to daughters.

Slide 48 · X inactivation explains variable female expression

INHERITANCE

Heterozygous X-linked variant

Random / skewed X inactivation

Mosaic cell populations

Variable phenotype in carriers

This using susceptibility to hemolysis in female G6PD carriers.

Slide 49 · Codominance: Both alleles contribute to phenotype

GENOTYPE AND PHENOTYPE

Neither expressed allele is necessarily masked by the other.

Both inherited alleles can contribute detectable products.

AB blood-group antigens are a classic example.

Histocompatibility antigens also exhibit codominant expression.

Slide 50 · AB blood group: Two detectable antigen products

GENOTYPE AND PHENOTYPE

The A and B alleles each contribute an expressed blood-group antigen.

The AB phenotype demonstrates expression from both alleles.

Codominance should not be confused with incomplete penetrance.

A allele → A antigen

B allele → B antigen

Two allelic products coexist in the same phenotype.

Slide 51 · Penetrance asks whether a phenotype appears

GENOTYPE AND PHENOTYPE

Complete penetrance

Incomplete penetrance

All variant carriers express the trait

Only a fraction of carriers express it

Genotype predicts presence of disease

Apparently unaffected carrier may exist

Expression can still vary in severity

Nonexpression is not evidence of absent allele

Slide 52 · Expressivity asks how strongly it appears

GENOTYPE AND PHENOTYPE

Variable expressivity occurs among individuals who exhibit the trait.

Phenotype can range from mild to severe even for one genetic condition.

Neurofibromatosis type 1 to illustrate this range.

Mild expression

Intermediate expression

Severe expression

Illustrative spectrum, not measured severity data.

Slide 53 · Modifier genes and environment influence expression

GENOTYPE AND PHENOTYPE

Pathogenic primary allele

Context modifies phenotype

Other genes (e.g., HbF loci)

Environment (e.g., dietary lipids)

Different clinical severity or consequences

Slide 54 · Pleiotropism: One mutation, many consequences

GENOTYPE AND PHENOTYPE

Single pathogenic variant

Primary molecular lesion

Clinical effect A

Clinical effect B

Clinical effect C

Multiple organ-system manifestations

Slide 55 · Sickle cell disease illustrates pleiotropism

GENOTYPE AND PHENOTYPE

β-globin point mutation

Abnormal HbS and affected red cells

Hemolytic anemia

Vascular occlusion

Splenic fibrosis / infarction

One molecular lesion → multiple end-organ effects

Slide 56 · From vascular obstruction to tissue damage

GENOTYPE AND PHENOTYPE

Abnormal red cells in microvessels

Impaired perfusion

Ischemic injury

Organ infarction / fibrosis

The tissue changes are consequences of the primary hemoglobin defect.

Slide 57 · Genetic heterogeneity: Many genes, similar phenotype

GENOTYPE AND PHENOTYPE

Several distinct disease genes

Different pathogenic variants

Gene A affected

Gene B affected

Gene C affected

Shared clinical phenotype

Slide 58 · Congenital deafness illustrates locus heterogeneity

GENOTYPE AND PHENOTYPE

An apparently homogeneous clinical phenotype may have multiple genetic causes.

Profound congenital deafness as an example.

Distinct autosomal recessive loci may cause similar hearing-loss phenotypes.

Phenotype alone may not identify the causal gene.

Slide 59 · Pleiotropism versus genetic heterogeneity

GENOTYPE AND PHENOTYPE

Pleiotropism

Genetic heterogeneity

One mutation

Different genetic loci

Many phenotypic effects

A similar phenotype

Sickle cell disease

Congenital deafness

One cause → many consequences

Many causes → similar consequence

Slide 60 · Case: A healthy couple has an affected child

APPLICATION

Illustrative teaching case

Two unaffected parents have a child with a severe enzyme deficiency. Both parents carry a pathogenic variant in the same autosomal gene.

Which inheritance pattern fits, and what is the recurrence probability?

Answer and rationale are recorded in the speaker notes.

Slide 61 · Case: One variant, multiple organ injuries

APPLICATION

Illustrative teaching case

A patient has a β-globin mutation, chronic hemolysis, and ischemic injury involving several organs.

Which genetic concept unifies these apparently different findings?

Answer and rationale are recorded in the speaker notes.

Slide 62 · Case: One diagnosis, different genes

APPLICATION

Illustrative teaching case

Two unrelated families have profound congenital deafness but have pathogenic variants in different autosomal genes.

Which genetic principle explains the same clinical description?

Answer and rationale are recorded in the speaker notes.

Slide 63 · An efficient approach to monogenic disease

APPLICATION

1. Define the variant

Coding • regulatory • splice • structural • repeat

2. Determine gene-product effect

Absent • reduced • altered • excessive • toxic

3. Infer allele behavior

Dominant • recessive • codominant

4. Explain phenotype

Tissue consequences • penetrance • expressivity

Slide 64 · Major lessons from single-gene disorders

SYNTHESIS

Monogenic disease is defined by a large-effect alteration in one gene.

The biochemical effect of the allele determines much of the inheritance pattern.

Pleiotropism links one mutation to multiple manifestations; Heterogeneity links multiple genes to one phenotype.

Penetrance, expressivity, age of onset and modifying factors complicate prediction.

Slide 65 · Source and interpretive scope

SYNTHESIS

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. Chapter 5: Genes and Human Diseases, pp. 122–127.

Central heading: “Single-Gene Disorders,” p. 124; adjacent sections: Mutations and Transmission Patterns of Single-Gene Disorders.

Original conceptual schematics and practice vignettes; no reproduced pathology figures or generated specimens.