Lecture #60: Human Genetics III: Mendelian Exceptions and Genomic Imprinting

What are the major learning objectives of this lecture?

Differentiate Mendelian vs non-Mendelian inheritance, interpret non-Mendelian pedigrees, explain anticipation and dynamic mutations, recognize genomic imprinting disorders, and determine parental origin of imprinted alleles.

What is codominance?

Codominance occurs when both alleles are fully expressed, producing a phenotype in which both alleles contribute equally.

What disease is the lecture example of codominance?

Alpha-1 antitrypsin deficiency (AATD).

Which alleles are associated with alpha-1 antitrypsin deficiency?

M is normal, S is moderately deficient, and Z is severely deficient.

What is the phenotype of an MZ individual in AATD?

MZ individuals express both normal and deficient alpha-1 antitrypsin proteins and have an increased risk of lung disease, especially if they smoke.

What is pseudoautosomal inheritance?

Inheritance of genes located in the homologous pseudoautosomal regions (PARs) of the X and Y chromosomes that behaves like autosomal inheritance.

Why can pseudoautosomal traits show male-to-male transmission?

Because genes in the pseudoautosomal regions recombine between the X and Y chromosomes.

Which gene is the classic example of pseudoautosomal inheritance?

SHOX (short stature homeobox).

What disorders are associated with SHOX mutations?

Léri-Weill dyschondrosteosis and Langer mesomelic dysplasia.

How many genes are contained in mitochondrial DNA?

Thirty-seven genes.

What types of genes are encoded by mitochondrial DNA?

13 protein-coding genes, 22 tRNA genes, and 2 rRNA genes.

What cellular process depends on mitochondrial DNA?

Oxidative phosphorylation (OxPhos) for ATP production.

How is mitochondrial DNA inherited?

Exclusively through maternal inheritance.

What is replicative segregation?

Random distribution of mitochondrial DNA into daughter cells during cell division.

What is homoplasmy?

All mitochondrial DNA copies within a cell are identical.

What is heteroplasmy?

A mixture of normal and mutant mitochondrial DNA within the same cell.

Why do mitochondrial diseases show variable expression?

Because the ratio of normal to mutant mtDNA differs among tissues due to heteroplasmy.

What is pleiotropy?

A single gene influences multiple phenotypic traits.

What is reduced penetrance?

Not every individual carrying a mutation expresses the associated phenotype.

What is variable expressivity?

Individuals with the same mutation can have different degrees of disease severity.

What are dynamic mutations?

Mutations caused by expansion of repetitive DNA sequences, most commonly trinucleotide repeats.

What type of repeat expansion is most common?

Trinucleotide repeat expansion.

What is anticipation?

Progressively earlier onset and increased severity of disease in successive generations.

Which disorders discussed demonstrate anticipation?

Huntington disease, myotonic dystrophy, and Fragile X syndrome.

What trinucleotide repeat causes Huntington disease?

CAG repeat expansion.

Where is the Huntington repeat located?

In the 5′ translated region of the Huntingtin gene.

How many CAG repeats are considered fully penetrant for Huntington disease?

40 or more repeats.

What are the hallmark clinical features of Huntington disease?

Chorea, cognitive impairment, dementia, and mood changes.

How is juvenile Huntington disease most commonly inherited?

Usually through paternal transmission.

What trinucleotide repeat causes myotonic dystrophy?

CTG repeat expansion.

Where is the CTG repeat located in myotonic dystrophy?

In the 3′ untranslated region of the DMPK gene.

What are the major clinical features of myotonic dystrophy?

Progressive muscle weakness, myotonia, cataracts, and cardiac conduction defects.

Which parent most commonly transmits congenital myotonic dystrophy?

The mother.

What trinucleotide repeat causes Fragile X syndrome?

CGG repeat expansion.

Which gene is affected in Fragile X syndrome?

FMR1.

Where is the Fragile X repeat located?

In the 5′ untranslated region of FMR1.

How many CGG repeats cause Fragile X syndrome?

More than 200 repeats.

How does the CGG expansion cause Fragile X syndrome?

The repeat expansion causes hypermethylation of the FMR1 promoter, silencing gene expression.

What is the most common inherited cause of intellectual disability?

Fragile X syndrome.

What are classic physical findings in Fragile X syndrome?

Long face, prominent forehead, protruding ears, high-arched palate, hyperextensible joints, postpubertal macroorchidism, and hypotonia.

What neurodevelopmental findings are common in Fragile X syndrome?

Intellectual disability, autism, poor eye contact, language disorders, hand flapping, and biting behaviors.

What is epigenetics?

Heritable changes in gene expression that occur without changing the DNA sequence.

What are the three major epigenetic mechanisms discussed?

DNA methylation, histone modification, and non-coding RNA regulation.

What is genomic imprinting?

An epigenetic process in which gene expression depends on whether the allele was inherited from the mother or father.

How is genomic imprinting established?

By DNA methylation during gamete formation that is maintained through mitosis.

Which allele normally expresses IGF2?

The paternal allele.

Which allele normally expresses H19?

The maternal allele.

Why is genomic imprinting important?

It is critical for normal embryonic development, and imprinting errors cause several genetic disorders.

Which chromosome is affected in Beckwith-Wiedemann syndrome?

Chromosome 11p15.5.

Which genes are highlighted in Beckwith-Wiedemann syndrome?

IGF2, CDKN1C, H19, and KCNQ1OT1.

What are the major clinical features of Beckwith-Wiedemann syndrome?

Macrosomia, hemihyperplasia, macroglossia, omphalocele or umbilical hernia, neonatal hypoglycemia, ear pits/creases, and increased risk of Wilms tumor and hepatoblastoma.

Which chromosome region is involved in both Prader-Willi and Angelman syndromes?

Chromosome 15q11-q13.

What causes Prader-Willi syndrome?

Absence of paternal gene expression due to paternal deletion, maternal uniparental disomy, or imprinting defects.

What are the hallmark features of Prader-Willi syndrome?

Infantile hypotonia, hyperphagia, obesity, intellectual disability, behavioral problems, short stature, and small hands and feet.

What causes Angelman syndrome?

Absence of maternal gene expression due to maternal deletion, paternal uniparental disomy, or UBE3A mutation.

What are the hallmark features of Angelman syndrome?

Severe intellectual disability, minimal speech, ataxia, frequent laughter or happy demeanor, seizures, and sleep disturbances.

How are Prader-Willi and Angelman syndromes diagnosed?

Genetic testing including methylation analysis and FISH for deletions.

Which parent's chromosome deletion causes Prader-Willi syndrome?

The paternal chromosome 15.

Which parent's chromosome deletion causes Angelman syndrome?

The maternal chromosome 15.

What is the key board-style association for Prader-Willi syndrome?

Absence of paternal gene expression.

If a woman with Angelman syndrome has children, what is the expected outcome according to the lecture?

Both male and female children inherit the maternal chromosome carrying the mutation and are expected to have Angelman syndrome.

If a man with Angelman syndrome has children, what is the expected outcome according to the lecture?

His children inherit the paternal chromosome carrying the mutation but do not develop Angelman syndrome because they receive a functional maternal UBE3A allele.