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

What are Mendelian exceptions?

Inheritance patterns that deviate from classical Mendelian rules, including co-dominance, pseudoautosomal, mitochondrial, dynamic mutations, and genomic imprinting.

Define co-dominance.

Both alleles of a gene pair are fully expressed in heterozygotes, resulting in a combined phenotype. Example: α₁-antitrypsin deficiency.

What causes α₁-antitrypsin deficiency?

Co-dominant mutations in the SERPINA1 gene; heterozygotes express both normal and deficient alleles.

Define pseudoautosomal inheritance.

Genes located in homologous regions of the X and Y chromosomes behave like autosomal genes and can be transmitted from father to son.

Define mitochondrial inheritance.

Transmission of genes from mitochondrial DNA; inherited exclusively from the mother.

How many genes are in human mtDNA?

37 genes (13 for oxidative phosphorylation proteins, 22 tRNAs, 2 rRNAs).

Explain replicative segregation.

Random distribution of mitochondria to daughter cells during cell division, leading to variable mutant load (heteroplasmy).

Define heteroplasmy and homoplasmy.

Heteroplasmy = mixture of normal and mutant mtDNA; Homoplasmy = uniform mtDNA population.

Why do mitochondrial diseases show variable expression?

Due to heteroplasmy, pleiotropy, and reduced penetrance.

Define dynamic mutation.

Mutation caused by unstable expansion of nucleotide repeats (often trinucleotide repeats).

What is anticipation?

The tendency for some disorders caused by repeat expansion to present at an earlier age or with greater severity in successive generations.

List two disorders caused by dynamic mutations.

Huntington disease and Myotonic dystrophy.

Compare repeat regions in Huntington vs Myotonic dystrophy.

Huntington: CAG in 5′ translated region of HTT gene; Myotonic dystrophy: CTG in 3′ untranslated region of DMPK gene.

Which parent usually transmits early-onset Huntington disease?

Father (paternal transmission bias).

Which parent usually transmits congenital Myotonic dystrophy?

Mother (maternal transmission bias).

Describe Fragile X syndrome.

X-linked disorder caused by CGG repeat expansion (>200) in FMR1 gene → promoter hypermethylation → gene silencing.

What is the penetrance of Fragile X syndrome in females?

Approximately 50–60 %.

List characteristic features of Fragile X syndrome.

Long face, large ears, macroorchidism, hyperextensible joints, hypotonia, speech delay, intellectual disability, autism-like behaviors.

Define epigenetics.

Heritable changes in gene expression not involving DNA sequence alteration, such as DNA methylation, histone modification, and non-coding RNAs.

What is genomic imprinting?

An epigenetic process in which expression of a gene depends on its parental origin (only one allele—maternal or paternal—is active).

How is imprinting established and maintained?

Through DNA methylation of CpG islands during gametogenesis and maintained through mitosis.

Give an example of an imprinted gene pair.

IGF2 (paternal allele expressed) and H19 (maternal allele expressed).

What is the function of IGF2 and H19 in development?

IGF2 promotes fetal growth; H19 acts as a growth suppressor RNA.

Describe Beckwith-Wiedemann syndrome (BWS).

Overgrowth disorder due to abnormal imprinting of 11p15.5 affecting IGF2 (overexpression) and CDKN1C (loss of function).

List key clinical features of BWS.

Macrosomia, hemihyperplasia, macroglossia, omphalocele / umbilical hernia, neonatal hypoglycemia, ear creases, ↑ risk for Wilms tumor & hepatoblastoma.

What genetic changes cause BWS?

Impaired maternal methylation (≈ 50–60 %) or paternal uniparental disomy (≈ 20–30 %).

Define Prader-Willi syndrome (PWS).

Caused by loss of paternally expressed genes on 15q11.2-q13 (usually a paternal deletion).

Define Angelman syndrome (AS).

Caused by loss of maternally expressed UBE3A gene on 15q11.2-q13 (usually a maternal deletion).

What is the mechanism of PWS and AS?

Deletion of 15q11.2-q13 region (≈ 70 %) or mutations affecting imprinting / UBE3A gene.

Compare key features of PWS and AS.

PWS: hypotonia, hyperphagia, obesity, short stature, mild ID. AS: seizures, ataxia, severe ID, microcephaly, happy demeanor.

Why do PWS and AS illustrate genomic imprinting?

Because the same chromosomal region causes different syndromes depending on whether the maternal or paternal allele is deleted.

How are PWS and AS usually inherited?

Typically sporadic (de novo microdeletions), rarely uniparental disomy or imprinting center defects.

A 7-year-old boy with hypotonia, obesity, and developmental delay most likely has what defect?

Absence of paternal gene expression → Prader-Willi syndrome.

How does genetic counseling apply to imprinting disorders?

Counselors must consider parental origin of mutation and recurrence risk due to imprinting mechanisms.