A 4-year-old boy presents to his pediatrician for severe developmental delay. On exam he is noted to have macroorchidism, hypertelorism, large protruding ears, a large jaw, and a long thin face. Suspicious of what the diagnosis may be, the pediatrician orders a PCR and DNA sequencing. The results reveal an expansion of 250 repeats of CGG. What is the diagnosis of the boy?

Spinal and bulbar muscular atrophy

A 5-year-old boy is brought to the physician because of behavioral problems. His mother says that he has frequent angry outbursts and gets into fights with his classmates. He constantly complains of feeling hungry, even after eating a full meal. He has no siblings, and both of his parents are healthy. He is at the 25th percentile for height and is above the 95th percentile for weight. Physical examination shows central obesity, undescended testes, almond-shaped eyes, and a thin upper lip. Which of the following genetic changes is most likely associated with this patient's condition?

Loss of paternal gene expression on chromosome 15

Mitotic nondisjunction of chromosome 21

Mutation of FBN-1 gene on chromosome 15

Microdeletion of long arm of chromosome 7

Deletion of Phe508 on chromosome 7

A 13-year-old girl is brought to the physician by her mother because of a 1-month history of abnormal movements of her muscles that she cannot control. She has a younger brother with cognitive disabilities and epilepsy. Examination shows frequent, brief, involuntary contractions of the muscle groups of the upper arms, legs, and face that can be triggered by touch. An EEG shows generalized epileptiform activity. A trichrome stain of a skeletal muscle biopsy specimen shows muscle fibers with peripheral red inclusions that disrupt the normal fiber contour. Which of the following is the most likely underlying mechanism of the patient's symptoms?

Defective oxidative phosphorylation

CTG trinucleotide repeat expansion

Mutation of the methyl-CpG binding protein 2 gene

Autoimmune endomysial destruction

A 6-year-old male presents to the pediatrician with seizures. His mother reports that the patient has had two seizures lasting about 30 seconds each over the last three days. She reports that the patient has previously had seizures a few times per year since he was 12 months of age. The patient’s past medical history is otherwise notable for intellectual disability. He rolled over at 14 months of age and walked at 24 months of age. The patient’s mother denies any family history of epilepsy or other neurologic diseases. The patient is in the 3rd percentile for height and the 15th percentile for weight. On physical exam, he has a happy demeanor with frequent smiling. The patient has strabismus and an ataxic gait accompanied by flapping of the hands. He responds intermittently to questions with one-word answers. This patient is most likely to have which of the following genetic abnormalities?

Paternal uniparental disomy of chromosome 15

Chromosomal macrodeletion on chromosome 5

Maternal uniparental disomy of chromosome 15

Imprinting defect on chromosome 11

Given the pattern of inheritance shown in the pedigree, where might you find the disease gene in question?

On circular DNA in the mitochondrion

On helical RNA in the cytoplasm

On double stranded DNA in the nucleus

On single-stranded DNA in the cytoplasm

On linear DNA in the mitochondrion

Non-Mendelian inheritance Notes – USMLE Biochemistry

Mitochondrial Inheritance - It's All From Mom

Mitochondrial Inheritance Pedigree

Transmitted exclusively through the mother, as mitochondria are inherited from the ovum. All offspring of an affected female inherit the mutation.
Key Concepts:
- Heteroplasmy: A mixture of normal and mutated mtDNA in cells, leading to...
- Variable Expressivity: ...a wide range of clinical severity among affected family members.
Classic Syndromes:
- Leber hereditary optic neuropathy (LHON): Acute central vision loss.
- MERRF: Myoclonic epilepsy with ragged-red fibers.
- MELAS: Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes.

⭐ Muscle biopsy often shows "ragged red fibers" with Gomori trichrome stain, representing accumulations of abnormal mitochondria.

Genomic Imprinting - The Silencing Game

Genomic imprinting silences genes based on parent of origin, typically via DNA methylation. If the expressed allele is deleted, disease occurs. This affects gene clusters, most notably on chromosome 15.

Syndrome	Locus	Deletion Origin	Key Features
Prader-Willi	15q11-q13	Paternal	Hyperphagia, hypotonia, obesity.
Angelman	15q11-q13	Maternal	Inappropriate laughter, seizures, ataxia.

⭐ Uniparental disomy (inheriting both chromosome copies from one parent) is another key cause for these syndromes.

Genomic Imprinting and UBE3A Expression in Angelman Syndrome

Trinucleotide Repeats - Genetic Stutters

Dynamic mutations: Unstable repeats that can expand in number between generations. This leads to anticipation-earlier onset and increased severity in successive generations.

📌 Mnemonic: The Crazy Giants Hunt For Gummies (CTG, CGG, CAG, GAA).

Disorder	Repeat	Inheritance	Key Feature
Huntington's Disease	CAG	AD	Chorea, dementia, caudate atrophy
Myotonic Dystrophy	CTG	AD	Myotonia, cataracts, toupee (frontal balding)
Fragile X Syndrome	CGG	X-linked	Large jaw, large ears, large testes
Friedreich's Ataxia	GAA	AR	Ataxia, hypertrophic cardiomyopathy

Other Patterns - Genetic Curveballs

Codominance: Both alleles in a heterozygote are fully expressed.
- Example: ABO blood groups (A and B alleles are codominant).
Incomplete Dominance: Heterozygous phenotype is a blend of the two homozygous phenotypes.
- Example: Familial hypercholesterolemia; heterozygotes have LDL levels intermediate between normal and homozygous individuals.
Mosaicism: Presence of genetically distinct cell lines in an individual.
- Somatic: Mutation arises after fertilization. Example: McCune-Albright syndrome.
- Germline: Mutation is confined to egg or sperm cells.

Postzygotic mutation and mosaicism inheritance patterns

⭐ Germline mosaicism is an important consideration when counseling parents who are phenotypically normal but have a child with an autosomal dominant condition.

High‑Yield Points - ⚡ Biggest Takeaways

Mitochondrial inheritance is transmitted exclusively from the mother; all offspring can be affected, often with variable expressivity due to heteroplasmy.

Genomic imprinting is parent-of-origin-specific gene silencing via methylation, underlying syndromes like Prader-Willi and Angelman.

Anticipation describes how trinucleotide repeat disorders (e.g., Huntington's) worsen through generations.

Germline mosaicism can lead to disease in offspring from a phenotypically normal parent.

Uniparental disomy is inheriting two copies of a chromosome from one parent.

Continue reading on Oncourse

CONTINUE READING — FREE

or get the app

App Store|Google Play