A genetic counselor sees a family for the first time for genetic assessment. The 24-year-old businessman and his 19-year-old sister are concerned about having a mutant allele and have decided to get tested. Their grandfather and great aunt both have Huntington’s disease which became apparent when they turned 52. Their father who is 47 years old appears healthy. The geneticist discusses both the benefits and risks of getting tested and orders some tests. Which of the following tests would best provide evidence for whether the siblings are carriers or not?

Restriction enzyme digestion products

A 12-year-old boy develops muscle weakness and pain, vomiting, seizures, and severe headache. Additionally, he presents with hemiparesis on one side of the body. A muscle biopsy shows 'ragged red fibers'. What is true about the mode of inheritance of the disease described?

It is transmitted only through the mother.

It can be transmitted through both parents.

Mothers transmit to 50% of daughters and sons

A 32-year-old woman comes to the physician for genetic consultation. She has a history of recurrent generalized seizures, diffuse muscular weakness, and multiple episodes of transient left-sided paresis. She has been hospitalized several times for severe lactic acidosis requiring intravenous fluid hydration. Her 10-year-old daughter also has seizures and muscle weakness. Her 7-year-old son has occasional muscle weakness and headaches but has never had a seizure. Pathologic examination of a biopsy specimen from the woman's soleus muscle shows ragged-appearing muscle fibers. Genetic analysis of the patient's son is most likely to show which of the following?

Genetically distinct cell lines

Altered allele on the X chromosome

A 28-year-old man presents for severe abdominal pain and is diagnosed with appendicitis. He is taken for emergent appendectomy. During the procedure, the patient has massive and persistent bleeding requiring a blood transfusion. The preoperative laboratory studies showed a normal bleeding time, normal prothrombin time (PT), an INR of 1.0, and a normal platelet count. Postoperatively, when the patient is told about the complications during the surgery, he recalls that he forgot to mention that he has a family history of an unknown bleeding disorder. The postoperative laboratory tests reveal a prolonged partial thromboplastin time (PTT). Which of the following is the most likely diagnosis in this patient?

Thrombotic thrombocytopenic purpura

Genetic disorders for USMLE Step 2 CK: High-Yield Pathology Lessons

Mutations & Inheritance - Gene Jumbles & Family Fumbles

Point Mutations: Single nucleotide substitution.
- Silent: Same amino acid (tRNA wobble).
- Missense: Different amino acid (e.g., Sickle Cell).
- Nonsense: Becomes a STOP codon.
Frameshift: Insertion/deletion not divisible by 3; alters reading frame. (e.g., Duchenne Muscular Dystrophy).

⭐ Mitochondrial inheritance is exclusively maternal. All offspring of an affected female inherit the mutation, often with variable severity (heteroplasmy).

Mendelian: Autosomal - The Dominant & Recessive Rumble

Feature	Autosomal Dominant (AD)	Autosomal Recessive (AR)
Transmission	Vertical; seen in every generation.	Horizontal; skips generations.
Recurrence Risk	50% with one affected heterozygous parent.	25% with two carrier parents.
Key Features	Often involves structural proteins. Variable expressivity & incomplete penetrance are common.	Often involves enzyme deficiencies. More uniform expression. ↑ frequency with consanguinity.
Examples	Familial hypercholesterolemia, Huntington's, Marfan syndrome, Neurofibromatosis.	Cystic fibrosis, Sickle cell anemia, Phenylketonuria (PKU), Tay-Sachs.

⭐ High-Yield: Many new AD cases arise from de novo mutations, especially with ↑ paternal age (e.g., Achondroplasia). In contrast, AR diseases often appear unexpectedly, with parents being asymptomatic carriers.

Mendelian: X-Linked & Atypical - X-ceptional Rules & Twists

X-Linked Recessive:
- Skips generations; no male-to-male transmission.
- Affected father to all daughters (carriers).
- 📌 Examples: Hemophilia, G6PD deficiency, Duchenne/Becker MD, Lesch-Nyhan, Bruton agammaglobulinemia.
X-Linked Dominant:
- No male-to-male transmission.
- Affected father to ALL daughters.
- Examples: Fragile X, Alport, Rett Syndrome.
Atypical Inheritance:
- Mitochondrial: Maternal inheritance only; all offspring affected. Variable severity (heteroplasmy).
- Imprinting: Parent-of-origin gene silencing.
  - Prader-Willi: Paternal gene deleted (Chr 15).
  - Angelman: Maternal gene deleted (Chr 15).
- Anticipation: Trinucleotide repeats worsen across generations (e.g., Huntington's, Fragile X).

⭐ Lyonization (X-inactivation): Random inactivation of one X chromosome in females (Barr body), causing variable expression of X-linked traits in carriers.

Pedigree chart showing X-linked recessive inheritance

Cytogenetic Disorders - Chromosome Chaos

Result from errors in meiosis (nondisjunction) or mitosis.
Leads to abnormal number of chromosomes (aneuploidy) or structural changes (e.g., deletions, translocations).

Disorder	Karyotype	Core Features
Down Syndrome	Trisomy 21	Flat facies, single palmar crease, duodenal atresia, congenital heart defects (AV septal defect).
Edwards Syndrome	Trisomy 18	Rocker-bottom feet, micrognathia, clenched hands with overlapping fingers, prominent occiput.
Patau Syndrome	Trisomy 13	Cleft lip/palate, polydactyly, microcephaly, severe CNS defects.
Klinefelter Syndrome	47,XXY	Male. Tall stature, gynecomastia, testicular atrophy, infertility.
Turner Syndrome	45,X	Female. Short stature, webbed neck, broad chest, coarctation of aorta.

📌 Mnemonic (Trisomies): Drinking age (21), Election age (18), Puberty age (13).

High‑Yield Points - ⚡ Biggest Takeaways

Autosomal Dominant disorders often affect structural proteins (e.g., Marfan) and show variable expressivity and pleiotropy.

Autosomal Recessive disorders are typically enzyme deficiencies (e.g., Tay-Sachs), with a more uniform presentation.

X-Linked Recessive disorders show no male-to-male transmission and often skip generations through carrier females.

Mitochondrial DNA is inherited exclusively from the mother and passed to all of her offspring.

Trinucleotide repeat disorders (e.g., Huntington, Fragile X) can show anticipation-worsening disease in subsequent generations.

Genomic imprinting causes disease when the single active parental allele is lost (e.g., Prader-Willi, Angelman).

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Genetic disorders