Imprinting
This syndrome results from a deletion in the paternal chromosome 15q11-q13 and is characterized by childhood obesity and hypotonia.
What is Prader-Willi Syndrome?
This syndrome is caused by defective nucleotide excision repair (NER) and leads to UV sensitivity and skin cancer.
What is Xeroderma Pigmentosum?
Which parent’s chromosome is normally imprinted in Prader-Willi Syndrome?
What is the maternal chromosome?
A 25-year-old woman has a strong family history of breast and ovarian cancer. Genetic testing shows defective homologous recombination repair. What is the syndrome, and which genes are most likely involved?
What is Hereditary Breast and Ovarian Cancer Syndrome (BRCA1/BRCA2)?
Xeroderma Pigmentosum is most associated with which type of UV-induced DNA damage?
What is pyrimidine dimers?
This syndrome presents with paroxysmal laughter, seizures, ataxia, and absent speech, caused by a deletion on maternal chromosome 15q11-q13.
What is Angelman Syndrome?
A defect in mismatch repair genes leads to colon and endometrial cancers. Name the syndrome.
What is Lynch Syndrome?
What explains why paternal deletion does not cause Angelman Syndrome?
Paternal UBE3A is silenced by imprinting, so loss has no effect.
A child presents with congenital abnormalities, growth over the 95th percentile, and an increased risk for Wilms tumor. Genetic analysis shows somatic UPD of 11p15.5. Which syndrome?
What is Beckwith-Wiedemann Syndrome?
A child develops multiple skin cancers and extreme UV sensitivity. Defective NER genes are identified. Why does this lead to both cancer and neurological abnormalities in some XP patients?
NER defects prevent repair of UV-induced DNA damage; neurological symptoms occur in variants with defective transcription-coupled NER in neurons.
Prader-Willi Syndrome can result from either deletion or uniparental disomy. Which mechanism is associated with more severe obesity?
What is deletion?
Ataxia-telangiectasia patients are sensitive to γ-rays. Which DNA repair pathway is defective?
What is double-strand break repair?
A newborn presents with macrosomia and organomegaly, but no chromosomal deletion is detected. Testing shows abnormal methylation at 11p15.5. How does this imprinting defect lead to overgrowth?
Abnormal methylation activates normally silenced maternal IGF2, resulting in biallelic expression and excessive growth.
A newborn presents with hypotonia and poor feeding. Genetic testing shows deletion of paternal 15q11-q13. What syndrome is most likely?
What is Prader-Willi Syndrome?
Fanconi Anemia patients show congenital abnormalities and genome instability. Which DNA repair process is defective, and why does this predispose to leukemia?
Crosslink repair is defective; unresolved DNA lesions accumulate in hematopoietic stem cells, leading to malignancy.
Beckwith-Wiedemann Syndrome is caused by somatic segmental uniparental disomy of 11p15.5. How does this lead to overgrowth?
What is biallelic expression of normally imprinted genes like IGF2 due to abnormal methylation?
Fanconi Anemia patients have congenital abnormalities and leukemia due to a defect in which DNA repair process?
What is crosslink repair?
Beckwith-Wiedemann Syndrome can be caused by loss of imprinting on 11p15. How does this differ mechanistically from somatic segmental UPD?
Loss of imprinting alters methylation patterns without changing chromosome number; UPD leads to homozygosity for the distal loci.
A patient with skin photosensitivity develops multiple skin cancers at a young age. NER testing is abnormal. What syndrome?
What is Xeroderma Pigmentosum?
Why are Ataxia-telangiectasia patients more prone to leukemia and lymphoma than skin cancers, unlike XP patients?
AT involves defective double-strand break repair, affecting rapidly dividing hematopoietic cells; XP involves NER defects affecting skin exposed to UV.
Compare the parent-of-origin effects in Prader-Willi vs Angelman syndromes. Which parent’s chromosome is normally imprinted in each, and what happens when the error occurs?
In Prader-Willi, the maternal chromosome is imprinted, and loss of paternal 15q11-q13 causes disease. In Angelman, the paternal chromosome is imprinted, and loss of maternal 15q11-q13 causes disease.
Hereditary breast and ovarian cancer syndrome is caused by defective homologous recombination repair. Name two genes commonly involved.
What are BRCA1 and BRCA2?
A patient shows hypotonia, short stature, hyperphagia, and maternal UPD 15. Could this be misdiagnosed as Angelman Syndrome, and why?
No, because Angelman requires maternal deletion or mutation of UBE3A, and maternal UPD affects paternal genes, not maternal expression.
A 3-year-old exhibits frequent laughter, absent speech, ataxia, and seizures. Genetic testing shows maternal deletion of 15q11-q13. Diagnosis?
What is Angelman Syndrome?
A 28-year-old woman with a BRCA2 mutation has family history of breast and ovarian cancer. She’s considering prophylactic surgery vs PARP inhibitors. Mechanistically, why might PARP inhibitors fail if tumor cells acquire secondary BRCA2 mutations?
Secondary mutations restore homologous recombination; cells regain ability to repair double-strand breaks, making PARP inhibition ineffective.