GEMD-101 Molecular Basis of Cellular Function and Dysfunction (Week 2) - Cases 1 & 2, Fall 2023 PDF

GEMD-101 Molecular basis of cellular function and dysfunction Week 2 – Organization and function of the genome CBL Cases 1 & 2 Fall 2023 Course Lead: Konstantinos Voskarides, PhD Case 1 A 2-year-old girl referred to the Genetics clinic beca...

GEMD-101 Molecular basis of cellular function and dysfunction Week 2 – Organization and function of the genome CBL Cases 1 & 2 Fall 2023 Course Lead: Konstantinos Voskarides, PhD Case 1 A 2-year-old girl referred to the Genetics clinic because of five brown skin spots (5 mm in diameter), known as “café au lait” spots. Physical examination revealed no malformations or neurofibromas (benign neural tumors). The consulting geneticist informed the parents and the referring pediatrician that the girl did not meet the clinical criteria for neurofibromatosis type 1 (NF1). (modified from Thompson & Thompson, Elsevier, 2016) 1. Why diagnosis of some genetic diseases in children, like NF1, is challenging? 2. The girl returned to the genetics clinic at 5 years of age. She now had Lisch nodules in both eyes (characteristic iris nodules seen in NF1) and 12 “café au lait” spots, plus skin neurofibromas. She was given the diagnosis of NF1. Frequently, NF1 patients, even in a single family, develop different symptoms. What do we call this in Genetics? Can you think of probable causes for this phenomenon? 3. NF1 displays autosomal dominant inheritance and complete penetrance. What “complete” or “100%” penetrance means? What does “reduced or incomplete penetrance” mean? 4. The parents of the girl are healthy. Can you think of any possible reasons for that? What is the recurrence risk (risk for next children of the couple to have the disease)? 5. Some NF1 patients have features of the disease limited only to one region of the body. If the parents of these patients are healthy, what phenomenon can explain that? Ruglgieri and Pratico, 2014 De novo mutation Can cause to mosaicism or not 6. 80% of the mutations cause protein truncation of the NF1 protein. What kind of mutation have this effect? 7. The parents declined molecular testing for their daughter. Would you try to change their mind? In either case, what are your arguments? 8. Explain the following terms: Homozygous, Heterozygous, Hemizygous, Compound heterozygotes, Phenotype, Genotype, Siblings Case 2 A 45-year-old man presented initially with declining memory and concentration. As his intellectual function deteriorated during the ensuing year, he developed involuntary movements of his fingers and toes as well as facial strange expressions. He was aware of his condition and became depressed. He had been previously healthy and did not have a history of any similarly affected relatives; his parents had died in their 40s in an automobile accident. After an extensive evaluation, the neurologist diagnosed the man with Huntington disease. (adopted from Thompson & Thompson, 2016, Elsevier) 1. What is the cause of Huntington disease? 2. The diagnosis of Huntington disease was confirmed by DNA analysis showing 43 CAG repeats in one of his HD alleles (normal,