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A 42-year old Caucasian man comes into your clinic experiencing chorea, depression, and anxiety.  His Father was diagnosed at 55-years of age with Huntington’s disease.  Your patient refused genetic testing for Huntington’s until now.  He undergoes testing and has a 55 repeat expansion of the CAG repeat in HTT gene.  His Father was tested for HTT and had a 44 repeat expansion.  What best explains the difference between the Father and the son?

Anticipation - Anticipation occurs when symptoms of a genetic disorder appear at an earlier onset with each generation.  Anticipation is common with trinucleotide repeat disease since the repeat can expand during meiosis and increase with each successive generation.


A 41 year-old male Indian patient comes to your clinic concerned about the results of a whole genome test he got from a commercial genomic sequencing company.  The data sheet from the company explained that he had an allele for Friedreich’s ataxia, an autosomal recessive condition found in roughly 1 in 50,000 people.  The disorder leads to the loss of sensory neurons at a young age leading to muscle weakness, loss of coordination, vision and hearing impairment, and later diabetes.  Your patient is concerned that his future offspring could suffer from this condition.  What is the percentage of heterozygous carriers in the population?

1 in 112 -  use the Hardy-Weinberg equation to calculate the % of heterozygous carriers.  The HW equation is p^2 + 2pq +q^2 = 1.  Solve for 2pq.  Since 1 in 50,000 is q2, q = .0045 while p = .9955.  Therefore the number of heterozygous carriers in the population is 1 in 112.


A 43-year-old Caucasian man presents to your neurology clinic with chorea and anxiety.    He has been having these symptoms for about 3 months.  Expecting the potential for Huntington’s disease, his DNA is analyzed by PCR and a CAG stretch is found containing 44 repeats within the HD
gene.  The affected Huntington’s protein is expressed in most tissues; however, the disease affects only neuronal tissue.  One argument for the damage to neuronal tissue is that the Huntington’s protein becomes sumoylated and is more soluble in this tissue.  How would you best describe the cellular mechanism of this mutation?

Gain of function - Huntington’s is an autosomal dominant disease caused by a repeat expansion in the polyglutamine stretch of the Huntington’s gene.  Autosomal dominant refers to the pattern of the inheritance and not to the mechanism of action.  This expansion causes the Huntington’s protein to gain novel toxic functions, which are exacerbated by the increased solubility of the protein in neuronal tissue.


2 siblings, a 15-year-old girt and a 13-year old boy, under your care suffer from neurofibromatosis caused by a mutation in the NF1 gene.  The girl presents with 8 café-au-lait spots on her back and torso while her brother has 25 café-au-lait spots over his back, shoulders, and abdomen; an optic glioma, and one plexiform neuroma.  The difference in symptoms between the two siblings is likely due to which of the following?

Variable expressivity - the range of signs and symptoms occurring in different people with the same genetic condition is variable expressivity and can be caused by a combination of genetic (such as modifier genes), environmental, and lifestyle factors.  Since both siblings show symptoms of the disorder the difference is not due to incomplete penetrance.


A new 24-year old female patient comes into your office for a checkup and you take a genetic history.  She explains that she is Jewish with Ashkenazi Jewish heritage.  In her family pedigree, there are no signs of recessive disorders common in Ashkenazi Jews?  What is the significance of her Ashkenazi Heritage in understanding her genetic history?

Founder population - a founder population is typically a small isolated population in which a mutation is more prominent due to the limited diversity of the gene pool.  These mutations can still be more abundant in a racial, ethnic, or religious group even after that group has moved to different geographic locations.  Importantly, most of the Jewish population in he United States has Ashkenazi heritage.


A 6-month old male Caucasian toddle comes into your clinic experiencing muscle weakness, vision and hearing loss, as well as, seizures.  These symptoms suggest the development of Tay-Sachs disease, and the child is genetically tested for the disease.  The sequence returns from the laboratory confirming Tay-Sachs disease.  The child has a deletion of 2 base pairs within the HEXA gene.  The loss of the two base pairs would lead to what type of mutation?

Frameshift - the deletion of 2 base pairs will alter the reading frame of the gene leading to a frameshift mutation.  This mutation could lead to a premature stop codon or transcription of a completely altered gene product.


A 42-year old Scottish female recently underwent amniocentesis during her 14th week of pregnancy.  After karyotyping, the fetus is found to have a trisomy of chromosome 21.  Which event is the most likely cause of the trisomy?

Decreased cohesion stability - Age related decreases in cohesion stability increase chances of a nondisjunction event.  Increased homologous recombination would not increase the risk of a nondisjunction event, while failure to depolymerize tubulin or loss of CDK1 activity would cause catastrophic meiosis and cell death.


A family under your care shows signs of long QT syndrome in which the QT interval of the electrocardiogram is exceptionally long.  Often, long QT syndrome is caused by mutations in the KCNQ1 gene, which codes for a voltage-activated potassium channel.  The family has a tyrosine to cysteine variant at amino acid 111 and an alanine to proline variant at amino acid 178.  The variant at 178 has been linked to long QT syndrome while the 111 variant has not.  The variant at 111 is an example of what?



A 35 year-old female from Fort Scott comes into your practice concerned about recent genetic testing that she underwent.  She decided to get tested for the BRCA1 mutation since her family has a history of breast cancer.  Her test results indicated that she had a hypomorphic mutation in the gene.  This mutation is best described to the patients as which of the following:


Leading to reduced gene product function - a hypomorphic mutation leads to reduced expression or activity of the gene product.  In the case of BRCA1, the gene product has reduced expression of the tumor suppressor.


A young married couple comes into your clinic to discuss issues about having children.  The father has a mutation on the OPN1MW gene on his X-chromosome causing him to suffer from color vision deficiency.  The father is concerned that he will have a son with color vision deficiency as well.  What is the probability that the son would have the disorder?

0% - the son of the father would inherent his Y-chromosome which does not carry the defect.  As long as the mother does not contain a color vision deficiency mutation on one of her X-chromosomes than the child has 0% chance of inheriting the disease.


A 52-year old African American patient of yours is concerned about genetic testing results he just received.  His testing reveled that he carries mutations in both copies of his HBB (beta-hemoglobin) gene, which should cause the patient to have Sickle Cell Anemia.  The patient has never experienced any of the symptoms of the disorder?  Which best explains the patient’s lack of symptoms?

Modifier Genes


An 8-year old female from Ecuador under your care presents to your clinic with a webbed neck and short stature.  Suspecting the child suffers from Turner Syndrome, you order a karyotyping assay.  The results conclude the child has only 1 copy of her X chromosome.  The loss of the X-chromosome is most likely due to what factor?

Nondisjunction event - A nondisjunction event leads to the improper segregation of chromosomes into the gamete.


A 1-year old male African American under your care is presenting with scattered normal pigmented and hypopigmented skin as well as the development of a white forelock of hair.  You expect the child has Piebaldism an autosomal dominant condition associated with highly penetrant point mutations in the KIT
gene.  However, neither the Father nor the Mother’s family shows a history of the condition.  How do you explain the diagnosis?

De novo mutation


A young girl of Ashkenazi Jewish heritage presents in your clinic with an enlarged liver and spleen, fatigue, and bruising.  You expect she suffers from Gaucher’s disease an autosomal recessive disorder more common in the Ashkenazi Jewish population.  Which pedigree best describes the disorder?

D - he pedigree in D is an example of autosomal recessive inheritance.  The fact that the Great Grandmother in D has the condition is consistent with there being a high carrier frequency in this population.  Pedigree A and B are autosomal dominant, and C is X-linked recessive.


High enough exposure to the Malaysian mountain slug toxin, rhodantimous, can cause errors in the synaptonemal complex and impairs strand inversion.  Disruption of this complex by the toxin leads to increased presentation of trisomies at birth.  The compound is interfering with what stage of meiosis?

Prophase I -  the synaptonemal complex forms at prophase 1.


A genome wide association study (GWAS) on the Wichita Indian tribe identified several natural variants in the MGEA5 gene on chromosome 10.  The tribe has a high incidence of Type 2 diabetes and two of the natural variants correlate with incidence of the disease.  This gene codes for an enzyme that removes a single N-acetylglucosamine sugar from intracellular proteins.  Interestingly, the two natural variants in the MGEA5 gene tended to occur with a set of natural variants found in the NPM3 gene on the same chromosome that the MGEA5 gene is found on.  This type of association describes what about the chromosome?

Haplotype - a haplotype is a set of polymorphisms in different genes that reside closely on a given chromosome and are often inherited together. A particular haplotype can correlate with disease severity.


A 16-year old male patient presents to your clinic with small genitals and breast growth.  You order karyotyping from peripheral blood lymphocytes.  The results show that the patient has Klinefelter syndrome (an extra X chromosome).  The mother is very upset by this news and wants the karyotyping performed again.  This time you perform a skin biopsy and perform the test on cultured fibroblast.  The karyotyping of these cells shows the patient to have a normal number of chromosomes.  Which of the following best describes these results?

Somatic mosaicism -  two different tissue having different karyotypes suggesting an error during mitosis in the early embryo leading to the development of somatic mosaicism.


A newborn Korean male child shows signs of increased bleeding after a routine heel prick suggesting the potential for Hemophilia Type A.  The child has 4 other siblings, 2 sisters and 2 brothers, neither of which have shown signs of having the disease nor his Mother, Father, or Grandparents on both sides.  The mutation leading to Hemophilia Type A likely resides on which chromosome?

Maternal X-chromosome (Grandmother) - Hemophilia is an X-linked recessive trait.  The Father of the child does not have hemophilia so the carrier of the mutation has to be the Mother.  The Mother does not have hemophilia since she has one X-chromosome with a normal gene for Coagulation Factor VIII.  Since the Mother’s Father (the child’s maternal Grandfather) did not have hemophilia, the Mother’s Mother was the carrier (maternal Grandmother).


A 24-year old female patient of Japanese heritage under your care is showing signs of hemolytic anemia, sphereocytosis, and fatigue.  The patient’s Mother has a history of anemia and fatigue as well.   These data suggest the patient and the Mother might suffer from hereditary spherocytosis; however, numerous possible gene mutations could lead to the symptoms of the disease.  Which of the following DNA sequencing methods would provide the best diagnosis of the genetic abnormality?

Whole Exome Sequencing - both whole genome and whole exome sequencing would provide the relevant information; however, the whole exome method is cheaper and faster than the whole genome method.


A 27-year-old female patient is thinking about having a child with her husband.  Although her husband shows no signs of Laron syndrome, an autosomal recessive disorder causing dwarfism, decreased intellectual capacity, and seizures, other members of his family have been diagnosed with the disorder.  She is afraid she might also be a carrier of the mutated gene and does not want to have a child with the disorder.  The observed frequency of the mutation in the population is 1 in 75,000.  What is the likelihood that your patient is a carrier of the disorder?

0.73% - from the Hardy-Weinberg equation (p2 + 2pq + q2= 1), 2pq is the carrier frequency.  To solve for 2pq, first determine q by taking the q2=1/75,000, so q=.004.  Now solve for P where p=1-q; p =.996.  Now calculate 2qp.  2qp = 0.73%


An African American newborn girl under your care is presenting with rhizomelic shortening of the arms and legs, thoracolumbar gibbus, a large head with frontal bossing, and a notch–like sacroiliac groove.  These findings demonstrate that the child suffers from achondroplasia, an autosomal dominant condition caused by a missense mutation in the FGFR3 gene.  However, neither parent suffers from the condition.  What is the most likely cause of the newborns condition?

De novo mutation - since the condition is autosomal dominant, caused by a missense mutation, and not present in either parent then the mutation in FGFR3 is a de novo mutation.


In the neonatal ICU, a female Caucasian newborn presents with infantile dwarfism, underossification, micromelia, and proliferation of multinucleated giant-cell chondrocytes.  After genetic analysis, the child shows a heterozygous (one normal allele and one mutated allele) mutation in the Filamin B (FLNB) gene leading to a lethal infantile form of osteochondrodysplasia (Boomerang Dysplasia).   Neither parent suffers from the disease suggesting that the mutation reflects what type inheritance pattern? 

De novo Autosomal Dominant - “Boomerang dysplasia” is caused by a de novo mutation in Filamin B gene located on chromosome 3.  This mutation is perinatal lethal. It cannot be X-linked recessive since she will have one normal X chromosome.


Eight year-old fraternal male and female twins of Eastern European descent under your care have started to develop an excessive number of warts. Further testing demonstrates that the twins have chronic noncyclic neutropenia.  After genetic testing, the twins are diagnosed with autosomal dominant childhood WHIM syndrome caused by a mutation in chemokine receptor CXCR4. Mutation of CXCR4 invariably gives rise to this childhood disorder. Interestingly, no one in the twins’ family has been diagnosed with the disease including their 15-year-old brother and 12-year-old sister.  The most likely cause for both children having WHIM syndrome is the following?

Germline mutation in the father - since neither parent has the disorder, the most likely cause for the twins’ phenotype is a de novo mutation in the germline of the father.  Since the mother’s germ cells are fixed at birth, there are fewer cell divisions needed to make all the mother’s oocytes and thus there is a much lower likelihood of de novo mutation occurring during oogenesis.  However, the father continually makes new germ cells throughout adulthood, therefore, a mutation in the father’s germline, perhaps occurring after the birth of the first two children, could be passed down to the younger children. If a primary spermatocyte acquires a mutation, then all the descendant sperm would carry that mutation.  The likelihood of two somatic mutations occurring and producing the same phenotype in the twins is small.  Of note, the mutation leads to the inability of the receptor to turn off after stimulation and is a gain of function mutation


A 14 year-old male patient of yours has struggled with neuroblastoma for several years.  Recently, the child underwent genetic testing and has a mutation in one allele of the tumor suppressor p53.  The mutation did not cause the loss of the protein or altered the stability of the protein.  What type of mutation in p53 is the most likely cause for the neuroblastoma formation in the patient?

Dominant Negative - the mutation in one allele of the p53 gene leads to a loss of function mutation that is a dominant negative mutation.  The dominant negative protein interferes with the normal function of the wild type protein leading to complete loss of the activity of the tumor suppressor.  The best answer is dominant negative.