Genetics and Prenatal Diagnosis Flashcards
. Which of the following tests has the lowest false positive rate in low-risk women?
A. Cell-free DNA testing
B. Chorionic villus sampling
C. Integrated screen
D. Sequential screen
E. Amniocentesis
E. The correct answer to this question is amniocentesis. Of the choices listed, only amniocentesis and chorionic villus sampling (CVS) are diagnostic tests; the remainder are screening tests. As diagnostic tests, CVS and amniocentesis are designed to have very low false-positive rates. Since CVS samples chorionic villi, there is a 1-2% rate of confined placental mosaicism, which would contribute to the false-positive rate. It should be noted that cases of confined placental mosaicism are at high risk for adverse pregnancy outcomes, including growth restriction and intrauterine demise, despite a euploid fetus. Cell-free DNA testing is a technology that became publicly available in 2011. It relies on circulating cell-free fetal DNA in the maternal plasma that originates from placental tissue. Therefore, like CVS, cell-free DNA test results are subject to confounding due to confined placental mosaicism. Several studies have been published showing the very high sensitivity and specificity of this technology for certain chromosomal aneuploidies when applied to a high-risk population. However, a large study by Bianchi et al using this technology in a low-risk population revealed a false-positive rate of >50%. Integrated and sequential screening tests are strategies incorporating ultrasound findings and maternal serum biomarkers to provide a risk ratio for trisomy 21, 18, and in some cases 13.
American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics; Committee on Genetics; Society for Maternal-Fetal Medicine. Screening for Fetal Chromosomal Abnormalities: ACOG Practice Bulletin, Number 226. Obstet Gynecol. 2020;136(4):e48-e69.
Bianchi et al, DNA. Sequencing versus standard prenatal aneuploidy screening, N Engl J Med 2014;370:799-808.
SMFM. Cell-free DNA testing is not a simple blood test. https://www.smfm.org/publicati…Accessed May 21, 2021.
. A 35 year old G2P1 presents for a comprehensive scan due to advanced maternal age. The scan reveals a single intrauterine pregnancy, appropriate for gestational age with a ventricular septal defect. The remainder of the anatomy appeared normal. She declined testing for aneuploidy. At delivery, the neonate is hypotonic. What is the most likely chromosomal abnormality?
A. Trisomy 13
B. Trisomy 18
C. Trisomy 21
D. Turner syndrome
E. XXY
C. Trisomy 21 is an abnormality due to the presence of an extra copy of chromosome 21. The incidence of trisomy 21 is 1/920 live births, and it is the most common chromosomal abnormality. The frequency of Down syndrome increases with advanced maternal age. The ultrasonographic findings of Down syndrome are variable and can include no findings to multiple congenital abnormalities. Some sonographic findings that have been related to Down syndrome and are considered soft markers are thickened nuchal fold, shortened femur or humerus, echogenic intracardiac focus, echogenic bowel, and pyelectasis. However, controversy exists regarding the use of soft markers in patient counseling. Fetal anomalies that should raise suspicion of Down syndrome include endocardial cushion defect, duodenal atresia, mild ventriculomegaly, and cystic hygroma. Only 30-50% of fetuses with Down syndrome will have findings on ultrasound, making ultrasound a poor screening test for trisomy 21. At birth infants with Down syndrome are hypotonic. Facial features include midface hypoplasia, a round face, and epicanthal folds. Fifty percent of children have congenital heart abnormalities. Many of these children have feeding difficulties and have an increased risk of congenital hypothyroidism and leukemia. Trisomy 13 is an abnormality due to the presence of an extra copy of chromosome 13. Trisomy 13 is rare occurring in 1/5000 to 1/20000 births. The prognosis is poor with 70% of affected infants being stillborn or dying within the first 6 months of life and 85% die within the first year. Infants have a characteristic phenotype that includes cardiac, brain, gastrointestinal, and limb malformations. It can be detected in >90% of cases prenatally due to multiple structural anomalies. Trisomy 18 is the second most common autosomal trisomy detected in the second trimester after Down syndrome. Incidence at birth is 1/3000 to 1/5000 with a female predominance. Prognosis is poor with 50% of infants dying within the first 2 months of life and 90% dying within 1 year. The frequency of detection by ultrasound depends on gestational age and whether or not serum screening is incorporated. Turner syndrome is a sex chromosome abnormality in which there is complete or partial absence of an X chromosome resulting in monosomy X. XXY (Klinefelter syndrome) is a congenital abnormality causing primary hypogonadism occurring in approximately 1 in 1000 live male births. The syndrome occurs when males have at least 1 extra X chromosome. However greater and fewer numbers of X-chromosomes have been seen. Men affected with Klinefelter syndrome have significantly low sperm counts, infertility, elevated levels of FSH and LH, and low testosterone. Bianchi, D. In Fetology. Chapter 21 (Down Syndrome). Pgs. 919-925
. According to the guidelines published in June 2015 by ACOG and SMFM, in which of the following scenarios should circulating cell-free DNA (cfDNA) testing for aneuploidy screening NOT be used until further study?
A. 36 year old G2P1 who desires Down syndrome screening
B. 32 year old G3P0 who had an IUFD attributed to trisomy 13
C. 28 year old G0 who has a sister with DiGeorge syndrome
D. 26 year old G1P0 with a screen positive integrated serum screen
E. 30 year old G1P0 who was found to have a fetus with AV Canal defect on anatomical survey and declines amniocentesis
C. Circulating cell-free DNA (cfDNA) testing is an excellent screening test for all of the common trisomies (T21, T18, T13). In women who received an interpretable result, sensitivity and specificity for the common trisomies are greater than 90%. As with all screening tests, the negative and positive predictive values vary in accordance with the prevalence of disease. Thus, the positive predictive value is higher in women at higher risk of aneuploidy (e.g. advanced maternal age, previous infant with trisomy). Although circulating cfDNA testing is an excellent test, it is still a screening test. If a positive test returns, diagnostic testing through either CVS or amniocentesis should always be offered to confirm the results. ccfDNA does not screen for open neural tube defects, other chromosomal abnormalities, or other genetic syndromes (although some microdeletion panels are being introduced). Prior to offering prenatal screening, discussion of the risks, benefits, and alternatives (including the option of no testing) should occur with all patients. ACOG (in the September 2015 Committee Opinion) states that “high-risk” patients (defined below) should be offered screening with ccfDNA. High-risk patients are defined as those with: (1) advanced maternal age (2) abnormal ultrasound findings indicating an increased risk of aneuploidy (3) prior pregnancy with a trisomy (4) a family history of a translocation involving trisomy 13 or 21 (5) a positive serum screen. In low-risk women, due to the limits of cfDNA screening and lack of cost-effectiveness data, conventional methods of screening appear to be the most appropriate choice for first-line screening. Although there has been interest in detecting other chromosome anomalies with cfDNA, including DiGeorge syndrome (22q deletion), the positive and negative predictive values are not well established and further research is needed before these additional tests are incorporated into practice.
ACOG Committee Opinion No. 640: Cell-Free DNA Screening For Fetal Aneuploidy. Obstet Gynecol. 2015;126(3):e31-e37.
- Jane is a carrier for cystic fibrosis. Her caucasian husband was adopted, and his carrier status is unknown. What is the likelihood that their child will have cystic fibrosis?
A. 0.01%
B. 0.1%
C. 1%
D. 10%
E. 25%
A?. Cystic fibrosis is a disease affecting the exocrine glands, particularly the pancreatic, sweat, and mucous glands of the lung. It is an autosomal recessive disorder, affecting a single gene on chromosome 7 (the cystic fibrosis conductance transmembrane regulator, CFTR, gene). There are multiple mutations within the gene that have been identified as causative of this disease. In this case, Jane is a known carrier, and her risk of passing an affected gene to her offspring is 50% (her genotype is heterozygous, she has one healthy and one disease-causing allele). Her husband’s status is unknown, and therefore the general population prevalence of carrier status for Caucasians (4%, or 1/25) applies to him. The likelihood if he were a carrier that he would then pass on the diseased gene is 50% based on traditional Mendelian genetics. Therefore, the risk that their child will be affected is: 0.5 x 0.04 x 0.5 = 0.01. If her husband were to undergo testing and is found to be a carrier, their risk of an affected child is simply 25%, because the rules of Mendelian inheritance would apply. However, if he were tested using a common mutation panel and was negative, the risk of an affected child is not zero; the common mutation panels do not test for every possible disease-causing variant of the gene. In that case, it would be necessary to find out the sensitivity of the particular panel that was performed in order to complete the calculation. For example, if the panel was designed to detect 80% of the mutations and he tests negative, his residual risk of being a carrier is the general carrier rate (4%) multiplied by 20%, the percentage of untested mutations: 0.04 x 0.2 = 0.008. In that case, the risk of an affected child would be: 0.5 x 0.008 x .05 = 0.002.
Creasy and Resnick’s Maternal-Fetal Medicine: Principles and Practice. Chapters 11, Prenatal Genetic Diagnosis and 37, Respiratory Diseases in Pregnancy. 2009.
Cystic Fibrosis and Congenital Absence of the Vas Deferens. http://www.ncbi.nlm.nih.gov/bo… Accessed May 21, 2021.
A 43 year old G3P1102 at 10 weeks of gestation presents for consultation. Her two children from a previous marriage are 14 and 19 year old. Her pregnancy with the 14 year old child was complicated by hemolytic disease of the newborn. She wants to know the chances that this pregnancy will also be affected by hemolytic disease of the newborn. You have explained the options for testing and she opts for cell-free DNA for fetal RHD testing. The results show a female fetus with 4 of 92 single nucleotide polymorphisms (SNPs) that differ between mother and fetus. What is the next big step?
A. Follow maternal titres and begin surveillance if they reach the critical threshold
B. Perform an amniocentesis at 15 weeks to determine fetal antigen typing
C. Begin MCA-PCV surveillance at 19 weeks
D. Explain that the result is inconclusive and consider repeating in 4-6 weeks
E. Explain that the result is valid and that the fetus is RHD positive
D. This patient has had a previous pregnancy affected by hemolytic disease of the newborn. However, since this pregnancy is with a different partner there is a possibility that this pregnancy will not be affected. In order to adequately counsel, one needs to determine fetal antigen status. Options include paternal antigen typing if paternity is assured, cell-free DNA for RHD, or amniocentesis for other red cell antigens. This patient opted for cell-free DNA. In order to qualify a female fetus result as valid, more than 6 of 92 SNPs must differ between mother and fetus. Since this patient only had 4 unique SNPs, the result is not valid. As this patient is only 10 weeks pregnant, there is enough time to repeat the test in 4 – 6 weeks. If the fetus is RHD +, surveillance should be initiated at 18 – 20 weeks. A is incorrect as maternal titers are not predictive of fetal disease if a patient had a previously affected pregnancy. B is not the next best answer as the patient desired cell-free DNA and there is ample time to obtain the new result. C is incorrect as surveillance will not be needed if the fetus is not affected. E is incorrect as 6 of 92 SNPs must differ for the result to be valid. Of note, at the time of publication cell-free DNA is only available for RHD and not any of the other red cell antigens in the United States.
- Ms. MC is 19 weeks pregnant, and she and her husband have a son with congenital adrenal hyperplasia (CAH). Neither Ms. MC nor her husband have CAH. What is the likelihood that her second child, a daughter, will be affected?
A. <1%
B. 25%
C. 50%
D. 100%
B. Congenital adrenal hyperplasia (CAH) occurs in approximately 1/14,000 births and is an autosomal recessive disorder characterized by a deficiency of one of the enzymes needed to transform cholesterol into cortisol by the adrenal glands. The enzyme block results in excessive stimulation of the adrenal glands by adrenocorticotropic hormone, adrenal hyperplasia, and excessive androgen (male sex hormone) synthesis, leading to either masculinization of the female fetus or excess masculinization of the male fetus. The most common defect is a deficiency of the enzyme 21-hydroxylase, representing more than 90% of CAH cases, and caused by a mutation of the CYP21 gene on chromosome 6. There are multiple mutations within that gene that result in various degrees of CAH (e.g., non-classic form, salt-wasting form, simple-virilizing form). The other enzymes involved in CAH are aromatase, 11-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase, and aldosterone synthase. If the parents have an affected child and are not themselves affected, they are known heterozygote carriers of a genetic mutation causing CAH. They have a 25% chance of having a subsequent child with this condition (regardless of gender), and there is a 50% chance of the offspring being carriers. If the mother or father has CAH, and the partner is not affected, all of their offspring will be carriers. If the affected individual has a partner that is a carrier, 50% of the offspring will be affected and the other 50% will be carriers.
A patient undergoes an amniocentesis at 16 weeks gestation. Which of the following indications for the prenatal diagnostic procedure is most likely to reveal a pathogenic abnormality on microarray testing if the karyotype is normal?
A. Advanced maternal age
B. Positive Down syndrome screening risk
C. Fetal anomaly detected by prenatal ultrasound
D. Prior child with 22q11 microdeletion
C. Karyotype has been the standard cytogenetic technique for women undergoing invasive prenatal diagnostic testing. The resolution of karyotype is approximately 5-10 Mb. Recent advances in array-based molecular cytogenetic techniques have improved the detection of smaller genomic deletions and duplications (copy number variants) within the genome that may be missed by standard karyotype. Some copy number variants are known to be associated with pathologic conditions, while others may be unknown to be associated with pathogenic conditions. The ambiguity with variations of unclear significance (VOUS) has limited widespread integration of microarray testing into prenatal diagnosis. In a recent prospective study of over 4400 women undergoing prenatal diagnostic testing from 29 centers, samples were separated into two possible options for testing: one was submitted for standard karyotyping and the other was sent to one of four laboratories for chromosomal microarray. Microarray analysis revealed all the aneuploidies and unbalanced rearrangements identified on karyotyping but did not identify balanced translocations and fetal triploidy. Among the samples with a normal karyotype, microarray analysis revealed clinically relevant deletions or duplications in 6.0% of women with a structural anomaly on ultrasound, but only 1.7% in those whose indications were advanced maternal age and 1.6% in those with a positive prenatal screen result
. Which of the following ultrasound abnormalities are most commonly associated with 22q11.2 deletion (DiGeorge syndrome)?
A. Cleft palate and interrupted aortic arch
B. Holoprosencephaly and clubbed feet
C. Omphalocele and choroid plexus cyst
D. Intracardiac echogenic focus and hydronephrosis
E. Bladder outlet obstruction and a Dandy walker malformation
A. 22q11.2 deletion is the most common microdeletion syndrome that has been reported in humans. It is also the most common syndrome associated with cleft palate and conotruncal cardiac anomalies. The clinical findings of 22q11.2 deletion syndrome are highly variable, both between and within families. The variation in phenotype and presentation is related to the actual size of the particular deletion in the patient and the genes involved. While the same region is consistently involved, the size of the particular deletion can vary from one patient to the next. Approximately 75% of patients with the disorder have congenital heart abnormalities, most commonly involving the outflow tracts and aortic arch. Additional findings may include characteristic facial features, immunodeficiency due to thymic hypoplasia, velopharyngeal dysfunction with or without cleft palate, hypocalcemia due to hypoparathyroidism, developmental and behavioral problems, and psychiatric problems. The incidence of 22q11.2 is thought to be 1/6400 live births. The deletion should be considered in all fetuses with congenital heart abnormalities. Some authors believe 22q11.2 should be considered in fetuses with polyhydramnios, vertebral anomalies, holoprosencephaly, spina bifida, or renal anomalies. Approximately 10% of fetuses with an isolated heart defect and no family history of 22q11.2 are thought to have 22q11.2 deletion. 22q11.2 deletion is inherited in an autosomal dominant manner. However, most cases are de novo.
Manji S, Roberson JR, Wiktor A, Vats S, Rush P, Diment S, Van Dyke DL. Prenatal diagnosis of 22q11. 2 deletion when ultrasound examination reveals a heart defect. Genetics in Medicine. 2001 Jan 1;3(1):65-6
Ms. LS is a G1P0 22 weeks of gestation. A routine anatomic survey ultrasound is performed and reveals a singleton fetus with ascites, pericardial effusion, and pleural effusion. Maternal labs include type “O” Rh(D) positive blood, a negative antibody screen, and low risk cell-free DNA screen. The peak systolic velocity of the middle cerebral artery measures 1.1 MoMs. What is the most likely underlying cause of these findings?
A. Aneuploidy
B. Cardiovascular abnormalities
C. Hematologic abnormalities
D. COngenital infections
E. Metabolic disorders
B. The ultrasound findings are consistent with hydrops fetalis given that more than two abnormal fluid collections are identified within this fetus: ascites, pleural effusion, and pericardial effusion. Another possible fluid collection for the diagnosis of hydrops would be generalized skin edema > 5 mm. Fetal anemia is not suspected given that the peak systolic velocity on Doppler imaging of the middle cerebral artery measures less than 1.5 MoMs for gestational age. This woman’s antibody screen was negative categorizing this case of hydrops fetalis as non-immune (not caused by red cell alloimmunization). Many different diagnoses can lead to the development of non-immune hydrops fetalis (NIHF), but many share common underlying pathophysiologic processes involving irregular fluid flow between the fetal vascular and interstitial spaces. Hypothesized mechanisms include increased central venous pressure, obstruction of venous/arterial blood flow, inadequate diastolic ventricular filling, hepatic venous congestion, hypoalbuminemia, increased capillary permeability, high-output cardiac failure, and lymphatic vessel dysplasia/obstruction. This woman’s cell-free fetal DNA screen was negative making the most common aneuploidies unlikely. Chromosome abnormalities such as monosomy X and trisomy 21 are common causes of NIHF. Although all of the answer choices are known causes of NIHF and should be considered in the work-up of such fetuses, the most common cause of NIHF in most series is cardiovascular abnormalities, accounting for about 20% of all cases. In most cardiac cases, NIHF is likely caused by increased central venous pressure (often due to right heart defects) or from inadequate diastolic ventricular filling (often due to tachyarrhythmias).
Society for Maternal-Fetal Medicine (SMFM), Norton ME, Chauhan SP, Dashe JS. Society for maternal-fetal medicine (SMFM) clinical guideline #7: nonimmune hydrops fetalis. Am J Obstet Gynecol. 2015 Feb;212(2):127-39.
- A 32 year old G4P0211 at 13 weeks of gestation presents for consultation. Her obstetric history is significant for a stillbirth at 33 weeks due to hydrops later attributed to hemolytic disease of the newborn followed by a pregnancy that required intrauterine fetal transfusions and delivery at 35 weeks. This pregnancy is with the same partner, who is known to be homozygous for the D antigen. Which of the following is the best plan?
A. Draw maternal blood for cell-free DNA to test for fetal Rh (D)
B. Draw monthly titres and if they exceed critical levels begin MCA-PSV surveillance
C. Draw monthly titers and if they exceed critical levels perform an amniocentesis. Base management on OD450 results.
D. Begin MCA-PSV screening if titers exceed critical levels
E. Begin MCA-PSV surveillance at 18 weeks
E. The management of fetal anemia is broadly divided into two categories: women who have had a prior affected pregnancy and those who have not. In a patient’s first affected pregnancy, serial titers can be drawn as worsening titers are predictive of fetal disease. However, in a patient with a previously affected pregnancy, titers do not predict fetal outcomes (choices B-D). Therefore, fetal middle cerebral artery peak systolic velocity (MCA-PSV) measurements are recommended to guide management every 1 to 2 weeks starting at 18 to 20 weeks of gestation. (Initiating surveillance at 18 to 20 weeks is recommended because it is at this gestational age that most experts believe a cordocentesis is technically feasible.) If the multiple of the median (MOM) exceeds ≥ 1.5, a cordocentesis is recommended to evaluate fetal status. Choice A is incorrect as this pregnancy is with the same partner as her previous affected pregnancies, and paternal zygosity is known to be homozygous. If this pregnancy was with a new partner, one should determine the fetal antigen status or paternal D-antigen status.
A patient decides she wants genetic testing after an ultrasound exam at 18 weeks of gestation reveals fetal anomalies including enlarged kidney and hypotelorism. What is the most appropriate option for testing?
A. Cell-free DNA screening
B. Microarray
C. FISH
D. Expanded carrier screening
B. In this patient, the ultrasound detects anomalies that are not specific for any particular genetic disorder. In the presence of an abnormal ultrasound, a screening test such as cell-free DNA screening would not be the best choice. Fluorescence in situ hybridization testing (FISH) is a rapid way to assess chromosomal number or the presence or absence of a specific area within a chromosome. The limitation of this testing is that pre-existing knowledge of the particular defect that is being tested is required; if the ultrasound findings had been indicative of a specific chromosomal abnormality such as trisomy 21 or monosomy X, or of a specific deletion such as 22q11, FISH could be performed. However, FISH is not the best choice in this situation. Karyotype has been the gold standard for prenatal diagnosis for many years; however, studies comparing karyotype to microarray have demonstrated the superiority of microarray in detecting clinically significant pathology; approximately 6% of fetuses with an ultrasound abnormality and a normal karyotype will have an abnormal microarray. ACOG and SMFM recommend that if there is an abnormality on ultrasound without a clearly suspected diagnosis, the most appropriate option is microarray.
A CVS result is positive for an autosomal dominant disorder. Although there is a family history of the condition in the maternal lineage (the patient’s mother, uncle, and cousins have documented symptoms), the patient herself does not have any signs or symptoms of the condition. Which of the following best explains this finding?
A. Mitochondrial inheritance
B. Incomplete penetrance
C. Germline mutation
D. Balanced translocation
E. Imprinting
B
The correct answer is incomplete penetrance. This is a situation where a person may carry a particular disease-causing allele, but not express the condition. One example would be retinoblastoma; of people who carry the rb gene variant responsible for the tumors, approximately 20% do not develop them. Another example would be women who have the deleterious mutation in the BRCA1 or 2 gene; some will not develop cancer. A related concept is variable expressivity – someone who has a mutation responsible for Marfan’s syndrome or neurofibromatosis may display many different signs or symptoms.
Mitochondrial genetic disorders are caused either by mutations in the DNA within the mitochondria (these conditions are only inherited in a matrilineal fashion) or by nuclear DNA mutations that primarily affect the mitochondria (these can be inherited in any way). They are very rare conditions affecting all organ systems, including rare myopathies.
A germline mutation is one in which the mutation occurs only in the gonadal tissue, such that the offspring are affected but not the adult. In this case this is not the best answer because there is a family history, suggesting that the mutation was transmitted from a previous generation.
A balanced translocation is a situation where there is breakage of a chromosome and regrouping, which usually does not cause symptoms in the proband but can cause pregnancy loss or other complications in the offspring if they inherit an imbalanced chromosome complement.
Imprinting refers to the epigenetic modification of inherited chromosomes such that each parent’s contribution to the zygote is not identical. In cases where there is uniparental disomy, meaning that the zygote inherits two copies of a chromosome from one parent and none from the other, depending on which parent is the source of the genetic material there will be a different phenotype because of imprinting. One classic example of this is Prader-Willi syndrome or Angelman syndrome, both involving chromosome 15; if there is loss of the maternal contribution of chromosome 15, then the child will have the phenotype consistent with Angelman, and vice versa.
“Patterns of Inheritance” in Creasy and Resnik’s Maternal-Fetal Medicine: Principles and Practice, 7th edition, Elsevier 2014.
US National Library of Medicine, Genetics Home Reference, “What are reduced penetrance and variable expressivity?” accessed March 2018. https://ghr.nlm.nih.gov/primer…
A patient has marfans syndrome. Amniocentesis reveals that her fetus has the same pathogenic variant in the FBN1 gene that she has. Which of the following concepts is most relevant to your counseling of this patient regarding risk to her fetus?
A. Variable expressivity
B. Balanced translocation
C. X-linked inheritance
D. Imprinting
E. Epigenetics
A.
The correct answer is variable expressivity. This is a situation where the same pathogenic variant may lead to many different signs or symptoms (referred to in genetics as phenotype) in members within that family. This leads to some real challenges for providers when counseling patients, because it is often not possible to predict the severity of disease in the antepartum period for these conditions. Marfan’s is a well-established example of this, where some family members may exhibit a severe phenotype with cardiac or aortic disease, and others may have a very mild phenotype with tall stature but no other findings.
A balanced translocation is a situation where there is breakage of a chromosome and regrouping, which usually does not cause symptoms in the proband but can cause pregnancy loss or other complications in the offspring if they inherit an imbalanced chromosome complement.
X-linked inheritance refers to conditions that are caused by a gene carried on the X chromosome, and demonstrate a sex bias in prevalence.
Imprinting refers to the epigenetic modification of inherited chromosomes such that each parent’s contribution to the zygote is not identical. In cases where there is uniparental disomy, meaning that the zygote inherits two copies of a chromosome from one parent and none from the other, depending on which parent is the source of the genetic material there will be a different phenotype because of imprinting. One classic example of this is Prader-Willi syndrome or Angelman syndrome, both involving chromosome 15; if there is loss of the maternal contribution of chromosome 15, then the child will have the phenotype consistent with Angelman, and vice versa.
Epigenetics is the influence of factors beyond the base pairs that are relevant to the rate of expression of a particular gene. The most common epigenetic mechanism is when methyl groups are added to the promoter region of a gene; by employing methylation, a gene is able to be downregulated or upregulated.
“Patterns of Inheritance” in Creasy and Resnik’s Maternal-Fetal Medicine: Principles and Practice, 7th edition, Elsevier 2014.
US National Library of Medicine, Genetics Home Reference, “What are reduced penetrance and variable expressivity?” accessed March 2018. https://ghr.nlm.nih.gov/primer…
. Which of the following conditions is affected by variable expressivity?
A. Down syndrome
B. Sickle cell anemia
C. Marfans syndrome
D. LHON (Leber hereditary optic neuropathy)
E. Prader-willi syndrome
C
The correct answer to this question is Marfan’s. Individuals who carry a pathogenic variant in the FBN1 gene may exhibit a wide range of signs and symptoms, consistent with incomplete penetrance. The incorrect answers include Down syndrome which is most commonly inherited as a trisomy or potentially as a balanced translocation, sickle cell anemia which is an autosomal recessive condition associated with a single base pair change in the beta hemoglobin gene, LHON which is a condition with mitochondrial inheritance, and Prader-Willi syndrome which is an example of a condition brought about due to imprinting and/or uniparental disomy.
“Patterns of Inheritance” in Creasy and Resnik’s Maternal-Fetal Medicine: Principles and Practice, 7th edition, Elsevier 2014.
US National Library of Medicine, Genetics Home Reference, “What are reduced penetrance and variable expressivity?” accessed March 2018. https://ghr.nlm.nih.gov/primer…
What principle explains why family members with the same pathogenic variant int he NF1 gene may have different phenotypes?
A. Imprinting
B. Balanced translocation
C. X Linked inheritance
D. Variable expressivity
E. Epigenetics
D.
“The correct answer is variable expressivity. This is a situation where the same pathogenic variant may lead to many different signs or symptoms (referred to in genetics as phenotype) in members within that family. This leads to some real challenges for providers when counseling patients, because it is often not possible to predict the severity of disease in the antepartum period for these conditions. Marfan’s is a well-established example of this, where some family members may exhibit a severe phenotype with cardiac or aortic disease, and others may have a very mild phenotype with tall stature but no other findings.
A balanced translocation is a situation where there is breakage of a chromosome and regrouping, which usually does not cause symptoms in the proband but can cause pregnancy loss or other complications in the offspring if they inherit an imbalanced chromosome complement.
X-linked inheritance refers to conditions that are caused by a gene carried on the X chromosome, and demonstrate a sex bias in prevalence.
Imprinting refers to the epigenetic modification of inherited chromosomes such that each parent’s contribution to the zygote is not identical. In cases where there is uniparental disomy, meaning that the zygote inherits two copies of a chromosome from one parent and none from the other, depending on which parent is the source of the genetic material there will be a different phenotype because of imprinting. One classic example of this is Prader-Willi syndrome or Angelman syndrome, both involving chromosome 15; if there is loss of the maternal contribution of chromosome 15, then the child will have the phenotype consistent with Angelman, and vice versa.
Epigenetics is the influence of factors beyond the base pairs that are relevant to the rate of expression of a particular gene. The most common epigenetic mechanism is when methyl groups are added to the promoter region of a gene; by employing methylation, a gene is able to be downregulated or upregulated.”
“Patterns of Inheritance” in Creasy and Resnik’s Maternal-Fetal Medicine: Principles and Practice, 7th edition, Elsevier 2014.
US National Library of Medicine, Genetics Home Reference, “What are reduced penetrance and variable expressivity?” accessed March 2018. https://ghr.nlm.nih.gov/primer…
