Advanced Concepts

You are a genetic counselor in a retinal dystrophy clinic. A first year genetic counseling student is rotating through your clinic and will be taking a targeted family history for new patients. Of the following questions which is least important: age of onset of vision symptoms whether the vision symptons are progressive or static presence of any abnormal eye movements presence of characteristics that might sugges a syndromic cause e.g. hearing loss history of infertility

history of infertility

A family is referred to clinic for a family history of hearing loss. Other targeted family history questions besides hearing loss include all of the following except: cardiac rhythm disturbances craniofacial anomolies infertility renal disease visual impairment

infertility

A full term newborn is proportionately small: 5th percentile for head circumference, weight and length. This is likely due to innate (genetic/medical causes) because the the baby is proportionately small including the HC placental insufficiency because the baby is proportionally small including the HC environmental causes since no dysmorphic features are described growth hormone deficiency since present in the newborn period

innate (genetic/medical causes) because the the baby is proportionately small including the HC

Which features below best describe retinitis pigmentosa: progressive decreased vision, constricted visual fields and inability to see in dim light/night minimal decreased vision that remains static, constricted visual fields and inability to see in dim light/night congenital blindness, aniridia and foveal hypoplasia nystagmus, optic nerve hypoplasia and coloboma

progressive decreased vision, constricted visual fields and inability to see in dim light/night

Individuals with Smith-Magenis ofter are managed by speech therapists, occupational/physical therapists, psychology, ENT, neurology and what other specialty endocrinology gastroentomology hematology pulmonology sleep medicine

sleep medicine

All individuals with SMA have neuromuscular findings due to the degeneration of anterior horn cells in which of the following: cerebrum diencephalon muscle spinal cord

spinal cord

In myotonic dystrophy type 1, concern for congenital subtype inheritance is highest when the father has a diagnosis of classic myotonic dystrophy type 1 the mother has a diagnosis of classic myotonic dystrophy type 1 at least two affected second-degree relatives have been identified with congenital myotonic dystrophy a trinucleotide repeat length greater than 100 has been identified in the father through genetic testing

the mother has a diagnosis of classic myotonic dystrophy type 1

Which of these patients would most likely be able to benefit from Luxturna—the first FDA approved gene therapy? 5 year old with anirida, ataxia, and intellectual disability 67 year old with night blindness, tunnel vision, and an affected parent 24 year old with low central vision and homozygous ABAC4 pathogenic variants. 4 year old with severe vision loss with a RPE65 mutation

4 year old with severe vision loss with a RPE65 mutation

A person with severe hemophilia has a clotting factor 8 level at <1% 10% 25% 50%

<1%

Cockayne Syndrome and Hutchinson Gilford Progeria are conditions with similar features. Both syndromes involve signs of advanced agin, failure to thrive, short stature and early death. However, there are several key differences between these two conditions; what is the main features which distinguishes Cockayne Syndrome from Hutchinson Gilford Progeria? A. Cockayne syndrome is characterized by neurodegeneration and changes to the white matter of the brain B. Cockayne syndrome is distinguished by an earlier age of death C. Cockayne syndrome is distinguished by being a laminopathy D. Cockayne syndrome is distinguished by being an autosomal dominant pattern of inheritance

A. Cockayne syndrome is characterized by neurodegeneration and changes to the white matter of the brain

The phenotype of several overgrowth disorders includes a radiographic bone age that is Advanced Delayed Dependent on the height of the individual Indicative of a leg length discrepancy

Advanced

You are seeing a 6 year old girl who was adopted from China. The physical features identified include those listed below. Sotos syndrome is part of the differential diagnosis although one feature doesn't quite fit. Select the feature that would not be typical for an individual with Soto Syndrome. Advanced bone age Brachydactyly Developmental delay Dolichocephaly Hypertelorism

Advanced bone age

Disorders of sexual development (DSD) are often treated with hormone replacement therapy and sometimes, for those conditions that present with short stature, with growth hormone therapy. Which one of the following conditions might be treated with growth hormone therapy? 45, X Turner syndrome 45,X/46,XY Mixed Gonadal Dysgenesis 46,XX Testicular DSD All of the above

All of the above

Regional overgrowth syndromes, in general, can be associated with which one of the following? Skeletal asymmetry Somatic mutations in genes involved in growth regulation pathways Vascular and cutaneous malformations All of the above

All of the above

Which of the following inheritance patterns can be true for inherited epilepsy disorders? Autosomal dominant Autosomal recessive X-linked All of the above None of the above

All of the above

A 5-year-old Caucasian girl is being evaluated for learning disabilities. On examination she has one 0.6 cm by 1.0 cm flat light brown oval spot on her left thigh and two approximately 0.8 by 1.5 cm flat white oval spots on her trunk. On her forehead you note a raised, bumpy, slightly hyperpigmented triangular shaped lesion above her right eyebrow that is 1.2 cm by 1.5 cm at its largest dimensions. She also has about a dozen small (less than 3 mm) reddish color discrete small raised round bumps on her cheeks near her nose. Her parents note that all of these skin findings are birth marks that she has always had except for the red bumps which they describe as a newer 'rash' that has developed over the past year. What molecular mechanism is most likely responsible for her condition? Alteration of cellular functions via the mTOR protein complex Alteration of cellular functions via K5 and K14 proteins Alteration of cellular functions via LAMA-5 and LAMA-6 proteins Alteration of cellular functions via the canonical WNT signalling pathway

Alteration of cellular functions via the mTOR protein complex

You work in the cleft palate/lip clinic and are asked talk with a patient who just delivered baby with a cleft. What are you most likely to see when you read the chart? A black male with a non-syndromic cleft lip. An Asian female with a non-syndromic CL/P A Caucasian female with a syndromic cleft L/P All of the above are equally likely.

An Asian female with a non-syndromic CL/P

A 2-year old boy is hospitalized for evaluation of severe hyperthermia resulting in transient neurological changes. He is otherwise healthy. His family was at an outdoor July 4th party on a sunny 84 degree F day. He was playing in the sand box with a 12-year old niece for 90 minutes when he became more tired and unresponsive at which time an ambulance was called. There is no evidence that he ingested anything unusual and he had been well prior to the party. He was wearing sunscreen. They noted, however, that he has never liked summer like other kids and has always become quite irritable and fussy in the heat so they usually do not play outside with him for prolonged periods of time. He responded well to cooling therapy and fluids in the hospital and was back to his usual self with 8 hours. His pediatrician requested a genetics consult for evaluation prior to discharge given he had only two cone shaped teeth, no hair on his head, and very sparse eyebrows. His exam was otherwise normal. His mom noted that teeth and hair problems run on her side of the family as both her father and one uncle have missing teeth and never had much hair. Based on his history and physical and your differential diagnosis, it is most likely that he has: An alteration in the non-canonical WNT10A signaling pathway An alteration in the ectodyplasin-EDAR-EDARADD pathway An alteration in the P63 encoding gene An alteration in the NEMO gene An alteration in neural interleukin 6 temperature homeostasis pathway

An alteration in the ectodyplasin-EDAR-EDARADD pathway

You are seeing a 26-year-old male who was referred for genetic testing for hereditary polyneuropathy. Even without knowing the patients family history, what is the most likely inheritance pattern? Autosomal dominant Autosomal recessive Digenic X-linked

Autosomal dominant

You are seeing an adult male in clinic because of a history of hearing loss. In your history gathering you learn that he has been deaf since birth. He was born following an uneventful pregnancy and all prenatal labs were normal. His loss is bilateral and non-progressive. He has no other associated minor or major anomalies. This pattern is most consistent with what type of hearing loss: Autosomal recessive non-syndromic hearing loss Autosomal recessive syndromic hearing loss Autosomal dominant non-syndromic hearing loss Atutosomal dominant syndromic hearing loss

Autosomal recessive non-syndromic hearing loss

Sotos syndrome is a condition caused by gene changes in the NSD1 gene. Which of the following best describes the inheritance pattern and most appropriate testing strategy for Sotos syndrome? A. Sotos syndrome is primarily a de novo condition but is inherited in an autosomal dominant fashion and testing typically should begin with sequencing followed by deletion/duplication studies B. Sotos syndrome is primarily a de novo condition but is inherited in an autosomal dominant fashion and testing typically should begin with deletion/duplication studies followed by sequencing C. Sotos syndrome is inherited in an autosomal dominant fashion but can be de novo condition and testing typically should begin with deletion/duplication studies followed by sequencing A. Sotos syndrome is inherited in an autosomal dominant fashion but can be de novo condition and testing typically should begin with sequencing followed by deletion/duplication studies

B

Which one of the hollowing best describes the relationship between SMN1, SMN2, and Spinal Muscular Atrophy? A. Heterozygous deletions of SMN2 cause SMA while SMN1 copy number modifies the phenotype B. Homozygous deletions of SMN1 cause SMA while SMN2 copy number modifies the phenotype C. Homozygous deletions of SMN2 cause SMA while SMN1 copy number modifies the phenotype

B. Homozygous deletions of SMN1 cause SMA while SMN2 copy number modifies the phenotype

Which of the following conditions should not co-occur in an individual: Both b-thalassemia and hemoglobin SC disease. Both a-thalassemia and b-thalassemia. C Both a-thalassemia and hemoglobin SC disease. Both a-thalassemia and hemoglobin SS disease. A total of 5 copies of the a-globin gene sequence (aaa/aa).

Both b-thalassemia and hemoglobin SC disease.

Which nerve or network of nerves is most commonly affected by hereditary neuralgic amyotrophy? Brachial plexus Lumbosacral plexus Thoracodorsal nerve Phrenic nerve

Brachial plexus

A 2-year old boy presents to clinic due to developmental delays. He was born at 24 3/7 weeks gestation by crash c-section, required a prolonged resuscitation, and spent 3 months in the NICU for respiratory support and intensive nutrition. He had seizures during the first few days of life and these have persisted and been difficult to control with medications. He is able to roll, but unable to sit independently. He babbles, but does not use words. On exam, he has no syndromic features. He is unable to straighten his legs fully and has brisk reflexes bilaterally. Sustained clonus is present. Which test is likely to reveal the cause of his symptoms? Brain MRI EMG Metabolic screening labs Neuropsychiatric testing

Brain MRI

A 42-year-old has developed a disease that has left her unable to care for herself. She suffers from irregular, purposeless, and asymmetrical movements of limbs, which are worse if she is irritated. Her magnetic resonance imaging (MRI) shows atrophy of the putamen and caudate nucleus. Her father had similar symptoms. Which of the following is the most likely genetic abnormality? CAG, repeats on the short arm of chromosome 4 CGG, abnormal methylation CTG, unbalanced DMPK/ZNF9 expression levels GAA, impaired transcription

CAG, repeats on the short arm of chromosome 4

A 6 month old baby presents to clinic with craniosynostosis as well as some other dysmorphic features. You decide to order a panel to test for syndromic causes of the craniosynostosis. Which if the following does NOT need to be on the panel you select? CNTNAP2 FGFR2 FGFR3 POR TWIST

CNTNAP2

A tissue specimen is submitted to your laboratory with the indication that it is a cystic placenta. They request chromosomes and array. Chromosome analysis shows 46,XX and array shows complete homozygosity. You discuss the risks associated with: Complete maternal inheritance Complete paternal inheritance Recessively inherited disease No additional risk discussion

Complete paternal inheritance

You are seeing an individual with progressive vision impairment. They have loss of central vision, are color blind but preserved peripheral vision. Family hx shows multiple affected individuals including males, females and male to female transmission. This history is consistent with which one of the following category of disorders: Rod dystrophies Cone-rod dystrophies Macular dystrophies Cone dystrophies

Cone dystrophies

You are asked to see a newborn baby boy in the NICU who was born with multiple blisters over his extremities. He was seen by a pediatric dermatologist who felt he most likely had Epidermolysis Bullosa. The boy's father reportedly had a skin condition of some type but is estranged from the mother and no further information is available. Given this, the NICU care team requested a consultation with genetics to provide genetic counseling with the family and possible genetic testing to confirm the clinical diagnosis. No prenatal testing was done. The baby was born at term and reportedly has been healthy and vigorous. His arms and legs are wrapped in gauze bandages to minimize trauma and help with healing. His 18-year-old G1P1 mother is tearful and anxious. After introducing yourself, what is the next best thing you might say of the following options? Your son has a severe inherited skin condition called Epidermolysis Bullosa. I was called to come here to tell you more about that condition including the inheritance pattern, genetic testing options, recurrence risk, and the natural history of the disease There are many different types of conditions that can cause blisters on the skin of newborns. Your son will need a genetics evaluation and genetic testing to know what kind of blistering condition he has and I am here to help arrange that for you Epidermolysis Bullosa is a genetic condition. In your son's case it was most likely inherited from his father. Thus, there is a 50/50 chance that another child with the same partner will have the same condition which is called Epidermolysis Bullosa I understand that your baby has been diagnosed with Epidermolysis Bullosa which is a genetic condition. Do you have any questions for me about the genetics of Epidermolysis Bullosa? Congratulations on the birth of your son. I am sorry to hear that he is in the NICU with many blisters but I was glad to hear that he is otherwise doing well right now. I am working with his health care team and am here to talk with you about what might be causing his blisters, help address your questions, and discuss next steps.

Congratulations on the birth of your son. I am sorry to hear that he is in the NICU with many blisters but I was glad to hear that he is otherwise doing well right now. I am working with his health care team and am here to talk with you about what might be causing his blisters, help address your questions, and discuss next steps.

A 35-year-old female is currently pregnant with her 3rd daughter and is concerned about the risk of her child having Rett Syndrome. She has a 2-year-old daughter with a diagnosis of Typical Rett Syndrome (also confirmed via genetic testing). Interestingly, the testing laboratory reported that the pathogenic variant in her affected daughter was mosaic (present in less than 50% of sequence reads). Targeted testing for the pathogenic variant in mom and dad using a saliva specimen was negative. She has another daughter who is developmentally typical and negative for the pathogenic variant. What is the best counseling statement regarding recurrence risk in her 3rd child? Considering that her affected daughter's variant was reported as mosaic, it suggests the variant arose during development (after fertilization). Therefore, it is unlikely that either parent is a gonadal mosaic. The recurrence risk of Rett Syndrome for the 3rd child is low. In 99.5% of Typical Rett Syndrome cases, variants occur de novo in MECP2 on the paternal allele. Since her husband was negative for the targeted variant, there is no risk that the 3rd child will have Rett Syndrome. In 99.5% of Typical Rett Syndrome cases, variants occur de novo in MECP2. However, variants may be inherited from unaffected mothers due to skewed X inactivation or gonadal mosaicism. Since gonadal tissue was not tested, it is unclear whether either parent is a gonadal mosaic. The recurrence risk for their 3rd child is unclear, and could be as high as 50%. There is a 50% chance their 3rd child will have the same pathogenic variant identified in her affected daughter.

Considering that her affected daughter's variant was reported as mosaic, it suggests the variant arose during development (after fertilization). Therefore, it is unlikely that either parent is a gonadal mosaic. The recurrence risk of Rett Syndrome for the 3rd child is low.

Which of the following is NOT true about autism spectrum disorder (ASD): Copy number variants are not important in sporadic or familial ASD Genetic causes of ASD are heterogeneous Many cases of ASD are multifactorial and/or polygenic Single gene defects are recognized for some syndromic forms of ASD but not idiopathic forms

Copy number variants are not important in sporadic or familial ASD

Of the following disorders or group of disorders which of the following has a dietary treatment option that can result in a reduction of seizures and improved development? MECP2 mutation disorders Creatine biosynthesis disorders PTEN mutation disorders 15q11 duplication disorders

Creatine biosynthesis disorders

A 13-year-old girl presents with recurring episodes of heavy epistaxis. On examination reddish spots are found on the lips, chin and neck. During the family history the patient's mother reports similar features in herself and her own father. Which of the following would not be a suitable screening tool for your patient? Brain MRI Chest CT Creatine kinase Hematocrit determination

Creatine kinase

You are evaluating a 4-year old boy due to concerns about delayed motor skills. He walked at 24 months and mother has always felt he is weak compared to his peers. First words emerged at 1 year of life and he now speaks in full sentences. He is social and doing well academically in preschool. On exam, he has no syndromic facial features. Reflexes are diminished in the lower extremities and calf muscles are enlarged. When he attempts to stand from a squatting position, he climbs up using this thighs (positive Gower's sign). Which of the following tests is most likely to confirm your suspicions Creatine kinase Echocardiogram EEG Microarray Plasma aminio acids

Creatine kinase

Non-invasive prenatal testing identified a deletion on chromosome 15 in the Prader-Willi/Angelman critical region. WHich of the following tests would NOT be informative in determining the expected phenotype of the baby? Deletion testing in the parents Methylation studies of amniotic fluid Short Tandem repeat of the parent-child trio Exome sequencing of the parent-child trio

Deletion testing in the parents

A 5 year old healthy boy with no medical or developmental problems is missing the distal third of his left arm and hand. There is a ring like skin indention around his arm. His right arm and hand are completely normal as are his legs, feet, and remainder of exam. He was born weighing 7 lbs 8 oz at 36 weeks to a G2P1 45-year old single Caucasian mother by emergency Cesarean section due to fetal distress. She had no prenatal care and amniotic fluid was meconium stained. Which term best describes the observed physical finding on his left arm? Disruption Deformation Dysplasia Malformation Minor anomaly

Disruption

A 2-year-old African American boy is referred to Pediatric Genetics clinic for noticeably short upper arms and legs and a large head size. He has reached normal developmental milestones for his age but his height is below the 5th centile and his head circumference is at the 90th centile. His father reportedly also has short stature but is otherwise healthy. Which of the following terms best describes the observed physical findings of this boy's limbs? Dysplasia Malformation Disruption Deformation Minor anomaly

Dysplasia

Pathogenic variants in which gene(s) is causal for the diagnosis of the condition in the question above? EZH2 GPC4 NFIX NSD1 All of the above None of the above

EZH2

You are the genetic counselor in a recently organized vascular anomalies clinic. You are scheduled to see an 8 week old infant, Martha, who presents with a vascular anomaly on her cheek. Other history includes: the anomaly was not present at birth, but appeared at about 2 weeks of age it started as a reddish spot but has grown rapidly in size (volume not radially) has coarctation of the disorder. The next best diagnostic step is: Imaging to look for similar findings in the brain Surgical biopsy to stain for Glut 1 Genetic testing for variants in known genes associated with cell proliferation Exclude PHACE syndrome

Exclude PHACE syndrome

In the above scenario, which single-gene test would be most appropriate to offer Tanya's parents? FGFR1 FGFR2 FGFR3 TWIST1

FGFR2

You are seeing a patient in teh NICU who has neonatal diabetes mellitus. NDM can be associated with uniparental disomy for chromosome 6. Which of the following testing options would be the least appropriate to order if you want to look for UPD(6)? FISH Methylation analysis SNP microarray STR marker analysis

FISH

A 5-year old boy presents to his pediatrician for severe developmental delay. On exam he is noted to have hypertelorism, large protruding ears, a large jaw, and a long thin face. Suspicious of what the diagnosis may be, the pediatrician orders a PCR and DNA sequencing. The results reveal an expansion of 250 repeats of CGG. What is the diagnosis of the boy? Fragile X Syndrome Huntington's Disease Freidrich ataxia Myotonic dystrophy type 1 Spinal and bulbar muscular dystrophy

Fragile X Syndrome

An 8 year old boy is seen in the genetics clinic with developmental delays, intellectual disability, and Autism-like features. He is described by the geneticist as having a long face, prominent forehead, and large ears with joint hyperextensibility. As you prepare this case, which genetic disorder is at the top of your differential? Angelman Syndrome Fragile X Syndrome Marfan Syndrome Prader-Willi Syndrome

Fragile X Syndrome

Which of the following Trinucleotide Repeat Disorders is least likely to demonstrate anticipation in successive generations? Fragile X Syndrome Friedreich Ataxia Huntington Disease Myotonic Dystrophy

Friedreich Ataxia

You are leaving your board exam as a newly certified genetic counselor. While waiting for the bus to take you home, you overhear a man talking on the phone about his niece who has congenital hearing loss but is otherwise healthy. The man says his niece had genetic testing that found a cause for her hearing loss, but he couldn't remember the name of the gene involved. Your professional ethics won't allow you to shout out the answer, but the most likely gene is: GJB2 GJB6 MYO7A USH2A

GJB2

Patients with hemoglobin SC disease: Frequently die in utero from complications of the hemoglobinopathy. Never experience sickle cell crises. Could not have a child with sickle cell disease. Exhibit an excess of embryonic z-chains in their adult red blood cells. Have a different mutation in each copy of their b-globin gene,though both are in the same codon.

Have a different mutation in each copy of their b-globin gene,though both are in the same codon.

A sixteen year old boy has a history since birth of blister formation on his extremities any time there is pressure, rubbing, or tugging on the skin. Because of this he sometimes has so many sores on his feet that he requires pain medication and a wheel chair. He notes that keeping his feet cool by wearing sandals or going barefoot and that controlling his stress decreases the amount of blisters on his feet. The most reasonable explanation for his symptoms is: He has localized epidermolysis bullosa simplex with a mutation in a gene encoding keratin 5 or 14 where gene expression may be modulated by temperature and/or stress He has dystrophic epidermolysis bullosa due to alterations in a gene encoding a type IV or VII collagen polypeptide chain where triple helix formation is impacted by cellular stress He has dystrophic epidermolysis bullosa due to a mutation in a gene encoding keratin 5 or 14 where gene expression may be modulated by temperature and/or stress He has localized epidermolysis bullosa simplex due to alterations in type 4 collagen genes where gene expression may be modulated by temperature and/or stress

He has localized epidermolysis bullosa simplex with a mutation in a gene encoding keratin 5 or 14 where gene expression may be modulated by temperature and/or stress

Overgrowth syndromes are often caused by variantss that interfere with the process of maintaining the epigenome. Sotos Syndrome is primarily caused by a variant that disrupts which epigenetic mechanism? CpG methylation Histone acetylation Histone methylation Phosphorylation

Histone methylation

Which of the following statements regarding imprinting is false? Establishment of "imprint" occurs in gametogenesis. Imprinted genes are preferentially involved in regulation of growth and behavior. Imprinted genes tend to be scattered across the genome. Imprinting utilizes epigenetic modifications, such as DNA methylation, to control gene expression.

Imprinted genes tend to be scattered across the genome.

Which of the following is NOT a classic example of epigenetics? Creation of iPSCs Genomic imprinting Independent assortment of alleles X-inactivation

Independent assortment of alleles

Tanya is a 1 month old girl who presents to Medical Genetics clinic with her parents for evaluation due to bicoronal craniosynostosis, conductive hearing loss, proprosis, midface hypoplasia, and hypertelorism. On exam, her hands and feet are normal. Based on the suspected diagnosis, how would you counsel her parents about her cognitive prognosis? Individuals with this condition typically have normal intelligence Individuals with this condition may have mild learning difficulties Individuals with this condition may have moderate to severe intellectual disability Individuals with this condition often have regression of cognitive ability in childhood

Individuals with this condition typically have normal intelligence

Which of the following features is known to be associated with Duchenne Muscular Dystrophy but NOT with Becker Muscular Dystrophy? Cardiomyopathy Intellectual disability Hypertrophic calves Reduced lifespan Wheelchair use

Intellectual disability

Your patient is a 4-year-old male named Ibram who comes in with his mother, Ilhan, following a diagnosis of PTEN Hamartoma Tumor Syndrome (PHTS). Ilhan had a high-risk pregnancy due to advanced maternal age of 36 years and a prenatal diagnosis of macrocephaly for Ibram at her 20-week ultrasound. Ilhan and her husband are now 40 years old and live very healthy and active lives and want the same for their son. If the genetic status of the parents is unknown but they have no clinical signs of PHTS, what is the likelihood that one of the parents also has PHTS? It is unlikely either parent is heterozygous for a PTEN pathogenic variant because of the nearly 100% penetrance of PHTS by the 30s. It is unlikely either parent is heterozygous for a PTEN pathogenic variant because of the high de novo rate of over 80%. PHTS is inherited in an autosomal dominant manner, therefore, one of Ibram's parents must be heterozygous for a PTEN pathogenic variant. PHTS is inherited in an autosomal dominant manner, therefore if Ibram's parents do not show symptoms of PHTS, germline mosaicism is likely present.

It is unlikely either parent is heterozygous for a PTEN pathogenic variant because of the nearly 100% penetrance of PHTS by the 30s.

The most common site of bleeding in hemophilia is: Joint Intracranial Mucosal Gastro-intestinal

Joint

Which of the following best describes the "classical triad" that characterizes Klippel Trenaunay Syndrome? Mucocutaneous telangiectasias, pulmonary AVMS, epistaxis Limb overgrowth, cutaneous capillary malformation, low flow vascular malformations Limb overgrowth, 2-3 toe syndactyly, macrocephaly Lipomatous overgrowth, scoliosis, venous malformations

Limb overgrowth, cutaneous capillary malformation, low flow vascular malformations

You work are seeing a patient in the General Genetics Clinic. He is 41 years old and presents with worsening psychomotor functions i.e. what started out 4 years ago with self-described occasional hand and arm tremors have become jerky movements throughout the day. You notice during the session he seems to sit on his hands, cross and uncross his legs and grimace. He has an older sister (age 50) who is healthy. A 39 year old brother who has recently started to fall frequently and has been complaining of memory lapses and mood swings. He reports his mother died at age 50 with similar symptoms; cause of death was said to be due to choking. Lastly, his maternal grandfather committed suicide when he lost his job as a carpenter because of his inability to perform the physical aspects of his job. Of the following, which statement is false with regard to the group of disorders in the differential? Increasing severity and/or decreasing age of onset may occur in successive generations within a family Most disorders in this grouping follow an autosomal dominant pattern of inheritance Loss of function is the primary mechanism of disease. Late age of onset is common with few exceptions

Loss of function is the primary mechanism of disease.

A female patient of 18 months old shows symptoms of regression of acquired skills after period of normal development, loss of hand skills and language; stereotypic hand movements, microcephaly and seizures, which makes you really think she might have Rett Syndrome. Which of the following genetic testing do you think would be mostly appropriate for this patient? CMA / Chromosomal microarray Comprehensive Epilepsy Panel Karyotype / Chromosome analysis MECP2 single gene test Whole exome sequencing

MECP2 single gene test

You are seeing a 8 year old girl who is described as short for her age. Notes indicate she is proportionate, doing well academically, her parents are of average stature and the family history is negative for other instances of short stature. Initial workup would include all of the following except: bone age dysmorphology exam labs including insulin-like growth factor 1, CBC and a metabolic panel karyotype and/or microarray Magnetic resonance imaging of the brain

Magnetic resonance imaging of the brain

During the appointment, for the patient in the previous question you learn that the patient was raised by his father as his mother abandoned him at a young age. As such, he only has information about his paternal family history. None of his paternal relatives has polyneuropathy. You order appropriate genetic testing, and your patient is found to have a PMP22 duplication. All of the following are correct counseling points except: Males with this genetic variant typically have more severe phenotypes than females with the same genetic variant There is a low possibility that this mutation was de novo in your patient This variant is typically associated with demyelination of peripheral nerves Your patient has a 50% chance of having an affected child

Males with this genetic variant typically have more severe phenotypes than females with the same genetic variant

How is DNA methylation of a specific allele most likely going to alter that allele's expression? Extremely increased expression Measurably decreased expression Moderately increased expression No change in expression No change in expression

Measurably decreased expression

A 4-year old boy presents to clinic due to developmental regression. He was born full term without issue, had a normal newborn screen, and had normal development for the first 3 years of life. However, over the past 12 months, parents have noticed that he has lost several skills. He had been speaking clearly in 3-word sentences, but now speaks sparingly with single words and mainly grunts for communication. He had been riding a tricycle, but now is very clumsy with a wide-based gait. He had been toilet trained, but is now back in diapers. Which test is most likely to help you reach a diagnosis? Creatine kinase EEG FraX testing Metabolic screening labs Neuropsyciatric assessment

Metabolic screening labs

Ben, a 14 year old male, presents to clinic with short stature, small testes, and gynecomastia. He was otherwise a typical healthy male until he hit puberty. A previous provider ordered chromosome analysis, which established a 46, XX karyotype in Ben. The provider, unsure of how to proceed, referred Ben to medical genetics. What is the next best follow up molecular genetic test to order? Metaphase FISH with SRY probe Nothing as you know what you need to help this patient SOX3 and SOX9 sequencing and del/dup SRY sequencing

Metaphase FISH with SRY probe

Which of the following is statements about DNA methylation is false? Cytosines on both strands are usually methylated. It occurs on cytosines adjacent to guanines. It is carried out by DNA methyltransferase Methylation is always permanent and cannot be reversed Methylation modifications are present in mammalian gametes removed in embryogenesis and re-established post-implantation.

Methylation is always permanent and cannot be reversed

You are evaluating a 6-year old girl in clinic for developmental delay. She was born full term without issue and had a normal newborn screen. She walked at 36 months and spoke first words at 24 months. She continues to make slow progress in development, without any loss of skills. She is very socially engaged and has no other health issues. On exam, you notice several syndromic facial features. Reflexes are normal. Remaining exam in unremarkable. Creatine kinase Echocardigram EEG Microarray and FraX testing Nerve conduction study

Microarray and FraX testing

A healthy 4 year old caucasion boy with normal cognitive and physical development has notable clinodactyly of his left 5th finger found on a pre-K physical examination. Which term best describes the observed physical finding on his left hand? Deformation Disruption Dysplasia Malformation Minor anomaly

Minor anomaly

Charcot-Marie-Tooth is a hereditary motor and sensory neuropathy. Which nerves typically become first affected with this condition? Sensory nerves of the arms and hands Motor nerves of the arms and hands Sensory nerves of the legs and feet Motor nerves of the legs and feet

Motor nerves of the legs and feet

The most common site of bleeding for those with von Willebrand disease is: Joint Intracranial Mucosal Gastro-intestinal

Mucosal

Bardet Biedl syndrome exhibits all of the following except: Locus heterogeneity Multiple patterns of inheritance Pleiotropy Phenotypic variability

Multiple patterns of inheritance

Johnathan is a 2-year-old boy who did not start walking until he was 18 months old. He now walks with a wide set gait, falls down often, and displays Gower's sign when moving from sitting to standing. Johnathan's PCP ordered a biochemical metabolic panel which revealed a highly elevated creatine kinase (CK) level. Johnathan is now being referred to your clinic for further evaluation. Which of the following tests would be most appropriate for establishing a diagnosis for Johnathan? Exome sequencing MIcroarray Muscle biopsy with western blot and IHC staining NGS sequencing with del/dup analysis Triplet PCR analysis

NGS sequencing with del/dup analysis

Amniotic fluid specimen was submitted to your laboratory along with parental blood specimens for SNP array trio analysis. The reason for referral is intrauterine growth retardation. The data from the array shows biparental inheritance of all chromosomes except chromosome 9, which shows uniparental heterodisomy. Your array interpretation recommends further evaluation for: Dominantly inherited disease on chromosome 9 Recessively inherited disease on chromosome 9 Methylation status of chromosome 9 None of the above

None of the above

Martin is a 3 year old healthy Caucasian child with a recent diagnosis of neurofibromatosis type I. The diagnosis in Martin was based on cutaneous findings and his father's confirmed molecular diagnosis of neurofibromatosis type I. Mom is very concerned about the possibility of intellectual disability, developmental delays, and behavior problems in her son. She notes the father did not graduate from high school, had long standing and significant social and behavior problems, and was in special classes while in school. Martin's father died about 6 months ago due to complications during surgery for resection of an NF 1 related spinal tumor. The boy's gross motor and cognitive developmental assessments are within the normal range for his age. He is in preschool and reportedly doing well. His hearing and vision are normal for his age. He is a cooperative, articulate, and well-behaved boy. His general neurological examination in genetics clinic is normal. The best thing to do at this time is: Although he is currently doing well he must be seen early and often by clinical psychology for comprehensive formal neuropsychological testing and behavioral testing Refer to pediatric neurosurgery clinic to assess for cranial and spinal lesions Note that most people with NF1 will have IQs within the normal range and reassure her that currently Martin is doing very well. However, ongoing monitoring for learning problems and developmental progress will be important since they are known to be associated feature of his diagnosis. Refer to a new preschool for children who have special needs and behavior problems so that the teachers can follow him closely and intervene quickly when issues arise.

Note that most people with NF1 will have IQs within the normal range and reassure her that currently Martin is doing very well. However, ongoing monitoring for learning problems and developmental progress will be important since they are known to be associated feature of his diagnosis.

A large cardiac rhabdomyoma is identified on ultrasound testing of a pregnancy at 20-weeks' gestation. The prenatal history, family history, and the remainder of the fetal exam were normal. Of the following which is the next best step: Offer prenatal genetic testing for TSC1 and TSC2 mutations Offer prenatal karyotype Inform parents that cardiac rhabdomyomas often grow in size and result in cardiac input/output disequalibrium. Offer parental mutation testing for TSC 1 and TSC 2 mutations

Offer prenatal genetic testing for TSC1 and TSC2 mutations

You are seeing a couple because they have had a previous child with a diagnosis of autism spectrum disorder (ASD). The child, now 4 years old, had a thorough evaluation looking for cause and none was identified. They are asking about the likelihood of recurrence if they were to have another child. Which of the following answers is the most accurate: Autism is not highly genetic and the recurrence risk is near 0 % The recurrence risk for another child to be affected is 4% to 7 % One study reported that ~19% of siblings of affected children also developed autism Without knowing a cause for your child's autism, a recurrence risk cannot be provided

One study reported that ~19% of siblings of affected children also developed autism

Proteus syndrome (PS) is a condition for which all of the following are true, except: All affected individuals are mosaic for PS PS is the most common overgrowth condition PS occurs as a result of a de novo mutation There is no evidence to support that vertical transmission of PS occurs

PS is the most common overgrowth condition

Examination of a 22-year-old female patient demonstrates that she has one very wide, thick, middle finger on her right hand. Reportedly, it has been notably wider than other fingers since birth. In comparison to her other fingers, including the middle finger of her left hand, it appears normal in length and that is supported by measurement of the finger compared to palm size. The term that would best describe this finding is: Brachydactyly Camptodactyly Pachydactyly Syndactyly

Pachydactyly

Which of the following statements is NOT TRUE about patient's diagnosis in the above scenario? : People with this condition are characterized by premature aging. People with this condition experience the same course of the diagnosis regardless of their subtype People with this condition have a shortened life span People with this condition have an increased risk of cancer.

People with this condition have an increased risk of cancer.

A child who is diagnosed with Usher Syndrome Type II is likely to be monitored by all of the following specialists EXCEPT: Audiology for hearing issues Ophthalmology for vision issues Speech and language pathology for communication issues Physical Therapy for balance issues

Physical Therapy for balance issues

Features of Hutchinson-Gilford Progeria Syndrome are associated with the accumulation of which molecule? A-Type lamin B-Type lamin Prelamin A Progerin

Progerin

An 8 year old boy presents to the genetics clinic where you work as a GC for an evaluation due to recently diagnosed retinal dystrophy. In your discussion with the family, you find out that this child was born with post-axial polydactyly and has had some learning challenges in school. On physical exam, he is noted to have central obesity. You are suspicious that this boy may have Bardet Biedl syndrome (BBS). Which of the following additional features is a major feature of BBS? Craniofacial anomalies Hydrocephalus Liver cysts Renal dysfunction

Renal dysfunction

A 2-year-old male presents in clinic with severe intellectual disability, weak muscle tone, feeding difficulties, absent speech, and is struggling to sit and walk. To date, there is no history of seizures. His mother comments that he has had numerous respiratory infections and feels his development has stagnated over the last few months. Previous genetic work up included Sanger sequencing of MECP2. However, no variant candidates were identified. Considering this information, which statement(s) is/are most likely applicable to this scenario? Atypical Rett Syndrome is also caused by variants in FOXG1 and CDKL5. Her son may have a potentially pathogenic variant in a different gene that may explain the observed clinical features. Rett syndrome is extremely rare in males. Males with pathogenic variants in MECP2 rarely survive past age one. Additionally, the patient may have a duplication encompassing MECP2, which Sanger sequencing would not identify. Methylation sequencing of the MECP2 locus is the next step to determine whether an epigenetic change is responsible for the patient's phenotype. There are numerous explanations for this patient's phenotype. Proceed directly to whole exome sequencing.

Rett syndrome is extremely rare in males. Males with pathogenic variants in MECP2 rarely survive past age one. Additionally, the patient may have a duplication encompassing MECP2, which Sanger sequencing would not identify.

Abhay is a 3-year-old with macrocephaly. He was referred to genetics after his mother reported "spots" on her son's penis and Abhay's primary care physician was suspicious of a genetic cause. Based on these symptoms, you are suspicious of Neurofibromatosis Type 1 or PTEN Hamartoma Tumor Syndrome. Which of the following additional findings would help in establishing a diagnosis of PTEN Hamartoma Tumor Syndrome? Endocrine tumors such as pancreatic neuroendocrine tumors Learning disabilities such as autism spectrum disorder Skin findings such as acral keratoses Skin findings such as café-au-lait spots

Skin findings such as acral keratoses

Your patient has a mild intellectual disability, tall stature and small testes without other major health problems. A diagnosis is confirmed after a karyotype test. What is the best counseling statement you can provide to your patient regarding family planning? All individuals with this condition have infertility and cannot have biological children. Many individuals with this condition do not have infertility and can have biological children. Some individuals with this condition are fertile and can have biological children through IVF or infertility treatment. Some individuals with this condition are fertile but cannot have biological children due to hormone therapy.

Some individuals with this condition are fertile and can have biological children through IVF or infertility treatment.

A two year old male presents in clinic with difficulty feeding and delayed milestones. He hasn't walked yet and when crawling, he tires quickly. While sitting up he has poor head control. The doctor reports a tongue tremor and a large diaphragm. What are you suspecting? Spinal Muscular Atrophy Tay Sach's Disease Usher Syndrome William's Syndrome

Spinal Muscular Atrophy

You are asked to see a 2 year old boy with a large geographic facial capillary malformation localized to the ophthalmic (V1) distribution of the trigeminal nerve. A brain MRI was performed as a result of profound seizure activity, revealing ipsilateral leptomeningeal angiomatosis. What is the most likely diagnosis for this constellation of findings? Sturge Weber Syndrome Parkes Weber Syndrome Tuberous Sclerosis Banyan-Riley-Ruvalcaba Syndrome

Sturge Weber Syndrome

A referral comes in for a suspected FGFR2 mutation. Upon physical exam, the presence of what clinical feature would lead you to be most suspicious of Apert Syndrome? Intellectual delay Jaw differences Midface h ypoplasia Syndactyly

Syndactyly

A family is meeting with you after their child's diagnosis of Saethre-Chotzen syndrome. This autosomal dominant condition is characterized by craniosynostosis, facial asymmetry, strabismus, ptosis, small ears with a prominent crus, and mild limb deformities. The parents have not had genetic testing and did not have craniosynostosis. They want an explanation for how this may have happened. Which of the following provides the most likely scenario to explain this situation? The child's mutation is de novo The child's mutation is de novo or inherited but the parents de novo or inherited (if the latter it is because the parents do not show features due to incomplete penetrance) The parents are both carriers The parents do not show features due to incomplete penetrance

The child's mutation is de novo or inherited but the parents de novo or inherited (if the latter it is because the parents do not show features due to incomplete penetrance)

Severe beta-thalassemia may not become clinically apparent until a child is several months old because: Elevated hemoglobin A2 compensates for the missing beta-globin genes. The oxygen needs of a newborn are minimal. Overexpression of zeta- globin compensates for the missing beta-chain. The gamma to beta globin switch is not complete until several months after birth. The alpha-globin genes don't turn on until several months after birth.

The gamma to beta globin switch is not complete until several months after birth.

A 23-year old college educated healthy Latino man is seen in genetics clinic for preconception counseling with his wife, who is African American. A physical exam identifies over a dozen CALM (>1.5 cm) and 6 cutaneous lumps on his body. Medical records review confirmed the presence of Lisch nodules and very mild learning disabilities. Neither he nor his wife have any known extended family history of a genetic or inherited condition. His wife's medical hx is unremarkable. They are concerned about the risk of having a child with his condition. The most reasonable information to give them is: Given his medical condition and their medical history, their risk for having a child with birth defects is higher than the 3% risk seen in the general population. There is a 50/50 chance that any offspring will inherit the same condition that he has and would likely have very similar symptoms and findings. There is a 50/50 chance that any offspring will inherit the same condition that he has but could have more mild or more severe findings. There is 50/50 chance that an offspring could inherit the same condition that he has and prenatal genetic testing will provide much more accurate prediction of possible severity of that condition in a fetus

There is a 50/50 chance that any offspring will inherit the same condition that he has but could have more mild or more severe findings.

Which of the following statements about DNA methylation in the pediatric population is FALSE? Pediatric changes in DNAm is primarily associated with developmental and immune functions It is important to adjust for age in disease-based DNAm studies Animal studies suggest that a in utero stress alters the expression of neurodevelopmental genes There is a unique pediatric DNAm profile associated with autism

There is a unique pediatric DNAm profile associated with autism

You received a referral for a 2 month-old female with profound hearing loss present since birth. She has no family history of hearing loss, and her medical history and review of systems are non-contributory. She is of northern European and Spanish descent. The referring provider ordered genetic testing for the patient and is asking you to discuss the results with the family. Upon reviewing the lab report, you notice that the provider had only ordered sequencing and del/dup analysis of GJB2. The report shows one pathogenic mutation: GJB2 c.35delG. How will you interpret the results for the family? This is the cause of their daughter's hearing loss. This GJB2 variant is inherited in an autosomal dominant manner, so it was a de novo variant. The parent's recurrence risk is low, but the daughter has a 50% chance of having affected children This could be the cause of their daughter's hearing loss. This GJB2 variant is inherited in an autosomal dominant manner, but it has incomplete penetrance. One of the parents is likely an unaffected carrier, so both the parent's and the daughter's recurrence risk could be up to 50%. This is not the cause of their daughter's hearing loss. This GJB2 variant is inherited in an autosomal recessive manner, so she would need to have a second GJB2 mutation to be affected. The parent's recurrence risk is unknown. The daughter is a carrier, and her recurrence risk depends on the carrier status of her future partner. This could be the cause of their daughter's hearing loss. This GJB2 variant is inherited in an autosomal recessive manner, and there is a small chance she has a deletion upstream of GJB2 that includes part of GJB6 that this genetic test would not have picked up. Additional testing would be needed to clarify recurrence risks for the parents. The daughter's recurrence risk depends on the carrier status of her future partner.

This could be the cause of their daughter's hearing loss. This GJB2 variant is inherited in an autosomal recessive manner, and there is a small chance she has a deletion upstream of GJB2 that includes part of GJB6 that this genetic test would not have picked up. Additional testing would be needed to clarify recurrence risks for the parents. The daughter's recurrence risk depends on the carrier status of her future partner.

A couple is referred to your clinic after their newborn died a few years ago. They bring genetic testing from a different genetics clinic showing that their newborn had two mutations in the PORgene indicating the newborn was diagnosed with Antley-Bixler syndrome. The parents are adamant that they do not want to do carrier screening for themselves but want to know their risks for their next pregnancy. What is the estimated recurrence risk with the information you have? ~1 % Up to 25% Up to 50% ~100%

Up to 25%

You are a genetic counselor in a general genetics clinic and are preparing to see an individual who is deaf-blind. Of the following diagnosis which is the most likely: Alstrom syndrome Heimler Syndrome Usher Type I Usher Type III

Usher Type I

You are a genetic counselor in general genetics clinic and are scheduled to see a couple whose newborn daughter has a cleft lip/palate. You notice mom has lower lip pits. What is a likely diagnosis in this family. Stickler syndrome Treacher Collins syndrome Van der Woude syndrome Velocardiofacial syndrome

Van der Woude syndrome

You are a genetic counselor in a inherited ophthalmologic disorders clinic. You are scheduled to see the parents of a child with aniridia. Record review indicates the child has Wilm's tumor, aniridia, genitourinary malformations and developmental delay. Which of the following is the likely diagnosis: Alagille syndrome Peters Plus Syndrome Stargardts Syndrome WAGR syndrome

WAGR syndrome

A 4-year-old patient presents to clinic with tall stature, mild intellectual disability, low pitched voice, and camptodactyly. The family history and pregnancy history are unremarkable. Upon assessment from a geneticist it is identified that this patient also as a broad forehead, a prominent wide philtrum and a deep horizontal chin groove. The family is interested in genetic testing. From the list of differentials which is the most likely diagnosis? Beckwith-Wiedemann Syndrome Simpson-Golabi-Behmel Syndrome Soto Syndrome Weaver Syndrome

Weaver Syndrome

You are seeing a 3 year old male with microcephaly, bilateral hearing loss and dental caries for a genetic consult. You see that the patient's past few growth measurements have been falling off the growth chart below the 5th percentile while his weight for length seems to be proportional. Parents also describe dermal photosensitivity and persistently cold hands and feet. The first thing you recognize when you see the patient are his facial features of a pointy nose and sunken eyes. A diagnosis is confirmed after genetic testing. Which of the following conditions is involved with the similar genetic mechanism as your patient's condition? Bloom Syndrome Hutchinson-Gilford Progeria Syndrome Werner Syndrome Xeroderma Pigmentosum

Xeroderma Pigmentosum

A 24-year old woman asks her primary care provider about her family history and what it means for her future reproductive planning. She is not currently pregnant and is not currently dating anyone but she hopes to get married in the future and have a family. Her family history is notable for: an older sister with a psychiatric condition that is well-controlled with medication a paternal female cousin with a neural tube defect a maternal male cousin with a history of developmental delays She has a personal history of: irregular menses short stature (4' 11") It is most appropriate that her PCP should first suggest that she should undergo: an infertility evaluation to determine if pregnancy is even possible a gynecology examination to determine if her short stature is sufficient to cause respiratory distress early in the pregnancy a neuropsychiatric evaluation to evaluate for a mental health condition and whether she is ready to parent a genetic evaluation to determine if she has a particular syndrome that may impact pregnancy or could be transmitted to an offspring

a genetic evaluation to determine if she has a particular syndrome that may impact pregnancy or could be transmitted to an offspring

A key difference between myotonic dystrophy type 1 and type 2 is different chromosomes are involved in each dx involvement of anticipation in type 1 there is distal muscle involvement in type 1 and proximal muscle involved in type 2 all of the above

all of the above

You are seeing patient in the Craniofacial clinic and are explaining the importance of a diagnosis for to a family. Which of the following surgical implications of a diagnosis are important for a craniofacial disorder: management of airway during surgery necessity of pre-operative cardiac assessment post-surgical risk for velopharyngeal insufficiency all of the above none of the above

all of the above