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1.A 3-day-old infant is evaluated for hypotonia, upslanting palpebral fissures, and a flat facial profile, raising concern for Down syndrome. The mother is 26 years old and has a history of two prior early pregnancy losses. Chromosome analysis is sent on the infant, and the karyotype reveals a total of 46 chromosomes.
Which of the following mechanisms is most likely to be the cause of Down syndrome in this infant?
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A 14-year-old is evaluated for easy fatigability, exercise intolerance, and bilateral ptosis. Over the past year, the patient has developed progressive muscle weakness and hearing loss. Muscle biopsy is significant for ragged red fibers. The patient’s mother has a history of migraines, and the patient's maternal aunt has diabetes and severe muscle weakness, while her 5-year-old child is healthy.
Which of the following best explains the wide variability in disease severity?
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A couple with no personal or family history of skeletal dysplasia have two consecutive pregnancies with perinatal lethal autosomal dominant osteogenesis imperfecta type II. Which of the following concepts could explain this history?
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What is the risk of recurrence for congenital heart disease without a known genetic etiology?
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A pregnant patient, III-2, presents for genetic counseling due to a family history of a rare autosomal recessive disease with a general population incidence of 1/40,000. What is the likelihood for the pregnancy to be affected with the disease?
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A 5-year-old child is evaluated for hypogonadism, mild intellectual disability, and insatiable appetite (hyperphagia), raising concern for Prader Willi syndrome. Which of the following mechanisms is the most likely explanation for Prader Willi syndrome in this child?
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A 3-day-old is brought to the emergency department for poor feeding, vomiting, and lethargy. The newborn is hypotonic and tachypneic. Labs show an elevated plasma ammonia level of 800 μmol/L (normal less than 50). Serum electrolytes and blood gas show a normal anion gap and normal pH. Urinalysis is negative for ketones.
A defect in which of the following pathways is most likely responsible for this patient's presentation?
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An 8-month-old is evaluated for gradually increasing loss of neck control and inability to roll over for the past 2 months. The parents state that the patient has an exaggerated startle response to loud noises. The patient was able to roll over from front to back at 5 months of age but has not yet begun to sit or crawl. Neurological examination shows generalized hypotonia. Fundoscopy shows bright red macular spots bilaterally.
Which of the following is most likely deficient in this patient?
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The total chromosome count of 46 is the key, since classic trisomy 21 from meiotic nondisjunction would result in a total of 47 chromosomes. A karyotype showing 46 chromosomes combined with classic features of Down syndrome suggests a Robertsonian translocation, in which chromosome 21 is fused to another chromosome, producing an extra functional copy of chromosome 21 without increasing the total chromosome count. The young maternal age and history of recurrent pregnancy loss further support this mechanism, as these findings suggest a parent may carry a balanced translocation that can lead to pregnancy loss or translocation Down syndrome in offspring.
Varying levels of heteroplasmy in different tissues results in a wide spectrum of symptoms. Individuals with a pathogenic variant in the mitochondrial DNA may be symptomatic depending on the number of abnormal mitochondria (heteroplasmy) and whether tissues depending more on mitochondrial metabolism have more or fewer abnormal mitochondria (threshold effect).
Gonadal mosaicism occurs when a pathogenic variant is present in a subset of a parent's germ cells but not their somatic cells, so the parent is phenotypically unaffected. This explains how two unaffected parents can have offspring with an autosomal dominant condition and carries an approximate 7% recurrence risk in future pregnancies.
Congenital heart disease is often a threshold multifactorial condition, resulting from the interaction of multiple genetic and environmental factors. The recurrence risk of a multifactorial condition in offspring depends on family history, disease severity, and the number of affected relatives, typically ranging between 2% and 5% for first-degree relatives.
The risk of II-2 being a carrier is 2/3 because she is unaffected and has an affected sibling (II-5). 2/3 x 1/2 chance that II-2 passes the disease allele to III-2. III-2 has a 1/3 chance of being a carrier.
Next, determine carrier frequency in the general population.
q2=1/40,000.
q=1/200.
Carrier frequency in general population = 2pq = 2*1*1/200 = 1/100
Chance of affected offspring = 1/100 (chance that III-1 is a carrier) X 1/2 (chance they pass on variant allele) X 1/3 (chance III-2 is a carrier) X 1/2 (chance they pass on variant allele) =1/1200.
Prader Willi syndrome (PWS) is an imprinting disorder that is typically caused by de novo alterations of paternally expressed genes on chromosome 15q11-q13. The most common cause for PWS is a 15q deletion of the paternally inherited chromosome. Other causes include uniparental disomy or imprinting center mutations/deletions.
The combination of hyperammonemia with a normal anion gap, normal pH, and no ketones is the classic biochemical signature of a urea cycle disorder. When there is a deficiency in a urea cycle enzyme (such as OTC), ammonia accumulates in the blood and leads to symptoms including poor feeding, hypotonia, and lethargy/coma due to ammonia's neurotoxic effects. Organic acidemias can cause secondary hyperammonemia, but they are distinguished from urea cycle disorders by the presence of metabolic acidosis with increased anion gap and positive ketones in the urine.
This clinical scenario describes Tay-Sachs disease, a lysosomal storage disorder caused by deficiency of hexosaminidase A. Lysosomal enzymes normally degrade macromolecules and their deficiency leads to progressive substrate accumulation within lysosomes. The characteristic features in this example include an exaggerated startle response, loss of previously acquired milestones, hypotonia, and a cherry-red spot which reflects the accumulation of GM2 ganglioside.
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