Prenatal/Newborn Screen and Inborn Errors of Metabolism Flashcards by Josh Klonoski

What is an anterior neural tube defect described as?
A.Deformation
B.Disruption
C.Dysplasia
D.Malformation
E.None of the above

D.Malformation

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Oligohydramnios causing multiple symmetrical joint contracture should be described as?
A.Deformation
B.Disruption
C.Dysplasia
D.Malformation
E.None of the above

A.Deformation

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Amniotic bands with constriction around hand and amputation of the thumb should be described as?
A.Deformation
B.Disruption
C.Dysplasia
D.Malformation
E.None of the above

B.Disruption

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What is the clinical sensitivity of the first-trimester screen for trisomy 21?
A.50%
B.65%
C.80%
D.99%
E.None of the above

C.80%

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What is the clinical specificity of the first-trimester screen for trisomy 21?
A.42%
B.65%
C.80%
D.92%
E.None of the above

D.92%

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What is the clinical sensitivity of the second-trimester screen for trisomy 21?
A.48%
B.74%
C.81%
D.93%
E.None of the above

C.81%

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What is the clinical specificity of the second-trimester screen for trisomy 21?
A.50%
B.75%
C.85%
D.95%
E.None of the above

D.95%

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Anencephaly - what would most likely NOT be the result of the second-trimester maternal serum screening?
A.High maternal serum alpha-fetoprotein (AFP)
B.Low hCG
C.Normal µE3 (estriol)
D.All of the above
E.None of the above

C.Normal µE3 (estriol)

High AFP, low uE3 and hCG

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Which one of the following studies provides the most accurate result for fetal aneuploidy carrier status at 12 weeks’ gestational age with a minimum risk of miscarriage?
A.First-trimester screen
B.Second-trimester screen
C.Amniocentesis
D.Chorionic villus sampling
E.Noninvasive prenatal test (NIPT)

E.Noninvasive prenatal test (NIPT) -cfDNA

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NIPT suggested trisomy 21, what would likely NOT be the result of second-trimester maternal serum screening test if the fetus had trisomy?
A.High hCG
B.Low inhibin A
C.Low maternal serum alpha-fetoprotein (MS-AFP)
D.Low µE3 (estriol)
E.None of the above

B.Low inhibin A

High inhibin A and hCG, low uE3 and AFP HI is high

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What would likely NOT be the results if the fetus has trisomy 13?
A.High hCG
B.Low maternal serum alpha-fetoprotein (MS-AFP)
C.Low µE3 (estriol)
D. Normal inhibin
E.None of the above

A.High hCG

trisomy 13 - low hCG, low uE3, low AFP and normal inhibin A

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10 wks 3 days uncomplicated but AMA so NIPT was offered. What else would also likely be offered?
A.First-trimester screen
B.Amniocentesis
C.Chorionic villus sampling (CVS)
D.Ultrasound evaluation
E.None of the above

D.Ultrasound evaluation

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10 wks 3 days uncomplicated but AMA so NIPT was offered. The results were indeterminate so what else would be offered?
A.First-trimester screen
B.Second-trimester screen
C.Amniocentesis
D.Chorionic villus sampling (CVS)
E.Repeat the NIPT
F.Ultrasound evaluation
G.None of the above

D.Chorionic villus sampling (CVS)

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20 wks gestational age with complete atrioventricular canal defect (CAVCD). NIPT was normal. What would be the next appropriate step?
A.Amniocentesis is recommended to further rule out aneuploidy. B.Chorionic villus sampling (CVS) is recommended to further rule out aneuploidy.
C.NIPT cannot be used to detect an open neural-tube defect; ultrasound is recommended for follow-up.
D.NIPT is a diagnostic study; there is no need for follow-up.
E.None of the above.

A.Amniocentesis is recommended to further rule out aneuploidy.

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What affects the analytical sensitivity of NIPT?
A.Advanced maternal age
B.Robertsonian translocation, 45,XY,der(13;21)(q10;q10), in the father
C.Fetus with increased risk for trisomy 21 by first-trimester screen D.High maternal body-mass index (BMI)
E.Previous pregnancy with trisomy 21
F.None of the above

D.High maternal body-mass index (BMI)

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What likely meets rejection criteria for NIPT?
A.Gestational age of 32 weeks
B.Robertsonian translocation, 45,XY,der(13;21)(q10;q10) in the father
C.Fetus with decreased risk for trisomy 21 by first-trimester screen D.Karyotype of 45,XY,der(13;21)(q10;q10) in the mother
E.Multiple gestations

E.Multiple gestations

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What likely DOES NOT meet rejection criteria for NIPT?
A.6 weeks’ gestation
B.Maternal BMI >40
C.Karyotype of 45,XY,der(13;21)(q10;q10) in the mother
D.Multiple gestations
E.None of the above

C.Karyotype of 45,XY,der(13;21)(q10;q10) in the mother

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ACOG first-line screening for low-risk obstetric population?
A.First-trimester screen followed by second-trimester screen B.Amniocentesis
C.Chorionic villus sampling (CVS)
D.Noninvasive prenatal test (NIPT)
E.None of the above

A.First-trimester screen followed by second-trimester screen

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US newborn screening (NBS) began in the US in which decade?
A.1950s
B.1960s
C.1970s
D.1980s
E.1990s

B.1960s

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Which of the following factors increases the potential False Positive (FP) NBS results in premature infants?
A.Preterm newborn in NICU with total parenteral nutrition (TPN) B.Newborn with PKU
C.Newborn with Beckwith–Wiedemann syndrome
D.Newborn from a cesarean section
E.None of the above

A.Preterm newborn in NICU with total parenteral nutrition (TPN)

-total parenteral nutrition (TPN), provided in the NICU, and the liver immaturity of the preterm infant’s metabolic system contribute to higher rates of presumptive positive NBS results in this group.

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Which one of the following prenatal studies gives the most accurate information on fetal aneuploidy at 12 weeks’ gestational age without the risk of miscarriage?
A.First-trimester screen
B.Second-trimester screen
C.Amniocentesis
D.CVS
E.Noninvasive prenatal test (NIPT)

E.Noninvasive prenatal test (NIPT)

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Which one of the following prenatal studies has the highest rate for miscarriage if it is done at 12 weeks’ gestational age?
A.First-trimester screen
B.Second-trimester screen
C.Amniocentesis
D.CVS
E.Noninvasive prenatal test (NIPT)

C.Amniocentesis

Amniocentesis is usually done between week 15 and 20 of pregnancy; the risk of miscarriage ranges from 1 in 400 to 1 in 200. Amniocentesis done before week 15 of pregnancy has been associated with a higher rate of complications.

Chorionic villus sampling (CVS) is an invasive diagnostic prenatal test for genetic conditions, usually done in the first trimester; the miscarriage risk is approximately 1 in 100.

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Which of the following most likely accounts for HDFN in newborns?
A.ABO incompatibility
B.Rhc incompatibility
C.RhD incompatibility
D.RhE incompatibility
E.RhK incompatibility

C.RhD incompatibility

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The mother was typed as R1R1 (DCe/DCe) and the father R1R2 (DCe/DcE). The baby was typed as R1R2 (DCe/DcE). Which one of the following conditions would this newborn baby most likely have?
A.ABO incompatibility
B.Rhc incompatibility
C.RhD incompatibility
D.RhE incompatibility
E.RhK incompatibility

D.RhE incompatibility

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How many core conditions are in this recommended uniformed screen program? A. 3 B. 29 C. 31 D. 35 E. 43

D. 35 Formerly 29 in 2006 26 secondary conditions

A 3-day-old boy was brought to an emergency department for lethargy, hypotonia, and shallow breathing, which eventually led to apnea and required a mechanical respirator. Laboratory results showed a plasma ammonium concentration of 3044 mmol/L (normal range, 18–54). Plasma amino acid analysis revealed elevated glutamine and undetectable citrulline levels. Urinary orotic acid was extremely elevated. Which one of the following genes would most likely harbor pathogenic variant(s) in this patient? A. ASS1 B. ASL C. CPS1 D. NAGS E. OTC

E. OTC liver transplantation by 6 months

A 2-year-old girl was brought to an emergency room for vomiting and tremors. The plasma ammonium level was 221 µM/L (normal range, 11–40). Laboratory testing revealed an elevated arginine in serum. Which one of the following enzymes would be the LEAST LIKELY to be deficient before further workup in this patient? A. Carbamoyl phosphate synthetase I B. Carbamoyl phosphate synthetase II C. Ornithine transcarbamoylase D. Arginase E. Argininosuccinate lyase F. None of the above

C. Ornithine transcarbamoylase only X-linked condition in urea cycle disorders - Xp11.4.

A. Carbamoyl phosphate synthetase I Step 1 of the urea cycle is condensation of CO2, ammonia, and ATP to form carbamoyl phosphate, which is catalyzed by mitochondrial carbamoyl phosphate synthase I (CPS I). Carbamoyl phosphate synthase II (CPS II) uses glutamine rather than ammonia as the nitrogen donor and functions in pyrimidine biosynthesis.

Postpartum woman with ammonia level was 452 µmol/L. Hyperammonemia (550 mmol/L; normal range, 14–38) and respiratory alkalosis led to suspicion for a urea-cycle disorder. There was no sign or finding of acute or chronic hepatic failure or cirrhosis. Which one of the following enzymes would most likely be deficient in this patient? A. Arginase B. Argininosuccinate lyase C. Carbamoyl phosphate synthetase I D. Carbamoyl phosphate synthetase II E. Ornithine transcarbamoylase F. None of the above

E. Ornithine transcarbamoylase

Which of the following statements about G6PD is correct? A. It appears more often in females than in males. B. It is an autosomal recessive disease. C. Haploinsufficiency causes the disease. D. Newborn screening for G6PD deficiency is not performed routinely in the United States. E. Patients with G6PD have a selection advantage.

E. Patients with G6PD have a selection advantage. X-linked Xq28 region

Boy with G6PD. Why did the probands mother NOT have any symptoms? A. A de novo pathogenic variant in the proband B. Clinical heterogeneity C. Nonpenetrance D. Variable expression E. X inactivation

E. X inactivation

In which population is G6PD relatively UNCOMMON? A. African American B. Arabic C. Asian D. Hispanic E. None of the above

D. Hispanic

African American with hemolytic anemia after primaquine for malaria prophylaxis. Which of the following pathogenic variants is this patient most likely to have? A. Hemizygous p.Asn156Asp in G6PD B. Homozygous p.Asn156Asp in G6PD C. Hemizygous p.Val32Met in GALK1 D. Homozygous p.Val32Met in GALK1 E. None of the above

A. Hemizygous p.Asn156Asp in G6PD

Which of the following would likely harbor pathogenic variants in a patient with phenylketonuria? A. APC B. PAH C. PC D. PROC E. None of the above

B. PAH

Which assay in NBS for PKU? A. Tandem mass spectrometry (MS/MS) B. High-performance liquid chromatography (HPLC) C. Molecular genetics test D. Sweat sodium chloride test E. None of the above

A. Tandem mass spectrometry (MS/MS)

Which assay in NBS for fatty acid oxidation disorder? A. Tandem mass spectrometry (MS/MS) B. Targeted genotyping C. Sanger sequencing D. Immunohistochemistry (IHC) E. Chromosome karyotyping

A. Tandem mass spectrometry (MS/MS)

Which disorder would likely be missed by newborn screening second sample at 6 days (instead of 1-2 weeks)? A. Amino acid disorders B. Congenital heart defects C. Fatty acid oxidation disorders D. Hearing loss E. Organic acidemia

C. Fatty acid oxidation disorders

The newborn screening (NBS) results were abnormal for elevated C16:0, C18:0, C18:1Ɯ9, and C18:2Ɯ6 acylcarnitine. Which one of the following disorders would the infant most likely have? A. Short-chain acyl CoA dehydrogenase (SCAD) deficiency B. Medium/short chain hydroxyacyl CoA dehydrogenase (M/SCHAD) deficiency C. Medium-chain acyl CoA dehydrogenase (MCAD) deficiency D. Long-chain hydroxyacyl CoA dehydrogenase (LCHAD) deficiency E. Very-long-chain acyl CoA dehydrogenase (VLCAD) deficiency F. Trifunctional protein deficiency G. None of the above

D. Long-chain hydroxyacyl CoA dehydrogenase (LCHAD) deficiency short 2-4C medium 6-10 long chain 12-18 VLC 14-20

A 6-month-old infant girl was brought to the emergency department of a local hospital by her mother for vomiting and lethargy. While in the hospital, the girl had a seizure. A physical examination showed hepatomegaly. A laboratory study revealed that her blood glucose was 26 mg/dL and ketone bodies were absent. MS/MS showed elevated C10:1, C8, and C10 acylcarnitine. Which one of the following disorders would the infant girl most likely have? A. Short-chain acyl CoA dehydrogenase (SCAD) deficiency B. Medium/short chain hydroxyacyl CoA dehydrogenase (M/SCHAD) deficiency C. Medium-chain acyl CoA dehydrogenase (MCAD) deficiency D. Long-chain hydroxyacyl CoA dehydrogenase (LCHAD) deficiency E. Very-long-chain acyl CoA dehydrogenase (VLCAD) deficiency F. Trifunctional protein deficiency G. None of the above

C. Medium-chain acyl CoA dehydrogenase (MCAD) deficiency

A 2-year-old boy was brought to an emergency department of a local hospital for vomiting and seizures. The medical history revealed that the patient had developmental delay and growth retardation. The blood glucose was 26 mg/dL and ketone bodies were absent. Organic acids analysis revealed elevated C4-carnitine. Which one of the following disorders would the infant girl most likely have? A. Short-chain acyl CoA dehydrogenase (SCAD) deficiency B. Medium/short chain hydroxyacyl CoA dehydrogenase (M/SCHAD) deficiency C. Medium-chain acyl CoA dehydrogenase (MCAD) deficiency D. Long-chain hydroxyacyl CoA dehydrogenase (LCHAD) deficiency E. Very-long-chain acyl CoA dehydrogenase (VLCAD) deficiency F. Trifunctional protein deficiency G. None of the above

A. Short-chain acyl CoA dehydrogenase (SCAD) deficiency

Genetic testing revealed compound heterozygous variants in the HADHB gene, c.182G>A(p.Arg61His) and c.788A>G(p.Asp263Gly). One of each of the mutations was identified in each parent. Which one of the following disorders would the patient most likely have had? A. Long-chain hydroxyacyl CoA dehydrogenase (LCHAD) deficiency B. Mitochondrial complex I deficiency C. Trifunctional protein deficiency D. Not clear E. None of the above

C. Trifunctional protein deficiency mitochondrial trifunctional protein, composed of 4 alpha and 4 beta subunits, catalyzes three steps in mitochondrial beta-oxidation of fatty acids: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase activities. Isolated LCHAD deficiency, due to mutation in the HADHA gene, is the most common form of MTP deficiency.

Muscle biopsy revealed nonspecific myositis changes. The serum acylcarnitine profile found increased C14:2 (0.26 µmol/L; normal range, <0.08 µmol/L), C14:1 (0.53 µmol/L; normal range, <0.18 µmol/L), and C16:1 (0.16 µmol/L; normal range, <0.08 µmol/L). Which one of the following disorders would the patient most likely have? A. Short-chain acyl CoA dehydrogenase (SCAD) deficiency B. Medium/short chain hydroxyacyl CoA dehydrogenase (M/SCHAD) deficiency C. Medium-chain acyl CoA dehydrogenase (MCAD) deficiency D. Long-chain hydroxyacyl CoA dehydrogenase (LCHAD) deficiency E. Very long-chain acyl CoA dehydrogenase (VLCAD) deficiency F. Trifunctional protein deficiency G. None of the above

E. Very long-chain acyl CoA dehydrogenase (VLCAD) deficiency

The follow-up measurement of very-long-chain fatty acids (VLCFAs) in plasma revealed a marked elevation of both C26:0 and C26:0/C22:0; in addition, there was a significant elevation of the branched-chain fatty acids (BCFAs)—phytanic acid and, particularly, pristanic acid. A diagnosis of peroxisomal biogenesis disorder was made. Which one of the following disorders would the patient least likely have? A. Infantile Refsum disease B. Neonatal adrenoleukodystrophy C. Rhizomelic chondrodysplasia punctata D. X-linked adrenoleukodystrophy E. Zellweger syndrome F. None of the above

D. X-linked adrenoleukodystrophy ABCD1 at Xq28. peroxisomal membrane protein, which may be involved in transport of the enzyme.

Which one of the following laboratory results usually is seen in patients with X-linked adrenoleukodystrophy? A. Increased VLCFA B. Increased phytanic acids C. Decreased plasmalogen D. All of the above E. None of the above

A. Increased VLCFA

Which one of the following genes would most likely harbor pathogenic variant(s) in this patient if he had adrenoleukodystrophy? A. ABCD1 B. ARX C. FMR2 D. SLC6A8 E. TNFRSF13B F. None of the above

A. ABCD1

The physician suspected that the patient had adrenoleukodystrophy and ordered a molecular study for it. Which one of the following assays would most likely be used to confirm/rule out the adrenoleukodystrophy in this patient? A. Chromosomal microarray B. Exome-sequence analysis C. Multiplex ligation-dependent probe amplification (MLPA) D. Next-generation sequencing panel E. Sanger sequencing analysis F. Target variant analysis of the founder pathogenic variants G. None of the above

E. Sanger sequencing analysis

A pathogenic variant, c.548T>G(p.V183G) in the ABCD1 gene was detected. His mother and sister carry the same variant. His father does not have the variant. Which one of the following would be the most appropriate next step in the workup for this patient? A. Confirming the results with deletion and duplication analysis B. Confirming the results with Sanger sequencing analysis using an alternative pair of primers C. Reporting it out supporting a clinical diagnosis of adrenoleukodystrophy (ALD) D. Requesting a second specimen from the patient and his family members for confirmation E. Not sure F. None of the above

C. Reporting it out supporting a clinical diagnosis of adrenoleukodystrophy (ALD)

Which one of the following statements regarding rhizomelic chondrodysplasia punctata is correct? A. It is one of the connective-tissue disorders. B. It is one of the fatty acid oxidation disorders. C. It is one of the lysosomal disorders. D. It is one of the mitochondrial disorders. E. It is one of the peroxisomal disorders. F. None of the above.

E. It is one of the peroxisomal disorders.

Which one of the following laboratory results usually is seen in patients with rhizomelic chondrodysplasia punctata? A. Decreased VLCFA B. Decreased phytanic acids C. Decreased plasmalogen D. All of the above E. None of the above

C. Decreased plasmalogen elevated plasma concentration of phytanic acid, and normal plasma concentration of very-long-chain fatty acids (VLCFA)

Which one of the following genes would most likely harbor pathogenic variant(s) in this patient if she had RCDP? A. ABCD1 B. COL1A1 C. FGFR2 D. FGFR3 E. PAX3 F. PEX7 G. None of the above

F. PEX7

A Sanger sequencing study detected a homozygous pathogenic variant, c.875T>A(p.Leu292Ter), in the PEX7 gene. Her mother had the same variant in the heterozygous state. Her father did not have the variant. Which one of the following would be the most appropriate next step in the workup for this patient? A. Confirming the results with alternative pairs of primers B. Performing reflex deletion and duplication analysis C. Reporting it as supporting a clinical diagnosis of rhizomelic chondrodysplasia punctata type 1 (RCDP1) D. Requesting a second specimen from the patient for confirmation E. Not sure F. None of the above

B. Performing reflex deletion and duplication analysis Sanger sequencing analysis detected a homozygous pathogenic variant for the autosomal recessive condition in the proband, whereas the parents were not related, which raised the suspicion of a large deletion/duplication or pathogenic variant at the primer region. Therefore, reflex deletion and duplication analysis of PEX7 would be a more appropriate next step in the workup than others

A Sanger sequencing study detected a homozygous pathogenic variant, c.875T>A(p.Leu292Ter), in the PEX7 gene. Her mother had the same variant in the heterozygous state. Her father did not have the variant. Which one of the following would be a more appropriate next step in the workup than others for this patient and her family? A. Confirming the results with deletion and duplication analysis B. Confirming the results with Sanger sequencing analysis using an alternative pair of primers C. Reporting that the patient had an inherited variant from the mother and a de novo variant D. Requesting a second specimen from the patient and the family members for confirmation E. Not sure F. None of the above

A. Confirming the results with deletion and duplication analysis It is possible that the patient had an inherited variant from the mother and a de novo variant at the paternal derivative allele. However, gross deletion/duplications and variants at the primer regions limitations of Sanger sequencing, and these should be ruled out before interpreting the result as an inherited variant from the mother and a de novo variant at the paternal derivative allele.

Which one of the following laboratory results usually is seen in patients with Zellweger syndrome? A. Overaccumulation of VLCFAs B. Overaccumulation of phytanic acids C. Deficiency of plasmalogens D. All of the above E. None of the above

D. All of the above

A molecular genetic study was ordered to confirm the diagnosis of Zellweger syndrome and for family management. Which one of the following molecular assays would be the most cost-effective and most sensitive for this patient? A. Exome sequencing B. Multiplex ligation-dependent probe amplification (MLPA) C. Next-generation sequencing (NGS) panel D. Sequencing analysis of the PEX1 gene E. TaqMan genotype assay F. None of the above

C. Next-generation sequencing (NGS) panel 12 different PEX genes (PEX1, PXMP3 [PEX2], PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, and PEX26). Therefore, next-generation sequencing (NGS) of all 12 genes at one time is the most cost-effective and sensitive method to confirm or rule out the diagnosis. Patients with neonatal adrenoleukodystrophy (NALD) have elevated plasma concentrations of VLCFA (C26:0 and C26:1; elevated ratios of C24/C22 and C26/C22), normal concentrations of phytanic acid and/or pristanic acid, and reduced amounts of C16 and C18 plasmalogens. Patients with infantile Refsum disease (IRD) usually have elevated plasma concentrations of VLCFA (C26:0 and C26:1; elevated ratios of C24/C22 and C26/C22), increased concentrations of phytanic acid and/or pristanic acid, and normal amounts of C16 and C18 plasmalogens. Patients with rhizomelic chondrodysplasia punctata type 1 (RCDP1) have deficient red-blood-cell concentration of plasmalogens, elevated plasma concentration of phytanic acid, and normal plasma concentration of very-long-chain fatty acids (VLCFA). Patients with X-linked adrenoleukodystrophy (X-ALD) have increased concentration of VLCFA in plasma, but not deficient red-blood-cell concentration of plasmalogens or elevated plasma concentration of phytanic acid. Therefore, patients with Zellweger syndrome have overaccumulation of very-long-chain fatty acids and branched-chain fatty acids, such as phytanic acid, and deficient levels of plasmalogens.

A homozygous pathogenic variant, c.2097dupT(p.Ile700TyrfsTer42), in PEX1 was detected in a skin specimen from this patient. Which one of the following would be the most appropriate next step in the workup for this patient and his family? A. Confirming the results with deletion and duplication analysis B. Confirming the results with Sanger sequencing analysis using an alternative pair of primers C. Reporting that the patient had Zellweger syndrome and recommending studies for the parents D. Requesting a second specimen from the patient and his family members for confirmation E. Not sure F. None of the above

C. Reporting that the patient had Zellweger syndrome and recommending studies for the parents

The patient was diagnosed with HH clinically (HFE C282Y). Which one of the following malignancies would the patient be at increased risk to develop? A. Hepatocarcinoma B. Colorectal cancer C. Lung cancer D. Leukemia E. Melanoma F. Rhabdomyosarcoma

A. Hepatocarcinoma

A couple come to an Ob/Gyn clinic for premarriage counseling. They both are carriers of the C282Y variant in HFE. Which one of the following symptoms would their future children NOT be at increased risk to develop due to hereditary hemochromatosis? A. Arthropathy B. Diabetes mellitus C. Dilated cardiomyopathy D. Hypogonadism E. Liver cirrhosis F. Rhabdomyolysis

F. Rhabdomyolysis

Which one of the following statements regarding HFE-associated hereditary hemochromatosis (HH) is appropriate? A. HH predominantly affects boys of Asian descent. B. Prenatal diagnosis is recommended to decrease mortality. C. Linkage analysis is cheaper and more accurate than other molecular diagnostic testing. D. In order for HH to be symptomatic, both copies of the HFE gene must be mutated. E. None of the above.

D. In order for HH to be symptomatic, both copies of the HFE gene must be mutated.

Which one of the following genes is NOT associated with iron overload? A. HFE B. HJV C. HFE2B D. HAMP E. ATP7A

E. ATP7A - Menkes HH has been demonstrated to result from pathogenic variants in several genes involved in the regulation of iron homeostasis such as HFE, TfR2, HJV, HAMP, and SLC40A1 (ferroportin). HFE-associated hereditary hemochromatosis (HFE-HH) is the most common form of HH.

Hereditary hemochromatosis was suspected. Which one of following molecular tests would be the most appropriate? A. Chromosomal microarray B. FISH C. Sanger sequencing D. Targeted mutation analysis E. None of the above

D. Targeted mutation analysis Approximately 60%–90% of patients with HFE-associated hereditary hemochromatosis (HFE-HH) have homozygous p.Cys282Tyr variants. Approximately 3%–8% of HFE-HH patients have compound heterozygous p.Cys282Tyr and p.His63Asp variants.

A molecular genetics study was ordered. Which one of the following genotypes would this patient be most likely to have if he had hereditary hemochromatosis? A. p.Cys282Tyr/p.Cys282Tyr B. p.Cys282Tyr/p.His63Asp C. p.His63Asp/p.His63Asp D. p.Cys282Tyr/p.Ser65Cys E. p.His63Asp/p.Ser65Cys

A. p.Cys282Tyr/p.Cys282Tyr

Which one of the following statements regarding hereditary hemochromatosis (HH) is NOT correct? A. Patients with p.Cys282Tyr/p.Cys282Tyr are at increased risk for hemochromatosis. B. Patients with p.Cys282Tyr/p.His63Asp are at increased risk for clinical hemochromatosis. C. Patients with p.His63Asp/p.His63Asp are at increased risk for clinical hemochromatosis. D. Females have a lower risk for hemochromatosis than males. E. Population screening for HH is a cost-effective method of proactive management.

E. Population screening for HH is a cost-effective method of proactive management.

Which one of following genes would most likely harbor pathogenic variant(s) for Menkes disease in this patient? A. ATP7A B. ATP7B C. HAMP D. HFE E. HFE2B F. HJV

A. ATP7A

A molecular study detected a homozygous pathogenic variant, c.2938C>T(p.Arg980Ter), in ATP7A. Parental testing revealed that his mother carried the same variant in heterozygous state, and remained asymptomatic. His father did not carry the variant. Which one of following would be the most appropriate interpretation of the findings in the family? A. Menkes disease has incomplete penetrance and variable expression. B. Reflex deletion/duplication testing was indicated. C. The patient inherited the variant from the mother and had Menkes disease. D. The patient had a de novo variant from the paternal side. E. Not sure. F. None of the above.

C. The patient inherited the variant from the mother and had Menkes disease.

The patient was diagnosed with Menkes disease clinically. A Sanger sequence study was ordered, and no PCR product was detected. The repetitive test did not show PCR products again. Which one of following would be the most appropriate next step in the workup for this patient? A. Reflex deletion/duplication testing B. Requesting another specimen from the family C. Sending the sample to another laboratory for confirmation D. Using a new lot of all reagents E. Not sure F. None of the above

A. Reflex deletion/duplication testing Xq21.1. Sequence analysis of the gene may detect 80% of probands. Gene-targeted deletion/duplication analysis may detect 20% of probands.

A diagnosis of Menkes disease was made clinically, and a hemizygous pathogenic variant, c.3056G>A (p.Gly1019Asp), was detected in ATP7A. Which one of following would most likely describe the pathogenesis of this variant? A. Dominant negative B. Gain of function C. Haploinsufficiency D. Loss of function E. None of the above

D. Loss of function

A diagnosis of Wilson disease was made clinically. Which one of following genes would most likely harbor pathogenic variant(s) for Wilson disease in this patient? A. ATP7A B. ATP7B C. HAMP D. HFE E. HFE2B F. HJV

B. ATP7B

A liver biopsy and biochemical investigations confirmed a diagnosis of Wilson disease. A Sanger sequencing analysis of ATP7B detected a homozygous pathogenic variant, c.2333G>T(p.Arg778Leu). Which one of following would be the most appropriate interpretation of the molecular findings? A. A new lot of all reagents should be used to confirm the findings. B. Another set of primers should be used to confirm the findings. C. Another type of specimen from the patient should be used to confirm the findings. D. Reflex testing is recommended to confirm/rule out deletions/duplications. E. The findings confirm the diagnosis of Wilson disease. F. The findings should be confirmed by another laboratory. G. None of the above.

E. The findings confirm the diagnosis of Wilson disease.

Which one of following would most likely describe the pathogenesis of Wilson disease in this patient and others with Wilson disease? A. Dominant negative B. Gain of function C. Haploinsufficiency D. Loss of function E. None of the above

D. Loss of function

His was diagnosed with Alagille syndrome clinically. A molecular genetic study was ordered to confirm the diagnosis. Which one of the following genes would most likely to harbor pathogenic variant(s) in this patient if he had Alagille syndrome? A. ATP7A B. ATP7B C. JAG1 D. JAG2 E. JAG3 F. None of the above

C. JAG1

Which one of the following genes most likely harbored pathogenic variant(s) than others in this patient if he had Alagille syndrome? A. JAG1 B. JAG2 C. JAG3 D. NOTCH1 E. NOTCH2 F. NOTCH3 G. None of the above

A. JAG1 The two genes in which pathogenic variants are known to cause ALGS are JAG1 and NOTCH2 JAG1 detects pathogenic variants in more than 89% of individuals who meet clinical diagnostic criteria;

He was diagnosed with Alagille syndrome clinically. A molecular genetic study detected a heterozygous pathogenic variant, c.550C>T(p.Arg184Cys), in JAG1. Parental studies detected the same variant in his mother, but not in his father. His mother was apparently healthy. Which one of following would be the most appropriate next step in the workup for this family? A. A new lot of all reagents should be used to confirm the findings. B. Additional testing of the patient’s mother should be considered. C. Another set of primers should be used to confirm the findings. D. Another type of specimen from the patient should be used to confirm the findings. E. Reflex testing to deletion/duplication is recommended in the patient. F. The findings should be confirmed by another laboratory. G. None of the above.

B. Additional testing of the patient’s mother should be considered. penetrance is 96%; however, only 53% meet the clinical diagnostic criteria for ALGS

He was diagnosed with Alagille syndrome clinically. A molecular genetic study detected a heterozygous pathogenic variant, c.550C>T(p.Arg184Cys), in JAG1. Which one of following would most appropriately describe the pathogenesis of Alagille syndrome in this patient? A. Dominant negative B. Gain of function C. Haploinsufficiency D. Loss of function E. None of the above

C. Haploinsufficiency

Urinary amino acid analysis revealed an abnormal increased N-acetylaspartic acid (NAA). A high level of NAA was also detected in serum and CSF. Assaying for aspartoacylase in fibroblast showed absent activity. A cranial CT scan revealed diffuse symmetrical attenuation in the white matter without ventricular dilatation. An MRI demonstrated marked prolongation of T1 and T2 in the white matter except for the deep part of the frontal area, brain stem, and cerebellum. Which one of the following lysosomal disorders would the patient most likely have? A. Canavan disease B. Metachromatic leukodystrophy C. Pompe disease D. X-linked adrenoleukodystrophy E. Zellweger syndrome spectrum disorders F. None of the above

A. Canavan disease spongiform degeneration of cerebral white matter,” is an autosomal recessive demyelinating disease caused by deficiency of aspartoacyclase, which catalyzes the breakdown of N-acetylaspartic acid (NAA).

A molecular study was ordered to confirm the diagnosis of Canavan disease. Which one of the following genes would most likely harbor pathogenic variants for Canavan disease in this patient? A. ASPA B. ELP1 (IKBKAP) C. GAA D. GLA E. MEFV F. None of the above

A. ASPA - aspartoacyclase,

AJ patient. His brain CT was compatible with leukodystrophy. Urinary amino acid analysis revealed an abnormal increased N-acetylaspartic acid (NAA). A high level of NAA was also detected in serum and CSF. Assaying for aspartoacylase in fibroblast showed absent activity. A molecular study was ordered to confirm the diagnosis of Canavan disease. Which one of molecular assays would most likely be used as a first-tier test to detect pathogenic variants for Canavan disease in this patient? A. Chromosomal microarray (CMA) B. Multiplex ligation-dependent probe amplification (MLPA) C. Next-generation sequencing (NGS) D. Sanger sequencing E. Target variant analysis of the founder pathogenic variants F. None of the above

E. Target variant analysis of the founder pathogenic variants Two pathogenic variants, p.Glu285Ala and p.Tyr231Ter, account for 98% of pathogenic variants in the Ashkenazi Jewish population.

Which one of following molecular assays would most likely be used as a first-tier test to detect pathogenic variants for Canavan disease in a non AJ patient? A. Chromosomal microarray (CMA) B. Multiplex ligation-dependent probe amplification (MLPA) C. Next-generation sequencing (NGS) D. Sanger sequencing E. Target variant analysis of the founder pathogenic variants F. None of the above 7

D. Sanger sequencing Sequence analysis may detect 87% disease-causing alleles in non-Ashkenazi Jewish

The result revealed that the wife carried a pathogenic variant, c.854A>C(p.Glu285Ala), in the ASPA gene for Canavan disease. As a follow-up, the same panel was offered to the husband, and the result was negative. Which one of the following would be the most appropriate estimation of the residual risk of this couple’s firstborn child with Canavan disease? A. 10% B. 5% C. 1% D. 0.25% E. None of the above

D. 0.25% The third one, c.914C>A(p.Ala305 Glu), was detected in 1% of Ashkenazi Jewish patients The residual carrier risk of the husband was 1% with the negative result on these three pathogenic variants in ASPA. The wife was a carrier. Therefore, the most appropriate estimation of the residue risk of this couple’s first-born child with Canavan disease would be 1%×1×1/4=1/400 (0.25%).

Wife with family history. Which one of the following is the most appropriate first-tier study for this family to estimate the fetus’s risk for Canavan disease? A. Measurement of the concentration of N-acetylaspartic acid (NAA) in the urine sample from the wife B. Measurement of the concentration of N-acetylaspartic acid (NAA) in the urine sample from the husband C. Targeted mutation analysis of ASPA in the peripheral-blood sample from the husband D. Targeted mutation analysis of ASPA in the peripheral-blood sample from the wife E. Testing aspartoacylase enzyme activity with amniocytes F. Testing aspartoacylase enzyme activity with chorionic villus sampling (CVS) G. None of the above

D. Targeted mutation analysis of ASPA in the peripheral-blood sample from the wife

There are 6 amino acid disorders recommended for testing by the Recommended Uniform Screening Program (RUSP). What are they?

1. Arginosuccinic aciduria 2. Citrullinemia type I 3. PKU 4. Homocystinuria 5. Maple syrup urine disease 6. Tyrosinemia type I

Describe SN, SP and PPV for NIPT at age 25 and 40 years.

What is the range of PPV for newborn screening panel?

0.5% - 6.0% - total parenteral nutrition (TPN), provided in the NICU, and the liver immaturity of the preterm infant’s metabolic system contribute to higher rates of presumptive positive NBS results in this group.

OTC deficiency requires ________________ by 6 months of life.

transplantation

ASS1 pathogenic variants cause arginosuccinate synthetase-1 deficiency and ______________ (build up of).

citrullinemia (citrulline)

Pathogenic variants in ASL cause __________________ aciduria

arginosuccinic aciduria argininosuccinate lyase, a urea cycle enzyme that catalyzes the cleavage of argininosuccinate to fumarate and arginine,

Argininosuccinate lyase, a urea cycle enzyme that catalyzes the cleavage of argininosuccinate to _________ and __________.

fumarate (and) arginine

The ___________ gene encodes the rate limiting step (1) of the hepatic urea cycle and synthesizes its product from NH4+, HCO3 and 2 ATP.

CPS1 (carbamoyl phosphate synthetase I)

The __________ gene encodes a mitochondrial enzyme that synthesizes an allosteric activator of CPS1 (rate-limiting step of urea cycle)

NAGS - N-acetylglutamate synthase

There are _______ enzymes and ________ transporters that underlie urea cycle disorders

5 enzymes (CPS1, OTC, ASS1, ASL, ARG1) 2 transporters (ORNT1 and citrin)

CPSII uses _____________ rather than NH4+ as the nitrogen donor and functions in __________ synthesis

glutamine (Q) pyrimidine

OTC transfers carbamoyl group to ornithine in urea cycle step 2 to form _________ and orthophosphate

citrulline

Step3 of the urea cycle by ASS uses _______________ (second nitrogen of the urea cycle) to link to citrulline

aspartate (N)

Step 4of the urea cycle by ASL retains nitrogen in _________ and releases aspartate skeleton as ____________

arginine (retained N) fumarate (released)

Step 5 of the urea cycle cleaves the guanidine group from _____ to release urea and ornithine

arginine (arginase ARG1)

The OTC reaction occurs in which cellular compartment?

mitochondrial matrix

_____ and _____ are responsible for transport of citrulline and ornithine

ORNT1 and citrin

Prenatal/Newborn Screen and Inborn Errors of Metabolism Flashcards

(96 cards)