Other Common Genetic Syndromes Flashcards by Josh Klonoski

What would most likely be the recurrent risk for this family with an affected infant if the patient had a hereditary form of polycystic kidney disease?
A.1/2
B.2/3
C.1/4
D.<1%
E.None of the above

C.1/4

PKD1: (polycystic kidney disease 1) on chromosome 16 80%
PKD2: (polycystic kidney disease 2) on chromosome 4 15%

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Adult PCKD with renal, pancreatic and hepatic cysts. Berryaneurysm. What would most likely be the recurrent risk of this disorder in the family?
A.<1%
B.5%–10%
C.25%
D.50%
E.100%
F.None of the above

D.50%

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Which one of the following molecular genetics studies would most likely be used as a first-tier test to confirm/rule out genetic etiologies in this adult polycystic kidney disease patient?
A.Chromosomal microarray
B.Multiplex ligation-dependent probe amplification (MLPA)
C.Sequencing the PDK1 and PKD2 genes
D.Sequencing the PKHD1 gene
E.Target variant analysis of the founder pathogenic variants in the PDK1 and PKD2 genes
F.Target variant analysis of the founder pathogenic variants in the PKHD1 gene
G.None of the above

C.Sequencing the PDK1 and PKD2 genes

autosomal dominant chromosomes 16 and 4

PKHD1 autosomal recessive on chromosome 6

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Which one of the following polycystic kidney disease does the adult patient most likely have if she has a genetic form of the disorder?
A.De novo autosomal dominant polycystic kidney disease
B.Inherited autosomal dominant polycystic kidney disease
C.De novo autosomal recessive polycystic kidney disease
D.Inherited autosomal recessive polycystic kidney disease
E.None of the above

B.Inherited autosomal dominant polycystic kidney disease

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Pt with adult PCKD. Of the family members who are potential kidney donors, only her youngest sister, age 25 years, is a good tissue match. This sister is evaluated by ultrasound, CT, and MRI as parts of comprehensive renal image analysis, and the results are negative. Which one of the following is the most appropriate next step in the workup?
A.Considering transplantation with a kidney from an unrelated donor
donor
B.Considering transplantation with a kidney from the brother
C.Considering transplantation with a kidney from the youngest sister
D.Considering transplantation with a kidney from a relative without pathogenic variant
E.Considering transplantation with a kidney from the youngest if she does not have a pathogenic variant
F.None of the above

E.Considering transplantation with a kidney from the youngest if she does not have a pathogenic variant

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Pt with adult PCKD with no identified mutation. Of the family members who are potential kidney donors, only her youngest sister, age 25 years, is a good tissue match. This sister is evaluated by ultrasound, CT, and MRI as parts of comprehensive renal image analysis, and the results are negative. Which one of the following is the most appropriate next step in the workup?
A.Considering transplantation with a kidney from an unrelated donor
donor
B.Considering transplantation with a kidney from the brother
C.Considering transplantation with a kidney from the youngest sister
D.Considering transplantation with a kidney from a relative without pathogenic variant
E.Considering transplantation with a kidney from the youngest if she does not have a pathogenic variant
F.None of the above

A.Considering transplantation with a kidney from an unrelated donor
donor

-linkage analysis not viable since only affected family member
- sibling should be considered at risk

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Which one of the following genes would most likely harbor a pathogenic variant if the patient had autosomal dominant polycystic kidney disease (ADPKD)?
A.PKD1
B.PKD2
C.PKHD1
D.None of the above

A.PKD1

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Because of a paternal history of bilateral renal cysts, genetic testing of PKD1 and PKD2 was ordered, and a 3-bp deletion, c.1602_1604TGT, was detected in the PKD2 coding region. Targeted molecular analysis of the father detected the same deletion. Which one of the following mechanisms would most likely contribute to the pathogenesis of the ADPKD in this patient?
A.Dominant negative
B.Gain of function
C.Loss of function
D.None of the above

C.Loss of function

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Communication with the laboratory that sent the sample confirmed the presence of the c.3817C>T, but not the 15-bp deletion in exon 3. Dr. Z sent this sample to a third clinical laboratory for Sanger sequencing, and the result confirmed the presence of the c.3817C>T, but not the 15-bp deletion in exon 3. Which one of the following mechanisms would most likely contribute to the discrepancy of the testing results with the same specimen in this case?
A.Interference of pseudogenes
B.Primers in polymorphic regions
C.Sample mess-up
D.Variation of enrichment methods
E.None of the above

A.Interference of pseudogenes

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Which one of the following genes would most likely harbor a pathogenic variant in a neonate (without FHx for 3 generations) if the patient had a hereditary form of polycystic kidney diseases?
A.PKD1
B.PKD2
C.PKHD1
D.None of the above

C.PKHD1

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Compound heterozygous pathogenic variants, c.10444C>T and c.5909–2delA, were detected in the PKHD1 gene in a neonate. Which one of the following would be the most appropriate next step in the workup for this family?
A.Counseling the family about the 25% recurrent risk
B.Recommending prenatal testing for future pregnancies
C.Testing the couple for the pathogenic variants
D.Testing the husband for the pathogenic variants
E.Testing the wife for the pathogenic variants
F.All of the above
G.None of the above

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The physician suspected that the patient had tuberous sclerosis and autosomal dominant polycystic kidney disease (ADPKD). Which one of the following molecular genetics assays would be most appropriate for this patient to confirm the diagnosis?
A.Multiplex ligation-dependent probe amplification (MLPA)
B.Next-generation sequence (NGS)
C.Quantitative PCR
D.Restriction-fragment–length polymorphism
E.Sanger sequencing
F.None of the above

A.Multiplex ligation-dependent probe amplification (MLPA)

MLPA is an appropriate technique to detect deletions/duplications for TSC2/PKD1 contiguous gene deletion syndrome

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A molecular genetics study was ordered to confirm/rule out genetic etiology, and pathogenic variant(s) were identified. Which one of the following genes would most likely harbor the pathogenic variant(s) in this patient?
A.PKD1
B.PKD2
C.PKD3
D.PKHD1
E.PKHD1L1

A.PKD1

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26 yo with clinical symptoms presents for sequencing based on FHx. The results showed a homozygous pathogenic variant, c.3817C>T(p.Gln1273Ter), in PKD1. Which one of the following would be the most appropriate interpretation of the result?
A.The c.3817C>T(p.Gln1273Ter) variant is pathogenic. The patient had polycystic kidney disease.
B.The parents of the proband may be related. The patient needs to be monitored closely for early-onset disease.
C.The result is questionable. The variant needs to be reanalyzed with another pair of primers.
D.The result is questionable. The lab should ask for a redraw of a peripheral-blood sample from the patient.
E.None of the above.

D.The result is questionable. The lab should ask for a redraw of a peripheral-blood sample from the patient.

In adult dominant autosomal dominant PCKD – two homozygous mutations is questionable

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Infant with affected sister has pathogenic variant(s) for ADPKCD were identified. Which one of the following genes would most likely harbor the pathogenic variant(s) in this family?
A.PKD1
B.PKD2
C.PKD3
D.PKHD1
E.PKHD1L1

D.PKHD1

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Which one of the following statements regarding polycystic kidney diseases is correct?
A.Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are caused by same genes. B.ADPKD usually causes more significant renal- and liver-related morbidity and mortality than ARPKD.
C.The onset of ADPKD is usually earlier than that of ARPKD.
D.The severity of ADPKD disease is attributed primarily to locus heterogeneity.
E.The contiguous gene deletion syndrome including symptoms for both ADPKD and tuberous sclerosis typically results from a deletion involving both PKD2 and TSC1.

D.The severity of ADPKD disease is attributed primarily to locus heterogeneity.

PKD1 and TSC2 (tuberin) on Chr 16

PKD2 on Chr 4 and TSC1 on chromosome 9

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Which one of the following statements regarding polycystic kidney diseases is correct?
A.The contiguous gene deletion syndrome including symptoms for both ADPKD and tuberous sclerosis typically results from a deletion involving both PKD1 and TSC1.
B.The contiguous gene deletion syndrome including symptoms for both ADPKD and tuberous sclerosis typically results from a deletion involving both PKD1 and TSC2.
C.The contiguous gene deletion syndrome including symptoms for both in ADPKD and tuberous sclerosis typically results from a deletion involving both PKD2 and TSC1.
D.The contiguous gene deletion syndrome including symptoms for both ADPKD and tuberous sclerosis typically results from a deletion involving both PKD2 and TSC2.
E.None of the above.

B.The contiguous gene deletion syndrome including symptoms for both ADPKD and tuberous sclerosis typically results from a deletion involving both PKD1 and TSC2.

16p13.3,

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A 28-year-old Caucasian man has been evaluated as a potential living-relative kidney donor for his mother (see the figure below for the pedigree). He is apparently healthy. Renal ultrasonography results were negative. The PKD1 and PKD2 studies for autosomal dominant polycystic kidney disease (ADPKD) did not identify pathogenic variants in the mother. Which one of the following is the most appropriate next step in the workup for this family?
A.Excluding the patient as a renal donor for his mother
B.Performing linkage analysis in the family
C.Sequencing the patient for an ADPKD pathogenic variant
D.Testing PKHD1 for autosomal recessive polycystic kidney disease (ARPKD)
E.Using a more sensitive renal imaging method, such as MRI or CT F.None of the above

B.Performing linkage analysis in the family

MPLA -

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A 4-year-old Caucasian boy was admitted to a local hospital for “febrile seizures.” An initial evaluation revealed nystagmus and pigmentary retinopathy, mild central obesity, hypogonadism, mental retardation, behavioral abnormalities, hypothyroidism, hypertension, and severe anemia. He had postaxial polydactyly. Ultrasonography revealed bilateral multiple renal cysts. He was the second offspring of consanguineous parents. His family history was notable for obesity, learning difficulties, six digits on both hands, and visual impairment in his 14-year-old sister; the etiology was unknown. Which one of the following pathogenic variants would this patient most likely have?
A.c.107C>T(p.T36M) in PKHD1
B.c.12258T>A(p.C4086X) in PKD1
C.c. 547A>G(p.G72S) in BBS5
D.46,XX,der(16)t(X;16)(q28;p13.2)
E.None of the above

C.c. 547A>G(p.G72S) in BBS5

Bardet–Biedl syndrome (BBS). cilia complex - 19 genes

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The medical geneticist suspected that the patient had Bardet–Biedl syndrome and ordered a molecular genetics study to confirm the diagnosis. Which one of the following molecular technologies would provide the most cost-effective testing strategy for this patient?
A.Next-generation sequencing (NGS)
B.Quantitative real-time PCR
C.Restriction-fragment–length polymorphism (RFLP)
D.Sanger sequencing
E.None of the above

A.Next-generation sequencing (NGS)

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The medical geneticist suspected that the patient had Bardet–Biedl syndrome and ordered a next-generation sequencing (NGS) panel to confirm the diagnosis, which includes 19 genes. Which of the following is this an example of?
A.Allelic heterogeneity
B.Cellular heterogeneity
C.Incomplete penetrance
D.Locus heterogeneity
E.Variable expression
F.None of the above

D.Locus heterogeneity

AR Bardet–Biedl syndrome (BBS): BBS1, BBS2, ARL6 (BBS3), BBS4, BBS5, MKKS (BBS6), BBS7, TTC8 (BBS8), BBS9, BBS10, TRIM32 (BBS11), BBS12, MKS1 (BBS13), CEP290 (BBS14), WDPCP (BBS15), SDCCAG8 (BBS16), LZTFL1 (BBS17), BBIP1 (BBS18), and IFT27 (BBS19). Approximately 20% of persons with BBS do not have identifiable pathogenic variants in any of the 19 known BBS-related genes;

cilia complex

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Which one of the following would most likely be the recurrent risk of the same condition in the family if Jerry (microscopic hematuria and and his cousin had a hereditary form of renal diseases?
A.10%
B.25%
C.50%
D.75%
E.99%
F.Unpredictable

B.25%

X-linked Alport syndrome

recurrent risk 1/2×1/2=1/4 COL4A5

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Dr. Z. suspects that Mrs. J. has early-onset Alzheimer disease. Which one of the following genes is NOT associated with autosomal dominant early-onset Alzheimer disease?
A.APOE
B.APP
C.PSEN1
D.PSEN2
E.All of the above
F.None of the above

A.APOE

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The APOE ε4 allele is the most significant risk factor, while the APOE ε2 allele is protective.

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The physician diagnosed the Finnish patient clinically with Alzheimer disease and ordered a molecular genetics study for it. Which one of the following molecular technologies would provide the cost-effective testing strategy for this patient?
A.Multiplex ligation-dependent probe amplification (MLPA)
B.Next-generation sequencing (NGS)
C.Quantitative real-time PCR D.Restriction-fragment–length polymorphism (RFLP)
E.Sanger sequencing
F.None of the above

A.Multiplex ligation-dependent probe amplification (MLPA)

A 4555-bp deletion spanning exon 9 of PSEN1 has been found in the Finnish population with founder effect; this mutation is rarely observed in other populations

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The physician diagnosed the patient clinically with Alzheimer disease and ordered a molecular genetics study for it. A 4555-bp deletion spanning exon 9 of PSEN1 was detected. The patient asked if her 33-year-old asymptomatic daughter may be tested. Which one of the following would be the most appropriate reaction from the physician to this request? A. A pretesting interview is recommended. B. Informed consent for such testing is required. C. Inform the patient that such testing is not useful in predicting age at onset, severity, type of symptoms, and rate of progression. D. The test should not be offered. E. A, B, and C. F. All of the above. G. None of the above.

E. A, B, and C.

Finnish middle-aged adult. A 4555-bp deletion spanning exon 9 of PSEN1 was detected. Her 33-year-old asymptomatic daughter was tested and confirmed to carry the same deletion. Her daughter asked if her 8-year-old son may be tested, too. Which one of the following would be the most appropriate reaction from the physician to this request? A. A pretesting interview is recommended. B. Informed consent for such testing is required. C. Inform the patient that such testing is not useful in predicting age at onset, severity, type of symptoms, and rate of progression. D. The test should not be offered. E. A, B, and C. F. All of the above. G. None of the above.

D. The test should not be offered.

Finnish middle-aged adult. A 4555-bp deletion spanning exon 9 of PSEN1 was detected. Her 33-year-old asymptomatic daughter was tested and confirmed to carry the same deletion. Her daughter asked if her 8-year-old son may be tested, too. Her daughter was 10 weeks pregnant for her second child, and asked if her unborn child may be tested, too. Which one of the following would be the most appropriate reaction from the physician to this request? A. The test may be offered. B. The test should not be offered. C. Not sure.

A. The test may be offered.

Her 75-year-old mother currently lives with Mrs. B., and has Alzheimer disease, which started at 65 years of age. Mrs. B. is concerned about her own risk for Alzheimer disease. Which one of the following genes may be associated with the Alzheimer disease in this family? A. APOE B. APP C. PSEN1 D. PSEN2 E. All of the above F. None of the above

A. APOE

The doctor orders a molecular genetics study for Mrs. B.’s mother. Which one of the following alleles in APOE does Mrs. B.’s mother most likely have? A. e1 B. e2 C. e3 D. e4 E. e5

D. e4

The doctor orders a molecular genetics study for Mrs. B.’s mother with Alzheimer's disease. Which one of the following APOE genotypes does Mrs. B.’s mother LEAST likely have? A. e1/e1 B. e2/e2 C. e3/e3 D. e4/e4 E. e5/e5

B. e2/e2 E3 MOST common allele E2 is protective

Which one of the following statements would be the most appropriate concerning early-onset dementia? A. The APOE molecular test may be useful as a predictive test. B. Her risk for Alzheimer is increased threefold to sixfold. C. She will have Alzheimer disease. D. She has nothing to worry about. E. She may consider a next-generation panel for early-onset Alzheimer disease.

E. She may consider a next-generation panel for early-onset Alzheimer disease.

Which one of the following genes would most likely be tested for a patient to confirm/rule out genetic etiologies in infant hearing loss associated with temporal bone abnormalities, vestibular dysfunction and euthyroid goiter? A. Connexin 26 B. Connexin 30 C. GJB2 and GJB6 D. SCL26A4, FOXI1, and KCNJ10 E. MYO7A, USH2A, CDH23, ADGRV1, CLRN1, PCDH15, USH1C, USH1G, and DFNB31

D. SCL26A4, FOXI1, and KCNJ10 Pendred syndrome - AR

Which one of the following genes is most likely mutated in patients with congenital hereditary hearing loss? A. CDH23 B. GJB2 C. GJB6 D. MYO7A E. SCL26A4

B. GJB2

Which one of the following molecular sequencing tests would most likely be the next step in the workup to confirm/rule out genetic etiologies in congenital hearing loss? A. Connexin 30 B. GJB2 and GJB6 C. MYO7A D. SCL26A4, FOXI1, and KCNJ10 E. Usher syndrome NGS panel

B. GJB2 and GJB6 GJB6 (connexin 30)

Congenital hearing loss. A molecular study of the GJB2 and GJB6 genes was ordered, and the results were negative. Which one of the following molecular sequencing tests would most likely be the next step in the workup to further rule out genetic etiologies in this patient? A. Connexin 26 B. Connexin 30 C. Mitochondrial panel D. SCL26A4, FOXI1, and KCNJ10 E. Usher syndrome panel with 11 genes

E. Usher syndrome panel with 11 genes - retinitis pigmentosa is adolescent onset so cannot rule out Usher syndrome - 50% of deafness–blindness in adults., 3-6% of hearing loss - otherwise NGS

36 yo woman with impaired hearing. MRI of inner ear showed normal anatomic structures. A molecular study of the GJB2 and GJB6 genes was ordered, and the results were negative. There was no blindness, vestibular dysfunction, temporal bone abnormalities, dysmorphism or goiter. Which one of the following molecular sequencing studies would most likely be the next step in the workup to further rule out genetic etiologies in this patient? A. Connexin 26 B. Connexin 30 C. Mitochondrial panel D. SCL26A4, FOXI1, and KCNJ10 E. Usher syndrome panel with 11 genes

C. Mitochondrial panel

11 yo girl with familial hearing loss in brother. Then a molecular study of the GJB2 and GJB6 genes detected a homozygous frameshift pathogenic variant, c.35delG, in the GJB2 gene. The family history was negative on both sides. Which one of the following recurrent risks would most likely apply to the parents? A. >99% B. 50% C. 25% D. 5% E. <1% F. Unpredictable

C. 25% AR

A molecular study of the GJB2 gene detected a heterozygous frameshift pathogenic variant, c.35delG. Which one of the following molecular genetics studies would most likely be the next step in the workup to further confirm/rule out genetic etiologies in this patient? A. Connexin 26 B. Connexin 30 C. Mitochondrial panel D. SCL26A4, FOXI1, and KCNJ10 E. Usher syndrome panel with 11 genes

B. Connexin 30 (GJB6) heterozgyous mutations can cause congenital nonsyndrome AR deafness

1 yo girl with congenital bilateral hearing and normal eye exam. Results of a molecular genetics study revealed that the patient had a heterozygous pathogenic missense variant in the GJB2 gene and a heterozygous deletion in the GJB6 gene. Which one of the following statements regarding the pathogenic variants in GJB2 and JGB6 would be most appropriate? A. The variants in GJB2 and GJB6 most likely were in cis. B. The variants in GJB2 and GJB6 most likely were in trans. C. The deletion in GJB6 causes hearing loss in this patient, and GJB2 is a pseudogene. D. The missense variant in GJB2 causes hearing loss in this patient, and GJB6 is a pseudogene. E. None of the above.

B. The variants in GJB2 and GJB6 most likely were in trans.

6 mo AJ girl with bilateral hearing loss. She had abnormal results on newborn hearing testing and auditory brain stem response testing. Which one of the following molecular genetics studies would most likely be used to confirm/rule out genetic etiologies in this patient? A. Chromosomal microarray B. Exome sequencing C. Methylation study D. Next-generation sequencing (NGS) E. Sanger sequencing F. Targeted variant assay G. All of the above

F. Targeted variant assay There are four common pathogenic variants in the Ashkenazi Jewish population—35delG and 167delT in the GJB2 (connexin 26) gene, GJB6 (connexin 30) gene deletion, p.Arg245X in the PCDH15 (USH1F) gene, and p.Asn48Lys in the CLRN1 (USH3A).

16yo girl with deceased parents. The maternal family history is unclear (her mother was an immigrant from Russia). A physical examination is unremarkable. Which one of the following molecular genetics tests is most likely the next step in the workup to confirm/rule out genetic etiologies in this patient? A. CLRN1 B. GJB2 and GJB6 C. PCDH15 D. SCL26A4, FOXI1, and KCNJ10 E. Usher syndrome NGS panel

A. CLRN1 The prevalence of Usher syndrome type III is 1 in 45,000 in the Ashkenazi Jewish population (the carrier frequency is 1 in 107 Ashkenazi Jews). The p.N48K pathogenic variant in the CLRN1 gene is detected in 75% of carriers in the Ashkenazi Jewish population. The p.Arg245Ter (c.733C>T) pathogenic variant in the PCDH15 gene is detected in 95% of carriers in the Ashkenazi Jewish populations, seen in Usher syndrome type 1F (USH1F). -- often with imbalances

AJ preconception planning in normal couple. Paternal brother congenital hearing loss with unknown positive molecular test. Which one of the following most likely describes the risk of the husband being a carrier of the familial pathogenic variant for hearing loss? A. 1 in 1 B. 1 in 2 C. 1 in 4 D. 2 in 3 E. 1 in 25

D. 2 in 3

AJ preconception planning in normal couple. Paternal brother congenital hearing loss with homozygous GJB2 positive molecular test. A molecular genetics study of the husband’s affected sibling detected a homozygous pathogenic variant in the GJB2 gene. The couple received genetic counseling. And a targeted genetic testing was ordered for the husband. Which one of the following pathogenic variants would the husband most likely have if he had one? A. c.35delG B. c.79G>A C. c.167delT D. c.235delC E. c.223C>T

C. c.167delT most common in AJ In the Ashkenazi Jewish population, the prevalence of heterozygosity for 167delT in GJB2, which is rare in the general population, was 4.03% (95% confidence interval, 2.5%–6.0%), and for 30delG the prevalence was 0.73% (95% confidence interval, 0.2%–1.8%). The c.35delG(p.Gly12Valfx*2) pathogenic variant is the most prevalent GJB2 pathogenic variant in Caucasians.

Caucasian couple preconception planning in normal couple. Paternal brother congenital hearing loss with unknown positive molecular test. A molecular genetics study of the husband’s affected sibling detected a homozygous pathogenic variant in the GJB2 gene. The couple received genetic counseling. And a targeted genetic testing was ordered for the husband. Which one of the following pathogenic variants would the husband most likely have if he had one? A. c.35delG B. c.79G>A C. c.167delT D. c.235delC E. c.223C>T

A. c.35delG

13 yo girl with hearing loss and retinitis pigmentosa. A molecular genetics study is ordered. Which one of the following molecular genetics assays provides the most cost-effective genetic testing strategy for this patient? A. Chromosomal microarray B. Multiplex ligation-dependent probe amplification C. Next-generation sequencing D. Quantitative PCR E. Sanger sequencing

C. Next-generation sequencing Usher syndrome CDH23, CLRN1, GPR98, MYO7A, PCDH15, USH1C, USH1G, and USH2A.

The mother mentioned that the infant had been given neomycin (aminoglycoside) at 1 month of age for an ear infection. Which one of the following genes would most likely harbor a pathogenic variant in the infant? A. GJB2 B. GJB6 C. MYO7A D. 12S rRNA in mtDNA E. None of the above

D. 12S rRNA in mtDNA

Hearing loss is one of the most common birth defects; it can affect as many as 3 in 1000 babies born in the United States. How much do genetic factors contribute to congenital hearing loss? A. 5% B. 30% C. 55% D. 80% E. >99%

C. 55%

Which one of the following statements regarding hearing loss is NOT correct? A. Approximately 50% of hearing losses are caused by genetics. B. Approximately 80% of hearing losses with genetic etiologies have recessive causes. C. Approximately 70% of hearing losses with genetic etiologies have nonsyndromic causes. D. Connexin 30 is estimated to be responsible for half of all recessive nonsyndromic hearing losses. E. None of the above.

D. Connexin 30 is estimated to be responsible for half of all recessive nonsyndromic hearing losses. Should be GJB2 or connexin 26

Which one of the following disorders can NOT cause dominant syndromic hearing loss? A. Branchio-oto-renal (BOR) syndrome B. Jervell and Lange-Nielson syndrome C. Neurofibromatosis type II (NFII) D. Stickler syndrome E. Treacher–Collins syndrome F. Waardenburg syndrome

B. Jervell and Lange-Nielson syndrome Lange-Nielsen syndrome is an autosomal recessive condition that causes profound hearing loss from birth and a disruption of the heart’s normal rhythm (arrhythmia). Branchio-oto-renal (BOR) syndrome, neurofibromatosis type II (NFII), Treacher–Collins syndrome, and Waardenburg syndrome are autosomal dominant conditions. Stickler syndrome could be autosomal dominant (COL2A1, COL11A1, and COL11A2) or recessive (COL9A1 and COL9A2)

Which one of the following disorders can NOT cause recessive syndromic hearing loss? A. Usher syndrome B. Pendred syndrome C. Stickler syndrome D. Branchio-oto-renal (BOR) syndrome E. Jervell and Lange-Nielson syndrome F. Alport syndrome

E. Jervell and Lange-Nielson syndrome

12 yo girl with hearing loss, white forelock, thyroid region swelling. Father and brother had similar findings. A clinical diagnosis of Waardenberg syndrome was made. A next-generation sequencing (NGS) panel detected a pathogenic variant, p.Asn47His, in PAX3 in the girl. And the same variant was detected in her brother and father by a targeted variant analysis. Which one of the following molecular genetic assays would most likely be used to confirm the diagnosis in this patient? A. Chromosomal microarray analysis B. Next-generation sequencing C. Sanger sequencing D. Targeted variant assay E. Whole-exome sequencing F. None of the above

B. Next-generation sequencing Pathogenic variants in the EDN3, EDNRB, MITF, PAX3, SNAI2, and SOX10

32 yo with hearing loss, lack of speech, dystopia canthorum (telcanthus), Partial heterochromia and patches of abnormal pigmentation. Son with same findings. Which one of the following genes would most likely be included in this NGS panel for Waardenberg syndrome? A. PAX3 B. PEX3 C. PAX5 D. PEX5 E. PAX7 F. PEX7

A. PAX3 Types I and III Waardenburg syndrome are caused by pathogenic variants in the PAX3 gene. Pathogenic variants in the MITF and SNAI2 genes are responsible for type II Waardenburg syndrome. Pathogenic variants in the SOX10, EDN3, or EDNRB genes cause type IV Waardenburg syndrome

A pathogenic variant, p.Asn47His, in PAX3 was detected; the same variant was detected in her brother and father by a targeted variant analysis. Which one of the following would be the most appropriate estimation of the recurrent risk of the same condition in this family? A. <1% B. 5%–7% C. 14% D. 25% E. 50% F. 100%

E. 50% autosomal dominant

12 yo girl with hearing loss, white forelock, thyroid region swelling. Father and brother had similar findings. A clinical diagnosis of Waardenberg syndrome was made. A next-generation sequencing (NGS) panel detected a pathogenic variant, p.Asn47His, in PAX3 in the girl. And the same variant was detected in her brother and father by a targeted variant analysis. Which one of the following mechanisms would most likely be the pathogenesis of the variant in this family? A. Epigenetic change B. Gain of function C. Loss of function D. Unclear E. None of the above

C. Loss of function

Which one of the following inheritances is most appropriate to describe mitochondrial DNA (mtDNA) depletion syndromes? A. Autosomal dominant B. Autosomal recessive C. Mitochondrial inherited D. X-linked E. Not clear

B. Autosomal recessive

Which one of the following statements regarding Leber hereditary optic neuropathy (LHON) is NOT correct? A. It is caused by pathogenic variants in nuclear DNA encoded for mitochondria proteins. B. More than 50% of males with pathogenic variant(s) never experience vision loss or related health problems. C. More than 85% of females with pathogenic variant(s) never experience vision loss or related health problems. D. LHON is a young-adult-onset disorder. E. None of the above.

A. It is caused by pathogenic variants in nuclear DNA encoded for mitochondria proteins.

Differential diagnosis included drug toxicity, metabolic disease, syphilis, hereditary optic atrophy or neuropathy (LHON), and compressive lesion. A molecular genetics study was ordered for LHON. Which one of the following molecular genetics assays would provide the most cost-effective genetic testing strategy for this patient? A. Chromosomal microarray B. Multiplex ligation-dependent probe amplification C. Next-generation sequencing D. Quantitative PCR E. Sanger sequencing F. Targeted variants analysis

F. Targeted variants analysis Three common mtDNA pathogenic variants account for 90%–95% of LHON.

Hereditary optic atrophy or neuropathy (LHON) was suspected. A molecular genetic study was ordered and confirmed the diagnosis. Which one of the following pathogenic variants would the patient most likely? A. m.3243A>G MTTL1 B. m.3460G>A in MTND1 C. m.8993T>C in MTATP6 D. m.8344A>G in MTTK E. All of the above F. None of the above

B. m.3460G>A in MTND1 Three common mtDNA pathogenic variants account for 90%–95% of hereditary optic atrophy or neuropathy (LHON). They are m.3460G>A in MTND1, m.11778G>A in MTND4, or m.14484T>C in MTND6. mitochondrially encoded NADH dehydrogenase 1

Based on the clinical symptoms and signs, hereditary optic atrophy or neuropathy (LHON) was suspected. A molecular genetics study was ordered and confirmed the diagnosis. Which one of the following pathogenic variants would the patient most likely have? A. Heteroplasmic m.11778G>A in MTND1 B. Homoplasmic m.11778G>A in MTND1 C. Heteroplasmic m.11778G>A in MTND4 D. Homoplasmic m.11778G>A in MTND4 E. None of the above

D. Homoplasmic m.11778G>A in MTND4

A diagnosis of bilateral optic neuropathy with a clinical suspicion of Leber hereditary optic neuropathy (LHON) was made. Which one of the following statements regarding Leber hereditary optic neuropathy (LHON) is *NOT* correct? A. It happens more frequently in males than in females. B. It is a mitochondrial disorder caused by mtDNA with heteroplasmy in some patients. C. It is a mitochondrial disorder caused by nuclear DNAs. D. Patients with LHON usually lose their vision in young adulthood. E. None of the above.

C. It is a mitochondrial disorder caused by nuclear DNAs.

A male with a diagnosis of bilateral optic neuropathy with a clinical suspicion of Leber hereditary optic neuropathy (LHON) was made. A blood sample was submitted for genetic analysis, and a homoplasmic pathogenic variant in m.11778 was detected. Which one of the following would be the risk of his future children having vision loss due to LHON? A. <1% B. 10% C. 25% D. 50% E. >99% F. Unpredictable G. None of the above

A. <1% maternally inherited

A diagnosis of bilateral optic neuropathy with a clinical suspicion of Leber hereditary optic neuropathy (LHON) was made. A blood sample was submitted for genetic analysis, and a homoplasmic pathogenic variant in m.3460 was detected. Which one of the following would be the recurrent risk of LHON in this family? A. <1% B. 10% C. 25% D. 50% E. >99% F. Unpredictable G. None of the above

F. Unpredictable The presence of the mtDNA pathogenic variant does not predict the occurrence, age at onset, severity, or rate of progression of visual loss. Therefore, the recurrent risk of LHON would not be predictable in this family.

48 yo with diabetes, elevated HbA1C and sensorineural hearing loss. Which one of the following genes would most likely harbor a pathogenic variant? A. MTATP6 B. MTND1 C. MTTH D. MTTL1 E. None of the above

D. MTTL1 Maternally inherited diabetes and deafness (MIDD) syndrome is a mitochondrial disorder, representing 1% of patients with diabetes. Pathogenic variants in MTTL1, MTTK, or MTTE have been seen in patients with maternally inherited diabetes and deafness (MIDD). The majority of MIDD patients have a pathogenic variant, m.3243A>G in MTTL1, which is typically in heteroplasmic form. MTTL1, MTTK, and MTTE encode tRNAs. Pathogenic variants in MTTL1, MTTK, or MTTE reduce the ability of tRNA to add amino acids for protein synthesis

She reported mild numbness and tingling in her feet and hands. Maternally inherited diabetes and deafness syndrome (MIDD) was suspected and a molecular study was ordered for it. Which one of the following pathogenic variants would the patient most likely have? A. Heteroplasmic m.11778G>A in MTND4 B. Homoplasmic m.11778G>A in MTND4 C. Heteroplasmic m.3243A>G IN MTTL1 D. Homoplasmic m.3243A>G IN MTTL1 E. None of the above

C. Heteroplasmic m.3243A>G IN MTTL1

13 yo girl with progressive decline, MERRF and maternal MSL/Madelungs disease.Which one of the following genes would most likely harbor a pathogenic variant in this patient? A. MTATP6 B. MTND1 C. MTTK D. MTTL1 E. None of the above

C. MTTK

A muscle biopsy showed ragged red COX-deficient fibers. A molecular study for mtDNA was ordered to confirm the diagnosis of myoclonic epilepsy with ragged red fibers (MERRF), and a pathogenic variant was detected. Which one of the following pathogenic variants would the patient most likely have? A. Heteroplasmic m.14484T>C in MTND6 B. Homoplasmic m.14484T>C in MTND6 C. Heteroplasmic m.8344A>G in MTTK D. Homoplasmic m.8344A>G in MTTK E. None of the above

D. Homoplasmic m.8344A>G in MTTK

A diagnosis of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome was suspected. A molecular study for mtDNA was ordered to confirm the diagnosis, and a pathogenic variant was detected. Which one of the following genes would most likely harbor a pathogenic variant in this patient? A. MTATP6 B. MTND1 C. MTTK D. MTTL1 E. None of the above

D. MTTL1 mitochondrially encoded tRNA-Leu (UUA/G) 1

2-year-old firstborn son with profound congenital bilateral hearing loss had arrhythmia related to a long QT interval found recently on ECG. The family history was unremarkable on both sides (see the figure below for the pedigree). Which one of the following disorders would the son most likely have if there was a genetic etiology? A. Andersen–Tawil syndrome B. Jervell and Lange-Nielsen syndrome C. Romano–Ward syndrome D. Timothy syndrome E. Usher syndrome

B. Jervell and Lange-Nielsen syndrome AR - carrier with long-QT syndrome KCNQ1 and KCNE1 genes

Pregnant couple presents for prenatal counseling. Their 2 yo boy was diagnosed with Jervell and Lange-Nielsen syndrome clinically. A molecular genetics study was pending. What would most likely be the risk that the fetus had the same disorder if the couple’s firstborn son had Jervell and Lange-Nielsen syndrome? A. <1% B. 25% C. 50% D. 75% E. >99%

B. 25%

A 2 yo boy was diagnosed with Jervell and Lange-Nielsen syndrome clinically. What would most likely be the risk that the fetus had the same long-QT intervals as his brother? A. Up to 1% B. Up to 25% C. Up to 50% D. Up to 75% E. Up to 100%

D. Up to 75% 25% JLNS + 50% carrier so 75% long-QT syndrome

Pregnant couple presents for prenatal counseling. Their 2 yo boy was diagnosed with long-QT syndrome. A molecular test revealed that both the mother and the son has a missense pathogenic variant in the KCNQ1 gene. Neither the mother nor the son had hearing loss or facial dysmorphic features. The mother had no history of fainting episodes and had been apparently healthy. Subsequent ECG confirmed the diagnosis for the mother. What would most likely be the risk that the fetus had long-QT syndrome? A. <1% B. 25% C. 50% D. 75% E. 100%

C. 50% Romano–Ward syndrome is one the autosomal dominant long-QT syndromes, caused by pathogenic variants in the KCNQ1 and KCNE1 genes. Autosomal dominant

What type of genes tend to be mutated in patients with long-QT syndrome? A. Myofilament proteins of the sarcomere B. Cardiac potassium channels C. Cardiac sodium channels D. Cardiac chloride channels E. Cardiac bicarbonate channels

B. Cardiac potassium channels Hypertrophic cardiomyopathy is caused by pathogenic variants in approximately 20 genes encoding proteins of the cardiac sarcomere.

Hypertrophic cardiomyopathy is one of the most common monogenic autosomal dominant cardiovascular diseases, which is caused by pathogenic variants in approximately 20 genes encoding proteins of the cardiac sarcomere. What is the maximum clinical sensitivity of a next-generation sequencing (NGS) panel of all 20 genes for hypertrophic cardiomyopathy? A. <1% B. 25% C. 55% D. 85% E. >99%

C. 55%

48 yo present with MI. His LDL cholesterol level was 249 mg/dL and total cholesterol 465 mg/dL at the time of admission. The family history was remarkable for coronary artery diseases in multiple members (see the figure below for the pedigree). Which one of the following inherited modes would the disorder most likely be in this family if it was genetic? A. Autosomal dominant B. Autosomal recessive C. Mitochondrial inherited D. X-linked E. None of the above

A. Autosomal dominant

Married man with a 13-year-old son and a brother. A molecular genetics study detected a heterozygous variant c.34C>T(p.Gln12Ter), in LDLR in this patient. His brother has a cholesterol of 300 mg/dL. Which one of the following family members should also be tested for familial hypercholesterolemia? A. His wife and son B. His brother and son C. His wife, brother, and son D. His brother, son, and all the other first-degree relatives E. His first-degree relatives older than 18 years F. None of the above

D. His brother, son, and all the other first-degree relatives

Familial hypercholesterolemia (FH) is suspected. Which one of the following genes may be tested for pathogenic variant(s) in this patient? A. APOB B. LDLR C. PCSK9 D. All of the above E. None of the above

D. All of the above

Familial hypercholesterolemia (FH) is suspected. Which one of the following pathogenic variants does the patient most likely have? A. Heterozygous c.3997C>T(p. Arg1306Ter) in APOB B. Homozygous c.3997C>T(p. Arg1306Ter) in APOB C. Heterozygous c.34C>T(p.Gln12Ter) in LDLR D. Homozygous c.34C>T(p.Gln12Ter) in LDLR E. None of the above

C. Heterozygous c.34C>T(p.Gln12Ter) in LDLR fyi Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)

Which one of the following disorders is associated with age-related penetrance? A. Familial hypercholesterolemia B. Hereditary hemochromatosis C. Huntington disease D. Hypertrophic cardiomyopathy E. All of the above F. None of the above

E. All of the above

Which one of the following disorders is associated sex-related penetrance? A. Familial hypercholesterolemia B. Hereditary hemochromatosis C. Huntington disease D. Hypertrophic cardiomyopathy E. All of the above F. None of the above

B. Hereditary hemochromatosis Reports suggest that of p.Cys282Tyr homozygotes, a higher proportion of males than females (28% vs. 1%) have definite disease manifestation of HFE-associated hereditary hemochromatosis because the menstrual period in adult females is preventive. fyi - hypokalemic periodic paralysis - SCNA4 - lower attacks in females BRCA2- less breast cancer in men

Which one of the following genes would most likely be tested in a patient with long segment Hirschsprung disease? A. EDN3 B. MEN1 C. RAS D. RB1 E. RET

E. RET RET, SOX10, EDNRB (endothelin receptor type B), and EDN3 (endothelin 3), other genes implicated in HSCR (long segment Hirschprung) include L1CAM, NRG1, and SEMA3C. NRTN, GDNF

The molecular genetics test results showed that both the proband (long segment Hirschsprung disease) and his mother had a pathogenic variant in the RET gene. Which one of the following statements explains the discrepancy of clinical presentation in the family? A. The pathogenic variant from the paternal copy is missed by the molecular test. B. Low (incomplete) penetrance explains why the mother does not have the disease. C. The disease affects only males. D. The test results were wrong. The sample should be sent to another lab to be tested again. E. Peripheral blood is the wrong sample type. An FFPE sample from resected colon should be sent for the study.

B. Low (incomplete) penetrance explains why the mother does not have the disease. RET alleles, penetrance is 65% in males and 45% in females.

The genetics of Hirschsprung disease are complex and are not completely understood. How frequently does Hirschsprung disease have an identifiable genetic etiology? A. 10% B. 30% C. 50% D. 70% E. 90% F. >99%

C. 50%

If a molecular study is performed to explore the genetic etiology of the Hirschsprung disease in this patient, which one of the following molecular genetic assays is most likely be used to explore the genetic etiology of the Hirschsprung disease in this patient? A. Chromosomal microarray analysis B. Next-generation sequencing C. Sanger sequencing D. Targeted variant assay E. Whole-exome sequencing F. None of the above

B. Next-generation sequencing

Which one of the following disorders is NOT associated with an elevated risk for intestinal obstruction in newborns? A. Cystic fibrosis B. Hirschsprung disease C. Multiple endocrine neoplasia type 1 (MEN1) D. Multiple endocrine neoplasia type 2 (MEN2) E. Waardenburg syndrome F. All of the above G. None of the above

C. Multiple endocrine neoplasia type 1 (MEN1) some conditions associated with Hirschsprung disease, such as Down syndrome, Waardenburg syndrome, neurofibromatosis, neuroblastoma, pheochromocytoma, multiple endocrine neoplasia type 2B (MEN2B), and others. MEN1 (for MEN1), RET (for MEN2), and CDKN1B (for MEN4) Multiple endocrine neoplasia type 1 (MEN1) includes varying combinations of more than 20 endocrine and nonendocrine tumors; the most common ones are parathyroid tumors, pituitary tumors, well-differentiated endocrine tumors of the gastroenteropancreatic (GEP) tract, carcinoid tumors, and adrenocortical tumors.

In which one of the following populations does Hirschsprung disease have the highest incidence? A. Female infants B. Male infants C. Female adults D. Male adults E. None of the above

B. Male infants 1 in 5000 births with a 4:1 predominance in males.

The wife had neurofibromatosis 1 (NF1) with a deleterious variant, p.Lys1423Glu, in the NF1 gene. The husband was apparently healthy. The family history was unremarkable on both sides. Which one of the following would most likely be the risk of their first child having NF1? A. <1% B. 25% C. 50% D. >99% E. Unclear F. None of the above

C. 50% AD

A 16 yo girl was diagnosed with neurofibromatosis 1 (NF1) clinically. A molecular genetics study detected a deleterious variant, p.Lys1423Glu, in the NF1 gene. Which one of the following would most appropriately describe the pathogenic variant identified in this teenage girl? A. Dominant negative variant B. Gain-of-function variant C. Loss-of-function variant D. De novo variant E. None of the above

C. Loss-of-function variant

The family history was unremarkable on both sides. A molecular genetics study detected a deleterious variant, p.Lys1423Glu, in the NF1 gene. Targeted molecular genetic analysis of the parents did not identify the same variant. Which one of the following descriptions would most likely be appropriate for the genetic etiology of NF1 in this family? A. Most likely the teenage girl had a maternally derived de novo pathogenic variant in NF1. B. Most likely the teenage girl had a paternally derived de novo pathogenic variant in NF1. C. It is hard to tell the origin of the de novo pathogenic variants in the teenage girl. D. Testing of the father may be suggested to further interpret the results in the family. E. None of the above.

B. Most likely the teenage girl had a paternally derived de novo pathogenic variant in NF1. Approximately 80% of the de novo pathogenic variants are paternal in origin, but there is no evidence for a paternal age effect increasing the mutation rate.

The family history was remarkable for the girl’s 9-year-old brother also being diagnosed with NF1. A molecular genetics study of the girl detected a deleterious variant, p.Lys1423Glu, in the NF1 gene. Targeted molecular genetic analysis of the parents and the brother found that none of them had the same variant. Subsequently genetics study of the girl’s brother identified a deletion involving exons 3, 4, and 5. Which one of the following might explain the discrepancy between clinical diagnoses and genetic testing results in this family? A. More than one de novo pathogenic variant exists in this family. B. Alternative paternity is possible in this family. C. Alternative maternity is possible through assisted reproduction in this family. D. One or both children in this family was adopted. E. All of the above. F. None of the above.

E. All of the above.

A molecular genetics study of the girl detected a deleterious variant, p.Lys1423Glu, in the NF1 gene. Targeted molecular genetics analysis of the parents and the brother found that the parents did not have the same variant but that the brother did. Which one of the following might explain the genetic findings in this family? A. More than one de novo pathogenic variant exists in this family. B. One of the parents was mosaic for the pathogenic variant. C. Alternative paternity is possible in this family. D. Alternative maternity is possible through assisted reproduction in this family. E. One or both children in this family is adopted. F. All of the above. G. None of the above.

F. All of the above.

The family history was remarkable for the girl’s 9-year-old brother also being diagnosed with NF1. A molecular genetics study of the girl did not detect pathogenic variant(s) in the NF1 gene. Which one of the following would be the most appropriate interpretation of the negative genetic results in this patient? A. She may still have NF1. B. She did not have NF1. C. She may have NF2. D. She may have NF3. E. All of the above. F. None of the above.

A. She may still have NF1.

Which one of the following benign or malignant tumors would a girl with NF1 LEAST LIKELY have an increased risk to develop? A. Central nervous system tumors B. Clear-cell renal-cell carcinoma C. Malignant myeloid disorders D. Optic-nerve gliomas E. Pheochromocytoma

B. Clear-cell renal-cell carcinoma FYI- JMML, pheochromocytoma, MPNST

In which of the following disorders are Lisch nodules a common feature? A. Hereditary hemochromatosis B. Neurofibromatosis 1 C. Neurofibromatosis 2 D. Tuberous sclerosis E. Wilson disease

B. Neurofibromatosis 1 benign hamartomas

In which of the following disorders is vestibular schwannoma is a common feature? A. Hereditary hemochromatosis B. Neurofibromatosis 1 C. Neurofibromatosis 2 D. Tuberous sclerosis E. Wilson disease

C. Neurofibromatosis 2

Which one of the following tumors is one of the primary tumor types in patients with neurofibromatosis 2 (NF2)? A. Neurofibroma B. Optic-nerve glioma C. Pheochromocytoma D. Schwannoma E. None of the above

D. Schwannoma

A clinical diagnosis of neurofibromatosis 2 (NF2) was made. Sanger sequencing and deletion/duplication testing of NF2 did not detect pathogenic variants. Which one of the following would be the most appropriate next step in the workup to identify the genetic etiology of this patient’s NF2? A. Exome sequencing B. Linkage study C. Molecular testing for NF1 D. Using fibroblast cells to test NF2 E. Whole-genome sequencing F. None of the above

D. Using fibroblast cells to test NF2

Based on clinical findings, a diagnosis of neurofibromatosis 2 (NF2) was made. Sanger sequencing and deletion/duplication testing of NF2 was pending. The patient’s wife was 10 weeks pregnant with their first baby. Which one of the following would be the most appropriate estimation of the fetus’s risk for NF2? A. <1% B. Up to 25% C. Up to 50% D. >99% E. Not sure F. None of the above

C. Up to 50%

Based on clinical findings and family history, a diagnosis of neurofibromatosis 2 (NF2) was made. Sanger sequencing of NF2 detected a pathogenic variant, c.1604T>C(p.Leu535Pro). The patient had a 14-year-old brother who remained asymptomatic but wanted to find out his risk for NF2. Which one of the following would be the most appropriate response to the request from the proband’s younger brother? A. Referring him to a pediatric clinic B. Refusing to test him, since NF2 is an adult-onset disease C. Refusing to test him, since insurance would not pay for testing of asymptomatic individuals D. Testing him for the familial pathogenic variant E. None of the above

A. Referring him to a pediatric clinic

A molecular genetics study was ordered to further assist the diagnosis of a 13 yo with ash leaf spots and cortical tubers. Which of the following genes would most likely be included in the molecular test for this patient? A. TSC1 B. TSC2 C. TSC3 D. A and B E. A and C F. A, B, and C G. None of the above

D. A and B

Which one of the following would most likely be the recurrent risk of TSC in a family with no FHx? A. <1% B. 25% C. 50% D. 99% E. Unpredictable

A. <1% likely de novo

What is the de novo mutation rate of TSC? A. <1% B. 15% C. 33% D. 50% E. 67% F. 99%

E. 67%

In which one of the following populations is the prevalence of Rett syndrome highest? A. Ashkenazi Jewish B. Boys C. Caucasians D. Girls E. Late adulthood F. Mediterranean

D. Girls

Based on these findings, the neurologist suggested a diagnosis of Rett syndrome. Which one of the following genes would most likely be tested to confirm the diagnosis in this patient? A. CDKL5 B. DCX C. FMR1 D. FOXG1 E. LIS1 F. MECP2

F. MECP2

Genetic testing detected a pathogenic variant, c.808C>T(p.Arg270Ter), in the MECP2 gene. Peripheral-blood samples from the parents were collected for a targeted molecular analysis. Which one of the following would most likely be the detection rate in at least one of the parents?A. <1% B. 25% C. 50% D. >99% E. Unpredictable

A. <1% de novo rarely from X-skewing

D. FOXG1 Two other genes, CDKL5 and FOXG1, can lead to Rett-like phenotypes. Pathogenic variants in CDKL5 at Xp22.13 are most likely to be found in females with early-onset severe seizures who have poor cognitive development but little in the way of Rett syndrome-like features, and they may be found in males with profound intellectual disability and early-onset intractable seizures. Pathogenic variants in FOXG1 are associated with the congenital form of Rett syndrome. FOXG1 on 14q12 are as likely to affect males as female. LIS1 and DCX are associated with lissencephaly.

Which one of the following molecular genetic assays would most likely be used for the genetic study offered to this RETT syndrome patient as the first-line test? A. Chromosomal microarray B. Deletion/duplication array C. FISH D. Karyotype E. Sanger sequencing F. Targeted variant assays

E. Sanger sequencing

In which one of the following populations does the MECP2 duplication syndrome most likely occur? A. Ashkenazi Jewish B. Boys C. Caucasians D. Girls E. Late adulthood F. Mediterranean

B. Boys B. MECP2 duplication syndrome is a panethnic severe neurodevelopmental disorder characterized by infantile hypotonia, delayed psychomotor development leading to severe intellectual disability, poor speech development, progressive spasticity, recurrent respiratory infections (in approximately 75% of affected individuals), and seizures (in approximately 50%). MECP2 duplication syndrome is 100% penetrant in males.

Which one of the following tests would most likely be ordered than others to confirm or rule out the Rett syndrome diagnosis in this patient? A. Deletion and duplication analysis of the CDKL5 gene B. Deletion and duplication analysis of the FOXG1 gene C. Deletion and duplication analysis of the MECP2 gene D. Sequencing analysis of the CDKL5 gene E. Sequencing analysis of the FOXG1 gene F. Sequencing analysis of the MECP2 gene G. None of the above

F. Sequencing analysis of the MECP2 gene

A molecular genetics study was ordered, and a pathogenic variant, c.806delG(p.V288X) in the MECP2 gene, was detected. During the evaluation, the mother was pregnant with a boy. Which one of the following would most likely be the risk of this future sibling have Rett syndrome? A. <1% B. 25% C. 50% D. 67% E. >99% F. None of the above

A. <1% Rett syndrome is an X-linked neurodevelopmental disorder that primarily affects girls and is lethal in embryonic males.

Which one of the following tests would most likely be ordered than others to confirm or rule out the Rett syndrome diagnosis in this male patient? A. Deletion and duplication analysis of the CDKL5 gene B. Deletion and duplication analysis of the FOXG1 gene C. Deletion and duplication analysis of the MECP2 gene D. Sequencing analysis of the CDKL5 gene E. Sequencing analysis of the FOXG1 gene F. Sequencing analysis of the MECP2 gene G. None of the above

C. Deletion and duplication analysis of the MECP2 gene 80% of patients with classic Rett syndrome have sequence variants detectable by sequencing of the gene, and 8% of patients with classic Rett syndrome have partial or whole gene deletions,

next-generation sequencing (NGS) panel for epilepsy. Which one of the following genes would least likely be included in this panel? A. FOXP3 B. KCNQ2 C. MECP2 D. SCN1A E. None of the above

A. FOXP3

Pathogenic variant for benign familial neonatal seizures (BFNS)? A. Chloride channels B. GABA receptor C. Nicotinic acid receptor D. Potassium channels E. Sodium channels

D. Potassium channels

Pseudohypoparathyroidism type 1B was suspected. A molecular study was ordered to confirm the diagnosis after the patient stabilized. Which one of the following molecular genetic assays would most likely be used as the first-line test to confirm the diagnosis in this patient? A. Chromosomal microarray B. FISH C. Methylation study D. Multiplex ligation-dependent probe amplification (MLPA) E. Next-generation sequencing F. Sanger sequencing

C. Methylation study PHP-1A (Albright hereditary osteodystrophy) has a characteristic phenotypic appearance, including short fourth and fifth metacarpals and rounded facies. It is also associated with resistance to thyroid-stimulating hormone. PHP-1A, 1B, and 1C are associated with lack of expression/function of the protein Gsα (encoded by the maternal GNAS complex locus) as a result of: (1) an inactivating GNAS pathogenic variant; (2) a genetic alteration in the imprinting regulatory elements in the GNAS complex locus or the nearby gene, STX16, that prevents proper maternal imprint of the GNAS complex locus; (3) isolated epimutations; and (4) uniparental paternal 20q disomy. PHP-1B is usually unknown; however, broad GNAS imprinting abnormalities involving multiple GNAS exon A/B differentially methylated regions (DMRs) have been observed in most affected individuals, some of whom had molecular genetic findings consistent with paternal uniparental 20q isodisomy (https://www.ncbi.nlm.nih.gov/books/NBK459117/). The patient’s family history was unremarkable, indicating that he is likely the only affected member in his family (singleton). Therefore, methylation study would most

The results showed hypermethylation at the NESP55 and hypomethylation at NESPAS, GNAS XL and GNAS A/B. Which one of the following genes is exclusively maternally expressed? A. GNAS A/B B. GNAS XL C. NESP55 D. NESPAS E. All of the above F. None of the above

C. NESP55 the GNAS locus would give rise to several transcripts, including alpha-subunit of the heterotrimeric stimulatory G protein α (Gαs), the Gαs extra-large variant (XLαs), neuroendocrine protein 55 (NESP55), untranslated exon A/B (exon 1A) and antisense transcript (AS). The NESP55 is maternal derived while the GNAS XLαs, AS, and A/B transcripts are exclusively paternally derived. Meng, Haiying. Self-assessment Questions for Clinical Molecular Genetics (pp. 691-692). Academic Press. Kindle Edition.

The results showed hypermethylation at the NESP55 and hypomethylation at the NESPAS, GNAS XL, and GNAS A/B. Which one of the following disorders would this patient most likely have? A. Pseudohypoparathyroidism type 1A B. Pseudohypoparathyroidism type 1B C. Pseudohypoparathyroidism type 2 D. Not sure E. None of the above

***B. Pseudohypoparathyroidism type 1B

Pseudohypoparathyroidism type 1B (PHP-1B) was suspected. A molecular study was ordered to confirm the diagnosis. Which one of the following testing results would most likely confirm the diagnosis of PHP-1B? A. Hypermethylation of GNAS A/B B. Hypermethylation of GNAS XL C. Hypermethylation of NESP55 D. Hypermethylation of NESPAS E. None of the above

***B. Hypermethylation of GNAS XL imprinting. Gsα is encoded by GNAS exons 1–13 from the transcript variant NM_000516.5, which is expressed from both maternal and paternal alleles in most cells. However, in some cells (e.g., pituitary somatotropes, proximal renal tubular cells, thyroid epithelial cells, and gonadal cells), Gsα is primarily expressed from the maternal allele; preferential maternal expression may also occur in other tissues. While the Gsα promoter is not methylated, it appears that cis-acting elements that control tissue-specific paternal imprinting of Gsα are located within the primary imprint region Pseudohypoparathyroidism (PHP)-1A and PHP-1C result from lack of expression of the maternal allele. Pseudopseudohypoparathyroidism (PPHP) results from lack of expression of the paternal allele. Progressive osseous heteroplasia (POH) and osteoma cutis (OC) can be associated with pathogenic variants in either the maternal or paternal allele; however, paternal pathogenic variants are more common.

Which one of the following pathogenic variants is most likely detected than others in a patient with pseudohypoparathyroidism (PHP)? A. De novo c.725Cdel in GNAS B. Maternally inherited c.725Cdel in GNAS C. Paternally inherited c.725Cdel in GNAS D. All of the above E. None of the above

***B. Maternally inherited c.725Cdel in GNAS

Heterozygous 3-bp deletion, p.Ile382del, in the GNAS gene was detected in this patient. Targeted variant studies detected the same pathogenic variant in his two affected brothers, their mother, and the maternal grandfather. At the time, his mother was pregnant with a girl. Which one of the following would most likely be the estimated risk that this unborn girl has the same condition? A. <1% B. 5%–7% C. 14% D. 25% E. 50% F. 100%

***E. 50% PHP-1B is a renal-specific resistance to PTH that lacks the phenotypic features and bone deformities seen in the more classic PHP-1A, but it is biochemically similar. The proband and his three brothers inherited the mutated GNAS allele from their mother. Their mother may have pseudopseudohypoparathyroidism (PPHP) or progressive osseous heteroplasia (POH), since she inherited the mutated allele from her father. Therefore, the unborn girl would have 50% risk to inherit the pathogenic variant from the mother to be affected with PHP.

Which one of the following characteristics is NOT common in patients with pseudohypoparathyroidism (PHP)? A. Increased 1,25-(OH)2D3 B. Decreased calcitriol C. Decreased calcium D. Increased parathyroid hormone (PTH) E. Increased phosphates

A. Increased 1,25-(OH)2D3 calcitriol, vitamin D3

A molecular study detected a pathogenic variant, c.344C>T(p.Pro115Leu), in the GNAS gene in his peripheral-blood specimen. Which one of the following would most likely be the estimated risk that this patient’s children would have the same condition? A. <1% B. 5%–7% C. 14% D. 25% E. 50% F. 100%

E. 50% complex GNAS gene locus located at 20q13.32. Maternal transmission causes PHP, whereas paternal transmission leads to PPHP or a more progressive form, progressive osseous heteroplasia (POH).

***A. <1% Therefore, this female patient’s children would have less than 1% risk to develop PPHP but a 50% risk to develop PHP by inheriting the pathogenic allele from this patient.

Which one of the following characteristics is NOT common in patients with pseudopseudohypoparathyroidism (PPHP)? A. Decreased calcitriol B. Decreased calcium C. Increased parathyroid hormone (PTH) D. Increased phosphates E. None of the above

E. None of the above The term pseudopseudohypoparathyroidism (PPHP) is used to describe a condition in which the individual has the phenotypic appearance of pseudohypoparathyroidism type 1a (PHP-1A) but is biochemically normal.

A routine CVS, done at 11 weeks of gestation for advanced maternal age, documented a normal female karyotype (46,XX). An ultrasound evaluation detected normal male external genitalia. Which one of the following analyses would most likely be used as the initial evaluation for the gender discrepancy in this fetus? A. FISH for the AZFa, AZFb, and AZFc genes B. FISH for the SRY gene C. Maternal cell contamination testing D. Sequencing the AR gene for androgen insensitivity E. Sequencing the CYP21A2 gene for congenital adrenal hyperplasia F. Waiting until the baby is born

C. Maternal cell contamination testing Deletions of the AZFa, AZFb, and AZFc genes on the long arm of the Y chromosome (Yq11.22) have been identified in patients with oligospermia and azoospermia. The SRY gene at Yp11.2, also called “testis determining factor,” encodes for a DNA-binding protein involving in male sexual development.

B. FISH for the SRY gene Deficiency of 21-hydroxylase, resulting from pathogenic variants or deletions of CYP21A, is the most common form of congenital adrenal hyperplasia (CAH) (90%).

Which of the following analyses is most likely used as the initial evaluation for ambiguous genitalia in this fetus? A. FISH for the AZFa, AZFb, and AZFc genes B. FISH for the SRY gene C. Sequencing the AR gene for androgen insensitivity D. Sequencing the CYP21A2 gene for congenital adrenal hyperplasia E. None of the above

D. Sequencing the CYP21A2 gene for congenital adrenal hyperplasia The most common cause of ambiguous genitalia is congenital adrenal hyperplasia. Deficiency of 21-hydroxylase, resulting from pathogenic variants or deletions of CYP21A, is the most common form of CAH, accounting for more than 90% of cases.

Which of the following would be used for initial evaluation for gonadal dysgenesis in this newborn? A. Chromosomal microarray analysis B. Exome sequencing C. FISH for the SRY gene D. Sequencing the SRY gene E. None of the above

B. Exome sequencing Swyer syndrome, or XY gonadal dysgenesis, is a type of hypogonadism in a person whose karyotype is 46,XY. Approximately 20%–30% of 46,XY females with complete gonadal dysgenesis have a pathogenic variant or deletion of the SYR gene. Other genetic alterations, such as DAX duplication, autosomal deletions (1p, 2q, 9p, and 10q), and WT1 pathogenic variants, may also cause XY gonadal dysgenesis.

A chromosomal microarray analysis identified a microdeletion on chromosome Y including the SRY gene. Which one of the following disorders would the newborn NOT be at increased risk to develop? A. Breast cancer B. Dysgerminoma C. Gonadoblastoma D. Infertility E. None of the above

***A. Breast cancer increased risk of dysgerminoma or gonadoblastoma, which is approximately 20%–30% without medical intervention.

A chromosomal analysis revealed a normal female karyotype (46,XX). A physical examination revealed penoscrotal hypospadias and cryptorchidism without identifiable Müllerian structures. Which one of the following would least likely be part of the workup for the diagnosis? A. Sequencing analysis of CYP21A2 B. Sequencing analysis of SOX9 C. SOX3 FISH D. SOX9 FISH E. SRY FISH

B. Sequencing analysis of SOX9 Most of 46,XX male patients have a normal SRY gene translocated to an X chromosome, especially when the patients have a normal male appearance at birth. In patients without the SRY gene, duplication of SOX3, or SOX9 have been described.

Which of the following analyses would most likely be used as the initial genetic evaluation for this Prader Willi patient? A. Chromosomal microarray analysis B. FISH for the 15q 11.2 deletion C. Karyotyping D. Methylation study E. Sequencing of the UBE3A gene

D. Methylation study Methylation analysis may identify patients with Prader–Willi/Angelman syndrome caused by deletion, UPD, and imprinting center pathogenic variants (https://decipher.sanger.ac.uk/syndrome). It determines whether the region is maternally inherited only (e.g., the paternally contributed region is absent) and detects more than 99% of affected individuals

The physician suspected that the patient had Angelman syndrome. Which one of the following analyses would most likely be used as the initial genetic evaluation for this patient? A. FISH for the 15q 11.2 deletion B. Chromosomal microarray analysis C. Karyotyping D. Methylation study E. Sequencing of the UBE3A gene

D. Methylation study Methylation analysis may identify patients with Prader–Willi/Angelman syndrome caused by deletion, UPD, and imprinting center pathogenic variants (https://decipher.sanger.ac.uk/syndrome). It determines whether the region is paternally inherited only (e.g., the maternally contributed region is absent) and detects approximately 80% of affected individuals

***

Constitutional BRAF pathogenic variants have NOT been detected in patients with which one of the following? A. Cardiofaciocutaneous (CFC) syndrome B. Cowden syndrome C. LEOPARD syndrome D. Noonan syndrome E. None of the above

***B. Cowden syndrome

The physician suspected that the patient had Noonan syndrome. Which one of the following genes would LEAST likely harbor a pathogenic variant for Noonan syndrome in this patient? A. KIT B. KRAS C. NRAS D. PTPN11 E. RAF1 F. SOS1

***A. KIT

***

Laboratory testing revealed very low levels of T and NK cells, but relatively normal B cells. A clinical diagnosis of X-linked severe combined immunodeficiency (SCID) was made. Which one of the following genes would most likely be tested first to confirm/rule out the diagnosis in this patient? A. ADA B. FOXP3 C. IL2RG D. STAT3 E. WAS F. ZAP70

C. IL2RG ADA is autosomal recessive FOXP3- IPEX

Which one of the following molecular genetic assays would most likely be used to confirm the diagnosis of SCID with a positive (low) TREC result? A. Chromosomal microarray analysis B. Next-generation sequencing C. Sanger sequencing D. Targeted variant assay E. Whole-exome sequencing F. None of the above

B. Next-generation sequencing TREC - TCR excision circles- PCR of thymus X-SCID remains one of the most common forms of SCID. The clinical presentations of X-SCID, JAK3-SCID, and IL7R-SCID are identical. In X-SCID, only males are affected; in JAK3- and IL7R-SCID, both males and females are affected. And a growing list of rare causes of SCID-like phenotypes include pathogenic variants in the following additional genes: CD3G, CD8A, CHD7, CIITA, DOCK8, FOXN1, LCK, LIG4, MTHFD1, NBS1, NHEJ1, ORAI1, PCFT, PGM3, PNP, PRKDC, RFX-B, RFXANK, RFX5, RFXAP, RMRP, STIM1, TBX1, TTC7A, ZAP70

Which one of the following genes would LEAST LIKELY be an appropriate candidate gene for the SCID in this patient? A. ADA B. IL2RG C. JAK3 D. STAT3 E. ZAP70

D. STAT3

6 yo girl with recurrent respiratory infections and low T and NK cells. Which one of the following genes would most likely be tested first to establish a diagnosis in this patient? A. ADA B. FOXP3 C. IL2RG D. WAS E. None of the above

A. ADA is autosomal recessive

A congenital hyper-IgM syndrome was suspected. Which one of the following molecular genetic assays would be the most cost-effective way to confirm/rule out the diagnosis in this patient? A. Chromosomal microarray analysis B. Next-generation sequencing C. Sanger sequencing D. Targeted variant assay E. Whole-exome sequencing F. None of the above

B. Next-generation sequencing CD40L X-linked- HyperIgM syndrome CD40 AICDA and UNG - antibody switching

A molecular study of the CD40L gene revealed a variant, c.409+5G>C, in intron 4. This splice-site variant is predicted to destroy the donor site of intron 4 and produce abnormal RNA and protein. A targeted variant analysis of his mother confirmed the mother was a silent carrier. The patient’s maternal grandmother and his maternal aunt were also carriers. His maternal aunt was pregnant with a boy. Which one of the following would most likely describe the risk for this patient’s unborn cousin with the same condition? A. <1% B. 5%–7% C. 14% D. 25% E. 50% F. 100%

E. 50%

A molecular study of the CD40L gene revealed a pathogenic variant, c.476G>A(p.W140X), in exon 5. Parental targeted analyses revealed that his mother was a silent carrier. Which one of the following disorders would the patient most likely have? A. Adenosine deaminase (ADA) deficiency B. Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) C. X-linked severe combined immunodeficiency D. X-linked hyper-IgM syndrome E. Wiskott–Aldrich syndrome F. 100%

D. X-linked hyper-IgM syndrome

The diagnosis of hypogammaglobulinemia with hyper-IgM was established in a girl without T-lymphocytes being affected. Which one of the following genes would most likely harbor pathogenic variant(s) in this patient? A. ADA B. AICDA C. CD40LG D. IL2RG E. None of the above

B. AICDA

A next-generation sequencing (NGS) panel was ordered for congenital immunodeficiency, and a homozygous pathogenic variant, c.260G>C(p.Cys87Ser), was detected in AICDA. Which one of the following disorders would the patient most likely have? A. Adenosine deaminase (ADA) deficiency B. Hyper-IgM syndrome C. Immunodysregulation, polyendocrinopathy, and enteropathy,X-linked (IPEX) D. X-linked severe combined immunodeficiency E. Wiskott–Aldrich syndrome F. None of the above

B. Hyper-IgM syndrome

The physician suspected that the patient had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). A molecular study was ordered to confirm the diagnosis. Which one of the following molecular genetic assays would most likely be used to confirm/rule out the diagnosis in this patient? A. Chromosomal microarray analysis B. Multiplex ligation-dependent probe amplification C. Next-generation sequencing D. Sanger sequencing E. Targeted variant assay F. Whole-exome sequencing G. None of the above

D. Sanger sequencing NOTCH3 - Chr 19q12

The physician suspected that the patient had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). A molecular study was ordered to confirm the diagnosis. Which one of the following genes would most likely be tested for in CADASIL? A. NOTCH1 B. NOTCH2 C. NOTCH3 D. All of the above E. None of the above

C. NOTCH3

A diagnosis of CADASIL was considered. A molecular genetic study was ordered for confirmation, and a pathogenic variant in NOTCH3 was detected. Which one of the following amino acid sequences did the pathogenic variant most likely involve in this patient? A. Alanine B. Cysteine C. Leucine D. Methionine E. Valine F. None of the above

B. Cysteine gain or loss of Cys in EGFR-like domains

A molecular genetic study was ordered for confirmation, and a pathogenic variant, c.291G>T(p.Try71Cys), in NOTCH3 was detected. The patient had a 6-year-old daughter. What would be the risk of the patient’s daughter having the same condition? A. <1% B. 5%–7% C. 14% D. 25% E. 50% F. 100%

E. 50%

A molecular genetic study detected a pathogenic variant, c.291G>T(p.Try71Cys), in NOTCH3. The patient had a 6-year-old daughter, who was at risk for the same condition. The patient asked the physician to test his daughter. Which one of the following would be the most appropriate response to this request? A. Getting consent from his daughter, then ordering a targeted molecular study for her B. Informing the patient that testing asymptomatic children does more harm than good C. Ordering a targeted molecular study for his daughter D. Providing genetic counseling to his daughter, then ordering a targeted molecular study for her E. Telling the patient this is an adult clinic, and it is better for him to make an appointment with his daughter’s pediatrician F. None of the above

B. Informing the patient that testing asymptomatic children does more harm than good

A diagnosis of Alagille syndrome (ALGS) was considered. A molecular analysis was ordered to confirm the diagnosis. Which one of the following genes was most likely tested to confirm the diagnosis in this patient? A. JAG1 B. JAG2 C. DLL1 D. DLL3 E. DLL4 F. None of the above

A. JAG1 JAG2 chromosome 20 NOTCH2 chromosome 1

His portal tract showed inflammation and fibrosis. Immunostaining for CK19 did not show bile ducts. A diagnosis of Alagille syndrome (ALGS) was considered. A molecular analysis was ordered to confirm the diagnosis. Which one of the following genes would most likely be tested for CADASIL in this patient? A. NOTCH1 B. NOTCH2 C. NOTCH3 D. All of the above E. None of the above

B. NOTCH2

A sequencing analysis was ordered for Alagille syndrome (ALGS), and no pathogenic variants in JAG1 were detected. The physician still suspected ALGS. Which one of the following studies would most likely be used as the next step in the workup to confirm/rue out ALGS in this patient? A. Deletion/duplication analysis of JAG1 B. Deletion/duplication analysis of NOTCH2 C. Linkage study D. Sequencing analysis of NOTCH2 E. None of the above

A. Deletion/duplication analysis of JAG1 If no pathogenic variants are detected by sequencing analysis of JAG1, deletion/duplication analysis can be performed to detect deletions or duplications of JAG1 exon(s) or of the whole gene.

Sequencing analysis detected a homozygous pathogenic variant, c.133G>T (p.V45L), in exon 2 of JAG1. A heterozygous c.133G>T variant was found in the mother but not in the father. Which one of the following molecular genetic studies would be an appropriate next step in the workup for this family? A. Chromosome karyotyping B. Multiplex ligation-dependent probe amplification C. Sequencing analysis of NOTCH2 D. Informing the family that the recurrent risk is low E. None of the above

B. Multiplex ligation-dependent probe amplification However, the presence of delayed growth and developmental in addition to the features commonly seen in Alagille syndrome (ALGS) increase suspicion for a chromosome deletion.

There are 15,846 genes and _________ genes have a phenotype-causing mutation

3880

_________ of the 3880 genes correspond to more than one phenotype

1223 (32%)

IL2RG (SCID), FOXP3 (IPEX), HGIM (CD40L) and WASP (WAS) have ______________ inheritance WASP

X-linked recessive

Other Common Genetic Syndromes Flashcards

(249 cards)