Which test can detect a balanced reciprocal translocation that a chromosomal microarray will miss?

Conventional G-banded karyotype

Multiplex ligation-dependent probe amplification

Hypotonia and poor feeding marked the first months of life of a boy who, at 3 years, eats constantly and is obese, with small hands and feet, almond-shaped eyes and undescended testes. His milestones are delayed, he has temper tantrums over food, and his karyotype is a normal 46,XY with no visible deletion. FISH for a 15q11-q13 deletion is normal, and the paediatrician concludes that he does not have Prader-Willi syndrome. The geneticist disagrees and points out that the FISH result does not exclude every cause of this condition. Which test is now most appropriate?

DNA methylation analysis of 15q11-q13

Repeat FISH with a second probe set

At a paediatric neurology clinic, a boy of 4 has global developmental delay, autistic features and mild facial dysmorphism; he made poor eye contact from 18 months and speaks only single words; there is no family history, and no single syndrome is suspected. Among the following, which is the recommended first-tier genetic test?

Mitochondrial genome sequencing

Genetic testing, NGS and precision medicine

25 NEET-PG practice questions on Genetic testing, NGS and precision medicine, part of Biochemistry. The first 25 are below; the first 5 with answers and explanations (tap Show answer after you have chosen), the rest in Learn with a free account.

Question 1 · Easy
Which test can detect a balanced reciprocal translocation that a chromosomal microarray will miss?
1. AConventional G-banded karyotype
2. BQuantitative real-time PCR
3. CWhole exome sequencing
4. DMultiplex ligation-dependent probe amplification
Show answerHide answer
Answer: A · Conventional G-banded karyotype
Chromosomal microarray measures DNA dosage, so it finds gains and losses but not rearrangements in which no DNA is gained or lost. A balanced translocation keeps the dosage normal and is seen on G-banded karyotype, which shows chromosome structure. Balanced carriers are healthy but have recurrent miscarriages or unbalanced offspring. Key point: Microarray detects copy number changes; only karyotype (or FISH or genome sequencing) shows balanced rearrangements.
- B: Quantitative PCR measures dosage of a target and misses balanced changes.
- C: Short-read exome sequencing does not reliably detect balanced translocations.
- D: MLPA measures copy number of selected exons and also misses balanced changes.
Question 2 · Easy
Newborn screening detects a raised blood phenylalanine. Deficiency of which enzyme causes classical phenylketonuria?
1. ATyrosine hydroxylase
2. BFumarylacetoacetate hydrolase
3. CHomogentisate oxidase
4. DPhenylalanine hydroxylase
Show answerHide answer
Answer: D · Phenylalanine hydroxylase
Classical PKU is autosomal recessive deficiency of phenylalanine hydroxylase, which converts phenylalanine to tyrosine using tetrahydrobiopterin. Phenylalanine builds up and is turned into phenylpyruvate and phenylacetate, giving a mousy odour, fair skin and intellectual disability if not treated early with a low-phenylalanine diet. A minority of cases are due to BH4 defects. Key point: Classical PKU is phenylalanine hydroxylase deficiency; early dietary treatment prevents intellectual disability.
- A: Tyrosine hydroxylase makes L-DOPA; its deficiency is a rare dopamine disorder.
- B: Fumarylacetoacetate hydrolase deficiency causes tyrosinaemia type 1.
- C: Homogentisate oxidase deficiency causes alkaptonuria.
Question 3 · Hard
Hypotonia and poor feeding marked the first months of life of a boy who, at 3 years, eats constantly and is obese, with small hands and feet, almond-shaped eyes and undescended testes. His milestones are delayed, he has temper tantrums over food, and his karyotype is a normal 46,XY with no visible deletion. FISH for a 15q11-q13 deletion is normal, and the paediatrician concludes that he does not have Prader-Willi syndrome. The geneticist disagrees and points out that the FISH result does not exclude every cause of this condition. Which test is now most appropriate?
1. ARepeat FISH with a second probe set
2. BWhole exome sequencing
3. CDNA methylation analysis of 15q11-q13
4. DKaryotype of both parents
Show answerHide answer
Answer: C · DNA methylation analysis of 15q11-q13
Prader-Willi syndrome is loss of paternally expressed genes at 15q11-q13: a paternal deletion in about 65-75%, maternal uniparental disomy in about 20-30% and an imprinting defect in a few. FISH detects only the deletion. Methylation analysis (methylation-specific PCR or MS-MLPA) shows only the maternal pattern in all three causes, so it diagnoses over 99% of cases and is the first-line test. Key point: Prader-Willi: DNA methylation analysis detects deletion, maternal UPD and imprinting defects; FISH misses UPD.
- A: Repeat FISH would still miss uniparental disomy and imprinting defects.
- B: Exome sequencing does not detect imprinting or UPD reliably.
- D: Parental karyotypes are useful only after a translocation is found.
Question 4 · Easy
At a paediatric neurology clinic, a boy of 4 has global developmental delay, autistic features and mild facial dysmorphism; he made poor eye contact from 18 months and speaks only single words; there is no family history, and no single syndrome is suspected. Among the following, which is the recommended first-tier genetic test?
1. AFISH for the 22q11.2 deletion
2. BMitochondrial genome sequencing
3. CG-banded karyotype
4. DChromosomal microarray
Show answerHide answer
Answer: D · Chromosomal microarray
Chromosomal microarray finds a causal copy number variant in about 15-20% of children with unexplained developmental delay, intellectual disability, autism or multiple anomalies, compared with about 3% for a karyotype. It is therefore preferred to karyotype as a first-tier test, and exome sequencing is increasingly used early as well. Targeted FISH is for a specific suspected syndrome. Key point: Unexplained developmental delay or autism: chromosomal microarray, not karyotype, is the first-tier chromosome test.
- A: FISH tests only one region and is used when one syndrome is suspected.
- B: Mitochondrial testing is for suspected mitochondrial disease, not general delay.
- C: Karyotype has a much lower yield for small deletions and duplications.
Question 5 · Hard
Comparing genetic tests for a counselling clinic, a registrar writes: 1. A SNP microarray can detect copy-neutral loss of heterozygosity, as in uniparental isodisomy. 2. A G-banded karyotype detects balanced translocations if the segments are large enough to see. 3. Short-read exome sequencing reliably sizes triplet repeat expansions. 4. FISH can only detect changes in the region its chosen probe targets. Which are correct?
1. A1, 2, 3 and 4
2. B1 and 3 only
3. C1, 2 and 4 only
4. D2, 3 and 4 only
Show answerHide answer
Answer: C · 1, 2 and 4 only
SNP arrays read genotypes along each chromosome, so long runs of homozygosity with normal copy number (isodisomy, consanguinity) show up, which array CGH cannot see. Karyotypes show structure, including balanced rearrangements, at a resolution of about 5-10 Mb. Short-read sequencing cannot span long repeats, so fragile X or myotonic dystrophy needs PCR and Southern blot. FISH is targeted: it finds only what the probe was chosen to look for. Key point: SNP arrays find copy-neutral LOH; karyotype finds balanced changes; exome misses repeats; FISH is targeted.
- A: Statement 3 is false, so all four cannot be correct.
- B: Statement 3 is false, and statements 2 and 4 are true.
- D: Statement 3 is false: short reads cannot size repeat expansions.
Question 6 · Medium
After tonsillectomy at a district hospital, a child given codeine syrup at the usual dose becomes very drowsy, with pinpoint pupils and a respiratory rate of 8/min on the first night, with an SpO2 of 86% on room air. He had obstructive sleep apnoea before surgery. Naloxone reverses it. Which genetic trait most likely explains this?
1. AButyrylcholinesterase deficiency
2. BCYP2D6 poor metaboliser
3. CCYP2D6 ultrarapid metaboliser
4. DSlow acetylator (NAT2)
Answer and explanation in LearnFree account
Question 7 · Medium
Exagamglogene autotemcel, approved for sickle cell disease, is given to a young man after busulfan conditioning, using his own CRISPR-edited haematopoietic stem cells. How does this therapy reduce sickling?
1. AIt adds an extra alpha-globin gene
2. BIt replaces the mutant beta-globin gene
3. CIt silences the gamma-globin genes
4. DIt disrupts a BCL11A enhancer to raise HbF
Answer and explanation in LearnFree account
Question 8 · Hard
Stent thrombosis presents as a new inferior STEMI in a man who received a drug-eluting stent 3 weeks ago and reports full adherence to aspirin and clopidogrel 75 mg. After primary PCI, platelet function testing shows high on-treatment platelet reactivity, and genotyping shows CYP2C19*2/*2. Which change in antiplatelet therapy is most appropriate?
1. ADouble the clopidogrel dose to 150 mg
2. BAdd omeprazole for gastroprotection
3. CReplace clopidogrel with ticagrelor
4. DReplace clopidogrel with dipyridamole
Answer and explanation in LearnFree account
Question 9 · Medium
Exome sequencing reports no pathogenic variant for a boy with moderate intellectual disability, a long face, large ears and enlarged testes after puberty; his maternal uncle is similar, and his mother had premature ovarian insufficiency at 36. The parents are told that this rules out a genetic cause. Why is that conclusion wrong?
1. AThe causal variant lies in mitochondrial DNA
2. BThe disorder is due to a balanced translocation
3. CExome sequencing cannot size CGG repeat expansions
4. DExome sequencing misses all X-linked genes
Answer and explanation in LearnFree account
Question 10 · Medium
Chromosomal microarray is normal in a girl of 2 with intractable infantile seizures, developmental regression and acquired microcephaly. Metabolic screen, MRI brain and fragile X testing are unremarkable. Her parents are healthy and not related. Which is the best next genetic test?
1. AG-banded karyotype
2. BRepeat microarray at higher resolution
3. CTrio whole exome sequencing
4. DMitochondrial DNA deletion study
Answer and explanation in LearnFree account
Question 11 · Medium
Rapid aneuploidy FISH on a newborn in the postnatal ward confirms trisomy 21 within 24 hours. The mother is 23 and has had one earlier baby with Down syndrome. The parents ask about the risk in their next pregnancy. Which test on the baby is now essential for counselling them?
1. AQuantitative fluorescent PCR
2. BRepeat interphase FISH on buccal cells
3. CConventional G-banded karyotype
4. DWhole exome sequencing
Answer and explanation in LearnFree account
Question 12 · Hard
A young woman of 24 has short stature, sensorineural hearing loss, diabetes and two stroke-like episodes in the occipital lobes that do not follow any vascular territory; serum and CSF lactate are raised. She has bilateral ptosis, mild proximal weakness and a pigmentary retinopathy, and needs insulin. Her mother has diabetes and deafness, her younger brother has epilepsy, and her father is healthy. Testing of mitochondrial DNA from blood leucocytes for the m.3243A>G variant is negative. The neurologist still strongly suspects the diagnosis. What is the most appropriate next step?
1. AAccept the result as excluding the diagnosis
2. BRepeat the blood test after a day of fasting
3. CTest mtDNA in urinary epithelial cells or muscle
4. DSequence the father's mitochondrial DNA
Answer and explanation in LearnFree account
Question 13 · Medium
Serum CK is 18,000 U/L (normal below 170) in a boy of 5 brought to the paediatric OPD because he climbs up his thighs to stand and has large calves. His mother's brother died at 19 after years in a wheelchair. Which is the most appropriate first genetic test?
1. AMLPA for dystrophin exon deletions
2. BMuscle biopsy with dystrophin staining
3. CG-banded karyotype
4. DWhole mitochondrial genome sequencing
Answer and explanation in LearnFree account
Question 14 · Medium
A man from Odisha with Plasmodium vivax malaria passes cola-coloured urine and becomes pale on day 3 of primaquine for radical cure. His G6PD status was not tested before treatment. The blood film shows bite cells, and supravital staining shows Heinz bodies. Which biochemical defect explains why his red cells cannot withstand the drug?
1. AComplement lysis from absent CD59
2. BDefective spectrin in the red cell skeleton
3. CToo little NADPH to keep glutathione reduced
4. DToo little ATP from a glycolytic block
Answer and explanation in LearnFree account
Question 15 · Easy
A district hospital joins the state newborn screening programme, and nurses collect a sample from each baby at 24-72 hours for tandem mass spectrometry, TSH, 17-hydroxyprogesterone and G6PD. What sample is used?
1. ASerum from cord blood in a plain tube
2. BSpot urine on filter paper
3. CHeel-prick blood dried on filter paper
4. DEDTA venous blood from the antecubital fossa
Answer and explanation in LearnFree account
Question 16 · Medium
Carbamazepine is planned for trigeminal neuralgia in a man of Han Chinese ancestry who works in Bengaluru. Before the first dose, which genetic test is recommended to prevent a life-threatening skin reaction?
1. ACYP2C9 genotyping
2. BHLA-B*15:02 genotyping
3. CTPMT activity assay
4. DHLA-B*57:01 genotyping
Answer and explanation in LearnFree account
Question 17 · Medium
On day 2 in the NICU, a neonate has a hypocalcaemic seizure; serum calcium is 6.4 mg/dL (8.5-10.5) with a low PTH. Echocardiography shows truncus arteriosus, and the chest X-ray shows no thymic shadow. She was born at term to healthy parents and has a small jaw and low-set ears. Which test will most directly confirm the suspected diagnosis?
1. AG-banded karyotype
2. BSanger sequencing of the PTH gene
3. CFISH for the 22q11.2 deletion
4. DSouthern blot for a repeat expansion
Answer and explanation in LearnFree account
Question 18 · Easy
Abacavir is planned for a man with HIV who is switching his regimen. Screening for which genetic marker prevents its serious hypersensitivity reaction?
1. AHLA-B*58:01
2. BHLA-B*57:01
3. CHLA-DR4
4. DHLA-B*15:02
Answer and explanation in LearnFree account
Question 19 · Medium
Tandem mass spectrometry on a newborn screening card shows a raised octanoylcarnitine (C8), with smaller rises in C6 and C10:1 acylcarnitines. The baby, born to consanguineous parents in Madurai, is feeding well at home. During a vomiting illness at 14 months, this child is most at risk of which metabolic picture?
1. AHyperammonaemia with high citrulline
2. BLactic acidosis with high pyruvate
3. CHypoketotic hypoglycaemia
4. DKetotic hypoglycaemia
Answer and explanation in LearnFree account
Question 20 · Medium
Parents of an infant with spinal muscular atrophy type 1 (homozygous SMN1 deletion) are counselled about genetic therapies: 1. Onasemnogene abeparvovec delivers a working SMN1 gene in an AAV9 vector. 2. Nusinersen is an antisense oligonucleotide that makes SMN2 include exon 7. 3. AAV vectors usually integrate into the host genome. 4. Risdiplam must be given intrathecally every 4 months. Which statements are true?
1. A1, 2 and 3 only
2. B2 and 4 only
3. C1, 2 and 4 only
4. D1 and 2 only
Answer and explanation in LearnFree account
Question 21 · Hard
Report from a genetics laboratory: exome sequencing of a boy of 12 with hypertrophic cardiomyopathy found a heterozygous missense variant in MYBPC3, classified as a variant of uncertain significance under ACMG criteria. His septum measures 22 mm on echocardiography. It is absent from population databases, and computer prediction tools disagree about its effect. His father is clinically well and has not been tested. His mother asks whether her younger daughter should have predictive testing for this variant and whether the boy needs an ICD because of it. What is the most appropriate advice?
1. ADrop all cardiac follow-up of the family
2. BTreat it as pathogenic and test the sister
3. CDo not act on it; test relatives for segregation
4. DImplant an ICD because of the variant
Answer and explanation in LearnFree account
Question 22 · Medium
Newborn screening reports a raised 17-hydroxyprogesterone on the heel-prick sample of a baby born at 30 weeks, taken at 36 hours of age. The baby is feeding well, with normal genitalia, Na 138 and K 4.6 mmol/L. The pregnancy was uncomplicated, and there is no family history of salt-wasting or infant deaths. What is the most appropriate next step?
1. AReassure; no further test
2. BKaryotype before any other test
3. CSecond-tier LC-MS/MS steroid profile
4. DStart hydrocortisone and fludrocortisone
Answer and explanation in LearnFree account
Question 23 · Medium
On day 6 of standard-dose capecitabine after surgery for colon cancer, a woman develops severe mucositis, bloody diarrhoea, hand-foot syndrome and neutropenic fever. Which inherited enzyme deficiency best explains the toxicity?
1. AThymidylate synthase
2. BUGT1A1
3. CThiopurine methyltransferase
4. DDihydropyrimidine dehydrogenase
Answer and explanation in LearnFree account
Question 24 · Medium
Two weeks into maintenance 6-mercaptopurine at the standard dose for acute lymphoblastic leukaemia, a child has a total leucocyte count of 600/µL, neutrophils 100/µL and platelets 18,000/µL; the marrow is aplastic without blasts. His elder sister had a similar reaction. Testing for which enzyme variant should guide future dosing?
1. AGlucose-6-phosphate dehydrogenase
2. BCytochrome P450 2D6
3. CDihydropyrimidine dehydrogenase (DPYD)
4. DThiopurine methyltransferase (TPMT)
Answer and explanation in LearnFree account
Question 25 · Medium
NexCAR19, an Indian-developed CAR T-cell product, is given to a man with relapsed B-cell lymphoma. On day 3 he has fever of 39.6 °C, hypotension and hypoxia, with a very high serum IL-6. Which pairing of the CAR target and treatment for this complication is correct?
1. ACD20 target; rituximab
2. BCD19 target; infliximab
3. CBCMA target; filgrastim
4. DCD19 target; tocilizumab
Answer and explanation in LearnFree account

Genetic testing, NGS and precision medicine

Which test can detect a balanced reciprocal translocation that a chromosomal microarray will miss?

Newborn screening detects a raised blood phenylalanine. Deficiency of which enzyme causes classical phenylketonuria?

Exagamglogene autotemcel, approved for sickle cell disease, is given to a young man after busulfan conditioning, using his own CRISPR-edited haematopoietic stem cells. How does this therapy reduce sickling?

Chromosomal microarray is normal in a girl of 2 with intractable infantile seizures, developmental regression and acquired microcephaly. Metabolic screen, MRI brain and fragile X testing are unremarkable. Her parents are healthy and not related. Which is the best next genetic test?

Rapid aneuploidy FISH on a newborn in the postnatal ward confirms trisomy 21 within 24 hours. The mother is 23 and has had one earlier baby with Down syndrome. The parents ask about the risk in their next pregnancy. Which test on the baby is now essential for counselling them?

Serum CK is 18,000 U/L (normal below 170) in a boy of 5 brought to the paediatric OPD because he climbs up his thighs to stand and has large calves. His mother's brother died at 19 after years in a wheelchair. Which is the most appropriate first genetic test?

A district hospital joins the state newborn screening programme, and nurses collect a sample from each baby at 24-72 hours for tandem mass spectrometry, TSH, 17-hydroxyprogesterone and G6PD. What sample is used?

Carbamazepine is planned for trigeminal neuralgia in a man of Han Chinese ancestry who works in Bengaluru. Before the first dose, which genetic test is recommended to prevent a life-threatening skin reaction?

Abacavir is planned for a man with HIV who is switching his regimen. Screening for which genetic marker prevents its serious hypersensitivity reaction?

On day 6 of standard-dose capecitabine after surgery for colon cancer, a woman develops severe mucositis, bloody diarrhoea, hand-foot syndrome and neutropenic fever. Which inherited enzyme deficiency best explains the toxicity?

NexCAR19, an Indian-developed CAR T-cell product, is given to a man with relapsed B-cell lymphoma. On day 3 he has fever of 39.6 °C, hypotension and hypoxia, with a very high serum IL-6. Which pairing of the CAR target and treatment for this complication is correct?