Molecular Pathology Practice Questions

Q: A child presents with a right transverse palmar crease, a cardiac defect, survival into childhood, and mild intellectual impairment. What chromosomal mechanism is most likely associated with these findings?

Mosaicism. ***Mosaicism*** - **Mosaicism** is the presence of two or more cell lines with different genetic constitutions in a single individual, allowing for a **milder phenotype** of chromosomal syndromes like Trisomy 21. - The combination of classic Down syndrome features (transverse palmar crease, cardiac defect) with relatively **mild intellectual impairment** and survival into childhood with better outcomes suggests **Mosaic Down Syndrome** (mosaic Trisomy 21). - In mosaicism, only a proportion of cells carry the extra chromosome 21, resulting in **less severe manifestations** compared to complete trisomy. *Incorrect: Trisomy* - While **complete Trisomy 21** (Down syndrome) presents with similar features, it typically causes **more severe intellectual disability** and greater phenotypic expression. - The emphasis on **"mild" intellectual impairment** in this case points toward mosaicism rather than complete trisomy. *Incorrect: Haploid* - **Haploid** refers to a cell having only one set of chromosomes (n=23), a state that is **incompatible with human survival** beyond early embryonic development. - A complete haploid individual cannot survive into **childhood**. *Incorrect: Monosomy* - **Monosomy** (loss of one chromosome, 2n-1) for autosomes is typically **lethal in utero**, making survival into childhood impossible. - The only viable monosomy is **Monosomy X** (Turner syndrome), which presents with distinct features (short stature, webbed neck, ovarian dysgenesis) without the characteristic Down syndrome features described.

Q: A child presents with micrognathia and low-set ears. These clinical features are commonly associated with which type of genetic abnormality?

Deletion. ***Correct: Deletion*** - **Micrognathia** and **low-set ears** are characteristic features of many syndromes caused by chromosomal deletions, such as **DiGeorge syndrome** (22q11.2 deletion) or **Cri-du-chat syndrome** (5p deletion). - The loss of a significant segment of a chromosome leads to **haploinsufficiency** for multiple genes, severely impacting craniofacial and auricular development. *Incorrect: Translocation* - This involves the exchange of segments between non-homologous chromosomes; while it can cause genetic disorders, it is not the most common genetic mechanism leading to the specific classic combination of micrognathia and low-set ears. - **Balanced translocations** usually do not cause clinical symptoms in the carrier, but can lead to abnormal gametes and offspring with partial monosomy or trisomy. *Incorrect: Amplification* - This refers to the increase in the copy number of a gene or DNA sequence, which is primarily linked to cancer development (**oncogenesis**, e.g., *HER2* amplification), not generalized congenital dysmorphism. - While large segmental duplications (a form of gain) can cause syndromes, specific amplification events are rarely the cause of micrognathia or low-set ears. *Incorrect: Inversion* - This involves a chromosomal segment reversing its orientation; the primary concern is the formation of **unbalanced gametes** during meiosis, particularly with **pericentric inversions**. - Although offspring can inherit unbalanced chromosomes resulting in abnormalities, deletions remain the most common cause for the specific constellation of features mentioned.

Q: Which gene would you test if the patient has a family history of breast and ovarian cancer?

BRCA1/2. ***BRCA1/2*** - Mutations in **BRCA1** and **BRCA2** genes are responsible for the majority of hereditary breast and ovarian cancer syndromes (*Hereditary Breast and Ovarian Cancer syndrome*). [1] - Testing these genes is the standard procedure when a patient presents with a strong family history of both breast and ovarian cancers, as they are **tumor suppressor genes** involved in DNA repair. [1] ***P53*** - Mutations in the **TP53** gene are associated with **Li-Fraumeni syndrome**, which increases the risk for a wide spectrum of cancers, including breast cancer, sarcomas, brain tumors, and adrenocortical carcinoma. - While breast cancer is a component, Li-Fraumeni is less specifically linked to the combined presentation of breast and ovarian cancer compared to BRCA mutations. ***PTEN*** - Mutations in the **PTEN** gene cause **Cowden syndrome**, characterized by multiple hamartomas and an increased risk of breast, thyroid, and endometrial cancers. - Ovarian cancer is a less prominent feature of Cowden syndrome, making it a secondary consideration after BRCA testing. ***CDH1*** - Mutations in the **CDH1** gene (which encodes **E-cadherin**) are primarily associated with **Hereditary Diffuse Gastric Cancer (HDGC)**. - These mutations also confer an increased risk for **lobular breast cancer**, but they are not the primary drivers for a syndrome involving both significant breast and ovarian cancer risk.

Q: A 15-year-old tall boy with long limbs presents to the OPD. On ocular examination, bilateral ectopia lentis is noted. Which gene is most likely affected in this inherited disorder?

FBN1 (Fibrillin-1). ***FBN1 (Fibrillin-1)*** - The clinical triad of tall stature/long limbs (**Marfanoid habitus**) and **ectopia lentis** (lens dislocation) is characteristic of **Marfan syndrome** [1]. - Marfan syndrome is caused by an autosomal dominant mutation in the **FBN1 gene** on chromosome 15, which codes for the connective tissue protein **Fibrillin-1** [1]. *COL5A* - Mutations in **COL5A** (Type V collagen) are typically associated with the Classical type of **Ehlers-Danlos syndrome (EDS)**. - Clinical features of EDS primarily include **skin hyperextensibility** and **joint hypermobility**, which are not the most prominent features in this presentation. *PAX6* - The **PAX6 gene** is a master gene for eye development, and its mutation primarily causes **Aniridia** (absence of the iris) or other widespread ocular developmental defects. - Although ophthalmological findings are present, aniridia is not the key ocular finding, making PAX6 mutation an incorrect association. *TGF-β R2* - Mutations in **TGF-β R2** are linked to **Loeys-Dietz syndrome**, which involves severe **aortic root dilation** and craniocervical instability [1]. - While Loeys-Dietz syndrome presents with Marfanoid skeletal features, **ectopia lentis** is rare or absent, differentiating it from Marfan syndrome (FBN1) [1]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 153-154.

Q: The pedigree chart shown in the image demonstrates a specific pattern of inheritance. Which of the following conditions is most likely to follow this pattern of inheritance?

Kearns-Sayre syndrome. ***Kearns-Sayre syndrome*** - This condition is caused by large-scale deletions in **mitochondrial DNA (mtDNA)**, leading to a pattern of **maternal inheritance** (non-Mendelian) [1]. - Mitochondrial disorders are passed exclusively from the mother, affecting all offspring, which defines this specific inheritance pattern [1]. *Duchenne muscular dystrophy* - This follows an **X-linked recessive** pattern of inheritance, where the defective gene is located on the X chromosome [2]. - It primarily affects males, with mothers typically being asymptomatic carriers, clearly distinguishing it from mitochondrial inheritance [2]. *Huntington's disease* - This is an **autosomal dominant** disorder, meaning it is caused by a mutation on a non-sex chromosome and can be passed from either parent [3]. - It affects both males and females equally, with a 50% chance of transmission regardless of the child's sex [3]. *Marfan syndrome* - This is an **autosomal dominant** condition resulting from a mutation in the **FBN1 gene** (nuclear DNA) [3]. - The inheritance does not rely exclusively on the maternal line, as expected in an autosomal dominant Mendelian disorder [3]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, p. 181. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, p. 151. [3] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 149-150.

Q: A 22-year-old tall male presents with long limbs, increased arm span, hypermobile joints, and high-arched palate. On examination, he has lens subluxation and a diastolic murmur suggestive of aortic root dilation. Which of the following genes is most likely mutated in this condition?

Fibrillin-1 (FBN1). ***Fibrillin-1 (FBN1)*** - The clinical presentation (tall stature, long limbs, increased arm span, aortic root dilation, and lens subluxation/ectopia lentis) is characteristic of **Marfan Syndrome** [1]. - Marfan syndrome is caused by an autosomal dominant mutation in the **FBN1 gene** on chromosome 15, which codes for the microfibrillar protein **fibrillin-1** [1]. *COL4A5* - Mutations in **COL4A5** (Type IV collagen) are associated with **Alport Syndrome**. - Alport syndrome primarily presents with **progressive sensorineural hearing loss**, ocular abnormalities (not typically lens subluxation), and **nephropathy** (hematuria/proteinuria). *COL1A1* - Mutations in **COL1A1** (Type I collagen) are most commonly associated with **Osteogenesis Imperfecta (OI)**. - OI is characterized by **recurrent fractures**, often with blue sclerae, hearing loss, and joint laxity, but not the specific cardiovascular and ocular features seen here. *Elastin* - Mutations in the **Elastin gene (ELN)** are responsible for **Supravalvular Aortic Stenosis (SVAS)**, often seen in **Williams Syndrome**. - Williams syndrome also involves intellectual disability and a characteristic 'elfin' facies, which are not mentioned in this patient's presentation. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 153-154.

Q: Which of the following is an incorrect gene-disease association?

TP53 - Mucosal Neuroma. ***TP53 - Mucosal Neuroma*** - This is an **incorrect association**. Mucosal neuromas are a hallmark feature of **Multiple Endocrine Neoplasia type 2B (MEN 2B)** [2]. - MEN 2B is caused by a germline gain-of-function mutation in the **RET proto-oncogene**, not the TP53 tumor suppressor gene (which is associated with **Li-Fraumeni syndrome**). *STK11 - Breast Cancer* - This is a **correct association**. Mutations in the **STK11** gene cause **Peutz-Jeghers syndrome (PJS)**. - Patients with PJS have a significantly increased risk of developing several malignancies, including gastrointestinal cancers and non-GI cancers like **breast cancer**. *PTEN - Thyroid Carcinoma* - This is a **correct association**. Germline mutations in the **PTEN** gene are responsible for **Cowden Syndrome**. - Cowden Syndrome is characterized by hamartomas and a high lifetime risk of developing cancers, most notably **follicular thyroid carcinoma** and breast cancer. *BRCA2 - Prostate Carcinoma* - This is a **correct association**. Germline mutations in **BRCA2** are strongly linked to hereditary breast and ovarian cancer syndromes [1]. - Men with **BRCA2** mutations have a substantially elevated risk of developing **prostate carcinoma**, often presenting with high-grade, aggressive disease. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Pancreas, pp. 898-899. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Endocrine System, pp. 1139-1140.

Q: The karyotypic anomaly in the given image denotes which of the following diseases?

Cri du Chat Syndrome. ***Cri du Chat Syndrome*** - Caused by **deletion of the short arm of chromosome 5** (5p deletion), resulting in karyotype **46,XX/XY,del(5p)**. - Characteristic features include **cat-like cry** in infants, **microcephaly**, and severe **intellectual disability**. *Down Syndrome* - Results from **trisomy 21** with karyotype **47,XX/XY,+21**, not a deletion syndrome. - Clinical features include **flat facial profile**, **epicanthal folds**, and **cardiac defects**. *Edwards Syndrome* - Caused by **trisomy 18** with karyotype **47,XX/XY,+18**, involving chromosome 18 not chromosome 5. - Associated with **clenched fists**, **rocker-bottom feet**, and severe **growth retardation**. *Wolf-Hirschhorn Syndrome* - Results from **deletion of chromosome 4p** (4p deletion), not chromosome 5p deletion. - Characteristic **"Greek warrior helmet" facial appearance** and severe **developmental delays**.

Question 1

A child presents with a right transverse palmar crease, a cardiac defect, survival into childhood, and mild intellectual impairment. What chromosomal mechanism is most likely associated with these findings?

Accepted Answer

Mosaicism

Answer

Haploid

Answer

Monosomy

Answer

Trisomy

Question 2

A child presents with micrognathia and low-set ears. These clinical features are commonly associated with which type of genetic abnormality?

Accepted Answer

Deletion

Answer

Amplification

Answer

Inversion

Answer

Translocation

Question 3

Which gene would you test if the patient has a family history of breast and ovarian cancer?

Accepted Answer

BRCA1/2

Answer

P53

Answer

CDH1

Answer

PTEN

Question 4

Which of the following is not an aneuploidy?

Accepted Answer

Bloom Syndrome

Answer

Trisomy 13

Answer

Trisomy 21

Answer

Klinefelter Syndrome

Question 5

A 15-year-old tall boy with long limbs presents to the OPD. On ocular examination, bilateral ectopia lentis is noted. Which gene is most likely affected in this inherited disorder?

Accepted Answer

FBN1 (Fibrillin-1)

Answer

COL5A

Answer

PAX6

Answer

TGF-β R2

Question 6

The pedigree chart shown in the image demonstrates a specific pattern of inheritance. Which of the following conditions is most likely to follow this pattern of inheritance?

Accepted Answer

Kearns-Sayre syndrome

Answer

Marfan syndrome

Answer

Duchenne muscular dystrophy

Answer

Huntington's disease

Question 7

A 22-year-old tall male presents with long limbs, increased arm span, hypermobile joints, and high-arched palate. On examination, he has lens subluxation and a diastolic murmur suggestive of aortic root dilation. Which of the following genes is most likely mutated in this condition?

Accepted Answer

Fibrillin-1 (FBN1)

Answer

COL4A5

Answer

Elastin

Answer

COL1A1

Question 8

Which of the following is an incorrect gene-disease association?

Accepted Answer

TP53 - Mucosal Neuroma

Answer

BRCA2 - Prostate Carcinoma

Answer

STK11 - Breast Cancer

Answer

PTEN - Thyroid Carcinoma

Question 9

The karyotypic anomaly in the given image denotes which of the following diseases?

Accepted Answer

Cri du Chat Syndrome

Answer

Down Syndrome

Answer

Edwards Syndrome

Answer

Wolf-Hirschhorn Syndrome

Question 10

A karyotype is shown in the image. What is the most likely diagnosis?

Accepted Answer

Klinefelter syndrome

Answer

Turner syndrome

Answer

Down syndrome

Answer

Cri-du-chat syndrome

Molecular Pathology — MCQs

Molecular Pathology — MCQs

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