37. In which one of the following human disorders, parents or grandparents are said to carry pre-mutations?
(1) Down syndrome
(2) Fragile X syndrome
(3) Klinefelter syndrome
(4) Alkaptonuria
The human disorder in which parents or grandparents are said to carry pre-mutations is Fragile X syndrome (option 2). Pre-mutations involve an expansion of a CGG trinucleotide repeat in the FMR1 gene on the X chromosome. While individuals with pre-mutations typically do not show full symptoms, the repeat expansion can further increase in offspring and lead to the full mutation causing Fragile X syndrome.
Explanation of options:
-
Down syndrome is caused by trisomy 21 (an extra chromosome 21) mostly due to nondisjunction; it is not linked to pre-mutations.
-
Fragile X syndrome is caused by CGG repeat expansions in the FMR1 gene. Pre-mutations (55-200 CGG repeats) can be carried by parents or grandparents without full symptoms but can expand to full mutations (>200 repeats) in children, leading to intellectual disability and developmental issues.
-
Klinefelter syndrome involves an extra X chromosome in males (XXY) caused by chromosomal nondisjunction, not pre-mutations.
-
Alkaptonuria is a recessive metabolic disorder caused by mutations in the HGD gene, with no role of pre-mutations.
Thus, the correct answer is Fragile X syndrome, where pre-mutations are a known stage in inheritance.
Introduction:
Pre-mutations are genetic alterations involving trinucleotide repeat expansions that do not cause disease symptoms in carriers but can expand in future generations to cause disorders. This phenomenon is notably seen in Fragile X syndrome, a leading inherited cause of intellectual disability. This article explains the role of pre-mutations in Fragile X syndrome and contrasts it with other human genetic disorders such as Down syndrome, Klinefelter syndrome, and Alkaptonuria.
What Are Pre-mutations?
Pre-mutations refer to an intermediate state of trinucleotide repeat expansions in genes that are unstable but do not typically lead to disease symptoms in carriers. These pre-mutations may expand further in offspring to cause full mutations, which result in disease manifestation. The most documented example involves the CGG repeat in the FMR1 gene linked to Fragile X syndrome.
Fragile X Syndrome and Pre-mutations
Fragile X syndrome results from excessive CGG repeats (more than 200) in the FMR1 gene on the X chromosome, leading to gene silencing and a lack of FMRP protein needed for neural development. Carriers with 55 to 200 CGG repeats have pre-mutations, often asymptomatic but with a risk of expansion to full mutation in descendants, causing intellectual disability and developmental delays.
Comparison with Other Disorders
-
Down Syndrome: Caused by trisomy 21, a chromosome number anomaly, unrelated to pre-mutations.
-
Klinefelter Syndrome: Results from an extra X chromosome (XXY), caused by nondisjunction, not by repeat expansions or pre-mutations.
-
Alkaptonuria: A metabolic disorder caused by mutations in the HGD gene with no involvement of repeat expansions or pre-mutations.
This knowledge highlights Fragile X syndrome uniquely involving pre-mutation carriers among these disorders, making genetic counseling essential for affected families.
