Question

I am reading a journal paper about a patient who has intellectual disability. The patient was found to have a balanced chromosomal translocation t(11;16)(q24.2;q24).

This chromosomal translocation disrupted two genes: CDH15 and KIRREL3. By using a genomic probe, the authors fine mapped the 16q24 translocation breakpoint to the second intron of CDH15. The chromosome 11 breakpoint junction sequence mapped to intron 1 of KIRREL3. Only one chromosomal copy of CDH15 and KIRREL3 were disrupted.

However, there is something about this paper that I don't fully understand. The authors state in the following:

We began by sequencing both copies of the CDH15 and KIRREL3 genes in the patient with the translocation. No alterations were identified, indicating that the t(11;16) translocation does not unmask a recessive mutation in either gene.

In the above, it seems that the authors are trying to identify whether there are any recessive mutations in the CDH15 and KIRREL3 genes. I have read online that a recessive mutation is one in which both alleles must be mutant in order for the mutant phenotype of be observed.

However, since the chromosomal translocation disrupted one of the alleles for both CDH15 and KIRREL3, wouldn't you need both alleles of the CDH15/KIRREL3 genes to be intact in order to successfully identify a recessive mutation?

Any insights are appreciated.

Answer 1

The authors of the study found no recessive mutations in the intact alleles of the CDH15 and KIRREL3 genes after a balanced chromosomal translocation disrupted the other alleles.

Step-by-step explanation:

The scenario described involves a balanced chromosomal translocation t(11;16)(q24.2;q24), which affects the CDH15 and KIRREL3 genes located on chromosomes 16 and 11 respectively. A balanced translocation means that there has been an exchange of chromosome segments without any apparent loss or gain of genetic material, which can sometimes result in a disruption of gene function if the breakpoints occur within a gene or near important regulatory regions. The authors sequenced both copies of CDH15 and KIRREL3 to determine if a recessive mutation was present. However, they found no alterations in the sequences of the remaining alleles.

Recessive mutations typically require both alleles to be affected for a phenotype to be expressed. The study findings imply that although one copy of each gene was disrupted by the translocation, there were no other mutations in the other copies. Consequently, the findings suggest that the intellectual disability in the patient is likely due to haploinsufficiency or a dominant negative effect, where having only one functional copy of a gene (CDH15 and/or KIRREL3) is insufficient for normal function or the normal allele is disrupted by the presence of an altered gene product, rather than unmasking a recessive mutation.

In summary, despite the translocation disrupting one allele of each gene, the authors concluded that the patient did not have a recessive mutation because the intact alleles of CDH15 and KIRREL3 appeared normal upon sequencing. Therefore, the patient’s condition might be the result of the single disrupted copy in each gene leading to a different kind of genetic issue rather than a recessive genetic disorder.