12 - Autosomal dominant disorders

Autosomal dominant disorders

© SPMM Course determining white colour and one determining black colour in the father, then these two alleles segregate and only one of them could be passed on to the second generation from each parent. This will produce three possible types of offsprings as shown in the table. This was later proved to be true by studying chromosomes during cell division. The third principle is the principle of independent assortment. It states that “different pairs of alleles are passed to offspring independently of each other. The result is that new combinations of genes present in neither parent are possible”. As a very simplistic example, if a man with blue eyes and brown hair mates a woman with brown eyes and black hair; their child can have blue eyes and black hair. The inheritance of blue eyes does not take brown hair ‘with it’; these traits are independently assorted. Thus Mendelian principles are applicable to human genetics as well. Note that all traits studied using Mendelian genetics refer to categorical, all or none traits i.e. black vs. brown, blue vs. brown, tall vs. short, etc. It does not apply with same simplicity to dimensional traits such as IQ or blood pressure. Mendel’s Laws (aide memoir) Explanations Law of uniformity: DD X dd  Dd Two alternative alleles at one locus Two homozygous parents (with a double dose of either one). All off springs are of uniform type (all Dds) Law of segregation Dd X Dd  DD | Dd Dd | dd Two heterozygous parents Three possible types of offsprings 1DD.2Dd.1dd Law of independent assortment DdHh (blue-eye:brown hair) X ddhh (brown eye: black hair)  DdHh | ddHh | Ddhh | ddhh Two loci with alleles D,d and H,h. Double heterozygote X Double homozygote parent Four possible types of offspring, each with equal probability (blue eye/brown hair, blue eye/black hair, brown eye/black hair, brown eye/brown hair). Adapted from McGuffin et al. (ed) Psychiatric genetics and genomics. Oxford Press: P37 A. Single gene inheritance (Mendelian) disorders Autosomal dominant disorders Each cell contains two copies of all the autosomes. An autosomal dominant disorder occurs when one of the two copies has a mutation and the protein produced by the normal form of the gene cannot compensate. So the mutant allele becomes dominant over the normal allele and results in disease expression. In this case, a heterozygous individual who has two different forms (or alleles) of the same gene will manifest the disease. The offspring of heterozygotes have a 50% chance of inheriting the chromosome carrying the disease allele, and therefore also of having the disease. If both parents are heterozygous, the recurrence risk is 75%. 'Incomplete penetrance' may occur if patients have a dominant disorder but it does not manifest itself clinically in them. This gives the appearance of the gene having 'skipped' a generation. Having incomplete