Multiple members of a family have a disease that is associated with a genetic change that involves substitution of adenine for thymine involving one base pair on homologous chromosomes. What is the best term to describe this finding?
A Copy number variation
C Epigenetic change
D Single nucleotide polymorphism
E Trinucleotide repeat mutation
F RNA alteration
D) Single nucleotide polymorphisms
(SNPs) are found in less than 0.5% of the genome, and only 1% of these are found in coding regions that affect protein synthesis. Some of these account for point mutations that may be associated with disease conditions. C number variations (CNVs) involve variations in large contiguous regions of DNA from 1000 to a million base pairs. Epigenetic changes involve modulation of gene expression without any change in the DNA. Trinucleotide repeats involve increased numbers of base pairs. RNA alterations may modulate DNA expression, such as noncoding micro RNAs.
A 15-year-old girl has developed multiple nodules on her skin over the past 10 years. On physical examination, there are 20 scattered, 0.3-cm to 1-cm, firm nodules on the patient’s trunk and extremities. There are 12 light brown macules averaging 2 to 5 cm in diameter on the skin of the trunk. Slit-lamp examination shows pigmented nodules in the iris. A sibling and a parent are similarly affected. Genetic analysis shows a loss-of-function mutation. Which of the following inheritance patterns is most likely to be present in this family?
A Autosomal dominant
B Autosomal recessive
E X-linked recessive
A) Autosomal dominant
Neurofibromatosis type 1 (NF-1) is characterized by the development of multiple neurofibromas and pigmented skin lesions. Neurofibromas are most numerous in the dermis but also may occur in visceral organs. Patients with NF-1 also may develop a type of sarcomatous neoplasm known as a malignant peripheral nerve sheath tumor (MPNST). NF-1 is a tumor suppressor that appears with an autosomal dominant pattern of inheritance, though some cases result from spontaneous new mutations (no prior family members with the mutation). NF-1 exhibits variable expressivity, because the manifestations (location and types of neoplasms) are not the same in all patients. The other forms of inheritance listed are not associated with tumor suppressor genes.
A female infant born at term shows failure to thrive and failure to achieve developmental milestones. A pedigree reveals only this child is affected out of four generations on both sides of the family. Tissue fibroblasts obtained from this child shows a 46,XX karyotype. Cultured fibroblasts show accumulation of an intermediate product in a metabolic pathway in which multiple enzymes are involved. What is the most likely recurrence risk for this condition in siblings of this infant?
Most inborn errors of metabolism involve mutations in genes encoding for enzymes. Because one active allele produces half the needed enzyme, this is likely sufficient to avoid dis- ease. Inheritance of two mutant alleles, one from each parent, is required for appearance of disease, so the pattern is autosomal recessive, and the recurrence risk is 25%. Most autosomal recessive genes are infrequent in the population, so a family history is unlikely. Even if 1 in 10 persons carries the mutant recessive gene, a homozygote will be 1 in 400. The standard recurrence risk for any pregnancy is 3%. The recurrence risk is increased to 7% in diseases such as diabetes mellitus, or when a syndrome is identified without a defined inheritance pat- tern, or with multifactorial inheritance. Autosomal dominant conditions usually result from mutations in genes encoding for structural genes and have a recurrence risk of 50%.