NF1 Genetic Inheritance Explained

• Kai's family seeks guidance on his NF1 diagnosis and potential inheritance risks, warranting consultation with a geneticist or counselor.

Familial Inheritance

• Genes are inherited from one generation to the next and are located on chromosomes.
• Offspring inherit chromosomes through the egg from the female and sperm from the male.
• Genes inherited from parents dictate traits such as height, hair color, metabolism, and sex.

Alleles and Genotypes

• Alleles represent different versions of a gene at a specific chromosome location, determining traits.
• Genotype is the allele combination representing the genetic makeup, written as two letters.
• Represent dominant alleles with uppercase and recessive with lowercase, i.e. "Nn".

Terminology for Genetic Inheritance

• Homozygous dominant is represented by NN.
• Heterozygous is represented by Nn.
• Homozygous recessive is represented by nn.
• NF1 is a dominant disorder, inheriting an "N" allele results in the disease.

Phenotype

• A phenotype is the observable expression of a gene, influenced by alleles that code for proteins.
• Individuals with the NN or Nn genotype will have the NF1 trait, while those with nn will have a normal phenotype.

Spontaneous Mutations of NF1

• Approximately half of NF1 cases result from inheriting a dysfunctional gene from a parent.
• The remaining cases arise from spontaneous mutations in the DNA of the sperm or egg.

Predicting Inheritance with Punnett Squares

• Punnett Squares can visualize the probability of gene inheritance to offspring.
• With one affected parent, offspring have a 50% chance of inheriting the damaged gene.

Autosomal Inheritance

• Autosomal Recessive Inheritance requires one dysfunctional gene from each parent.
• Autosomal Recessive Inheritance only affects homozygous recessive (rr) individuals.
• Heterozygous (Rr) individuals are carriers of the trait, but they are not affected.
• Autosomal Dominant Inheritance needs only one dysfunctional gene.

Patterns of Inheritance

• Autosomal Dominant inheritance requires only one mutated allele (Nn) to cause symptoms.
• Autosomal Recessive inheritance needs two mutated alleles (ss) for the condition to manifest.

Kai's Condition

• Kai's NF1 diagnosis results from a dominant mutation even though his parents were unaffected.
• Kai has a 50% chance of passing NF1 to his children due to inheriting one copy of his chromosome 17 with the mutation.

Pedigrees

• Pedigrees are used to trace traits through a family.
• Medical professionals analyze family history to determine if a disease is inherited, and if so, what its inheritance pattern is.

Symbols in Pedigrees

• squares typically represents males, and circles represent females.
• Affected individuals are indicated with filled-in shapes, carriers are indicated with half-filled shapes, and deceased persons have a diagonal line across their shape.

Interpreting Pedigrees

• Each row in a pedigree equates to a generation, with connecting lines indicating inter-familial relationships.
• Roman numerals signify generations, Arabic numerals signify individuals within a generation.

Dominant vs. Recessive Traits

• An individual must have at least one affected parent to exhibit a dominant trait.
• Two unaffected parents can produce affected children when exhibiting recessive traits.

Patterns of Pedigree Inheritance

Autosomal Dominant

• It requires only one affected parent.
• In order to occur parents must be heterozygous.

Autosomal Recessive

• It requires both parents to be carriers.
• In order to occur parents must be heterozygous.

Case Study: Riley

• Riley's medical history included concerns about her short stature, prompting previous nutritional interventions and a target height of 94 cm.

Considerations for Differential Diagnosis

• First consult the family history to determine any inherited conditions, then evaluate Riley for malnutrition.
• Additional testing would be necessary if previous blood tests show anomalies or Riley shows other signs of organ failure.
• Another issue could be abnormal hormone levels or a chromosomal abnormality.

Hormonal Regulation

• Hormones regulate development, metabolism, sleep-wake cycles, and other factors in the body.
• After finding that Riley's growth hormones levels were normal, her chromosomes remained to be tested.

Chromosomes

• Autosomes are 22 pairs of chromosomes determining individual characteristics.
• Sex chromosomes determines sex; XX in females and XY in males.
• It is the cytogeneticists job to analyze Riley's blood sample to check whether she is chromosomally abnormal.

Cytogeneticists

• Cytogeneticists harvest cells from blood samples and other body fluids for chromosomal analysis.
• These laboratory technicians then view the samples under a microscope.
• Chromosomes are prepared for microscopic examination by halting them in metaphase.
• They are stained with a dye and ordered by size and shape.

Karyotypes

• Chromosome spreads are important, due to their contribution in chromosomal analysis like karyotypes.
• A visual profile of a person's chromosomes is called a karyotype.
• A normal karyotype consists of two of all 23 chromosomes.

Meiosis

• Meiosis results in sperm and egg production.
• Meiosis halves the number of chromosomes.

Mistakes during Meiosis

Nondisjunction

• can result in gametes with either an extra or a missing chromosome.

Number of Chromosomes Present

• A missing or extra chromosome is called Aneuploidy.
• Monosomy occurs when there is a missing chromosome
• Trisomy occurs with an extra chromosome.

Chromosomal Structure

• Breakage of chromosome can occur.
• Changes may swap chromosome segments.

Case Study: Riley's Results

• Riley shows a monosomy, meaning she is missing a chromosome.
• This test result gives her a diagnosis of Turner's Syndrome.

Turner Syndrome

• Characteristics of this disorder include: short stature, low hairline, a shield-shaped thorax, and underdeveloped breasts.
• Shortened metacarpal IV on the hand, small finger nails, and brown spots are also characteristics.

Case Study: Aki Kim

• Aki seeks advice regarding family risks for familial hypercholesterolemia (FH), a disorder causing high LDL cholesterol.

Familial Hypercholesterolemia

• FH is a dominant genetic disorder.
• Those with this disorder inherit a dysfunctional gene for a cellular receptor for cholesterol (LDL receptor).

Genotypes and Phenotypes

• In individuals who have this disorder: Homozygous are normal for the LDL receptor and designated (ff).
• Heterozygous possess the defective LDL receptor, designated (Ff).
• Homozygous possess the defective LDL receptor, designated (FF).

FH diagnosis

• A blood sample is required to be taken from you and your family.
• Restriction enzymes help cut the DNA up.

Aki's Situation

• Aki does not have FH.
• Aki's mom has a heterozygousity that has the disease (Ff).
• There is no chance for Aki to pass it to his kids.