Genes and inheritance: from cleft chins to Huntington's disease

Transcript

RyanA 28-year-old client tells you her father was just diagnosed with Huntington's disease. Her first question is the one you'd ask too. Am I going to get it?

SoheeAnd then, more quietly: and what about my kids?

RyanWelcome to EPPP Prep, the podcast. I'm Ryan.

SoheeI'm Sohee. Today, how genetic information is passed down and expressed. We'll build from the basics in the OpenStax psychology textbook, then use the National Library of Medicine's MedlinePlus Genetics pages for the disorders the exam likes.

RyanStart with the building blocks. Egg and sperm each carry 23 chromosomes. At fertilization they combine into 46, or 23 pairs, so each parent contributes half of a child's genetic information.

SoheeChromosomes are long strings of DNA. Sequences of DNA make up genes. And a single gene can come in different versions, called alleles.

RyanThen two terms that get confused. Genotype is a person's genetic makeup. Phenotype is the person's inherited physical characteristics, which the textbook says are a combination of genetic and environmental influences.

SoheeDominant and recessive next. The textbook's example is the cleft chin, which is dominant. Having the dominant allele from one parent or both always produces the cleft chin. Smooth chin is recessive, so it shows only if you have two copies of the recessive allele.

RyanTwo copies of the same allele is homozygous. A mix is heterozygous. And here's the arithmetic. If a heterozygous cleft-chinned parent has a child with a smooth-chinned partner, each child has a 50 percent chance of a cleft chin.

SoheeNow apply that to a recessive disorder. Phenylketonuria, PKU. People with it lack an enzyme that converts harmful amino acids into harmless byproducts. Untreated, it causes significant cognitive deficits, seizures and increased risk of psychiatric disorders.

RyanBecause PKU is recessive, each parent must carry at least one copy for a child to have it. If both parents are heterozygous carriers, each child has a 25 percent chance of PKU.

SoheeAnd sickle cell is the textbook's story about why a harmful allele can persist. People who carry one copy are thought to be protected from malaria, while two copies cause sickle-cell anemia. Where malaria is common, being a carrier is an advantage.

RyanMost traits, though, aren't single-gene. The textbook says most are polygenic, controlled by more than one gene, like height, skin color and weight.

SoheeNow let's go to MedlinePlus for the inheritance patterns. Autosomal dominant: one altered copy of the gene is enough. Huntington's disease is the classic example.

RyanAnd MedlinePlus gives us the rule for our client. A person with an autosomal dominant disorder has a 50 percent chance of passing the altered gene to each child.

SoheeSo apply it to her. Her father has the disorder, which means she had a 50 percent chance of inheriting the altered gene from him. Her own children's risk then depends on whether she carries it. Whether to find out is a big, personal decision, and we'll come back to predictive testing in the last episode of this domain.

RyanAnd it's worth saying out loud that a 50 percent chance is also a 50 percent chance she didn't inherit it. MedlinePlus phrases it both ways, and clients often need to hear both.

SoheeAutosomal recessive: both copies are altered. Parents are usually unaffected carriers, and the condition is typically not seen in every generation. Two carriers have a 25 percent chance with each pregnancy, matching our PKU math.

RyanPause and think. Two parents who are both PKU carriers already have one child with PKU. What's the chance their next child will have it?

SoheeStill 25 percent. MedlinePlus is explicit: the chance applies equally to each pregnancy. Having one affected child doesn't protect future children. The tempting wrong answer is lower, as if the odds had been used up.

RyanX-linked recessive. In males, who have one X chromosome, one altered copy causes the condition. Females would need two. So males are affected much more often. Hemophilia is the example.

SoheeAnd the giveaway: fathers can't pass X-linked traits to their sons. The sons of a man with an X-linked recessive disorder won't be affected, and all his daughters will carry one copy.

RyanMitochondrial inheritance is the last unusual one. Only egg cells contribute mitochondria to the embryo, so only mothers pass on mitochondrial variants.

SoheeNow, Huntington's in depth. MedlinePlus describes it as a progressive brain disorder causing uncontrolled movements, emotional problems and loss of thinking ability. The adult-onset form usually appears in a person's thirties or forties.

RyanEarly signs can include irritability, depression, small involuntary movements, poor coordination and trouble learning or deciding. Many people develop jerking movements called chorea.

SoheeThe cause is a variant in the HTT gene, which makes a protein called huntingtin. It's a repeat of three DNA building blocks, C, A, G. Normally that CAG segment repeats 10 to 35 times. In Huntington's disease, it repeats 36 to more than 120 times.

RyanPeople with 36 to 39 repeats may or may not develop symptoms. People with 40 or more almost always do.

SoheeAnd here's the concept the exam loves. As the gene is passed down, the repeat often grows, and more repeats usually mean earlier onset. That's called anticipation.

RyanMedlinePlus defines anticipation as signs and symptoms becoming more severe and appearing earlier as a disorder passes from one generation to the next. It's most often seen with nervous system disorders like Huntington's disease, myotonic dystrophy and fragile X.

SoheePause and think. A grandmother developed a genetic movement disorder in her fifties, her son in his forties, and her grandson in his twenties. What's the term, and what's the mechanism?

RyanAnticipation, typically caused by a trinucleotide repeat expansion that grows from generation to generation. Huntington's disease is the textbook case.

SoheeFragile X is another repeat disorder. Mutations in the FMR1 gene cause it, nearly always an expanded CGG repeat. Normally it repeats about 5 to 40 times. In fragile X syndrome, more than 200, which silences the gene.

RyanPeople with 55 to 200 repeats have a premutation. In women, the premutation can expand past 200 in cells that become eggs, which raises the chance of a child with fragile X. MedlinePlus describes the inheritance as X-linked dominant, with males usually more severely affected.

SoheeDown syndrome is different. It's chromosomal. Most cases are trisomy 21, three copies of chromosome 21 instead of two.

RyanAnd most cases aren't inherited. Trisomy 21 happens as a random error in cell division called nondisjunction, usually in the egg. But translocation Down syndrome can be inherited from an unaffected parent who carries a balanced rearrangement.

SoheeThen genomic imprinting. Usually both copies of a gene are active. With imprinting, only one is, depending on which parent it came from. Disruptions on chromosome 15 can cause Prader-Willi syndrome, with behavioral problems and uncontrolled eating, or Angelman syndrome, with intellectual disability and impaired speech.

RyanTwo more terms. Penetrance is the proportion of people with a variant who actually show signs of the disorder. If some don't, that's reduced penetrance. Variable expressivity is the range of signs among people with the same condition.

SoheeFinally, epigenetics. The OpenStax textbook says it studies how the same genotype can lead to very different phenotypes. Identical twins share the same genes, yet sometimes one develops a disease and the other doesn't.

RyanMedlinePlus explains how. Epigenetics is the study of how cells control gene activity without changing the DNA sequence. A common mechanism is DNA methylation. When methyl groups are on a gene, it's turned off.

SoheeAnd environmental influences, like diet and exposure to pollutants, can impact the epigenome. In some cases, these modifications can be inherited through the generations.

RyanSo, the exam traps. Confusing genotype and phenotype. Thinking odds reset after one affected child. Forgetting that fathers don't pass X-linked traits to sons. And calling Down syndrome inherited, when most cases aren't.

SoheeRecap. Genes come in alleles. Genotype is the makeup, phenotype the expression, shaped by genes and environment. Dominant needs one copy, recessive needs two. Most traits are polygenic.

RyanAutosomal dominant: 50 percent per child, like Huntington's. Autosomal recessive: 25 percent per pregnancy for two carriers, like PKU. X-linked recessive mostly affects males. Mitochondrial comes only from mothers.

SoheeHuntington's and fragile X are repeat expansions, and repeats that grow across generations cause anticipation. Down syndrome is usually trisomy 21 from nondisjunction. Imprinting depends on the parent of origin. And epigenetics turns genes on and off without changing the DNA.

RyanAnd for our client, this is where a psychologist matters. Genetics professionals can help her understand her chances and make informed decisions, and you can help her carry the weight of it.

SoheeGenetics has a lot of vocabulary, and you just walked through most of it. Next time, we take on twins, adoptees and heritability. Thanks for listening to EPPP Prep.

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