Prenatal Exam 2

What should be done if one partner is identified as a carrier?

The reproductive partner should be offered testing to complete the risk assessment and inform further genetic counseling.

What is the role of family history in carrier screening?

To assess the risk of carrying the same mutation based on ethnic background and consanguinity.

What is the carrier frequency for cystic fibrosis in the white population?

Approximately 1 in 25.

What gene is associated with spinal muscular atrophy (SMA)?

SMN1 gene located at 5q13.2.

What is the carrier frequency for spinal muscular atrophy?

Between 1 in 40 and 1 in 60.

What is the major protein in red blood cells that carries oxygen?

Hemoglobin

What are the two families of hemoglobin genes?

The alpha family is on chromosome 16 (4 genes) and the beta family on chromosome 11 (2 genes).

What is the major form of hemoglobin in adults?

Hemoglobin A (Hgb A).

What genetic mutation causes sickle cell disease?

A point mutation in the beta-globin chain (c.20A>T in the HBB gene).

Major adult hemoglobin is made of:

2 alpha chains + 2 beta chains

Minor adult hemoglobin is made of:

2 alpha chains + 2 delta chains

Typical hemoglobin percentage in 3 forms:

- Major form is Hgb A (>96%)

- Minor form is A2 (1-3%)

- HbF (1-2%)

What is the prevalence of sickle cell trait (HbAS) in African Americans?

1 in 10.

What is the typical presentation of sickle cell disease?

Pain episodes, frequent infections, increased swelling, and delayed growth.

What is the significance of hemoglobin electrophoresis?

It measures levels of various hemoglobins and detects abnormal hemoglobin.

What is the recommendation for hemoglobinopathy testing according to ACOG?

Offer universal hemoglobinopathy testing to persons planning pregnancy or at the initial prenatal visit.

What is the de novo mutation rate for spinal muscular atrophy?

2%.

What is the relationship between SMN2 and SMA severity?

The number of SMN2 copies can offset malfunctioning SMN1 genes but is not 100% predictive.

What is the typical hemoglobin composition in adults?

Major form is Hgb A (>96%), minor form is A2 (1-3%), and a small percentage of HbF (1-2%).

What are the common types of hemoglobin in adults?

Fetal Hemoglobin (Hgb F), Major adult hemoglobin (Hgb A), and Minor adult hemoglobin (Hgb A2).

What is the impact of the polyT tract on cystic fibrosis?

It affects the severity and penetrance of CF, particularly in individuals with certain genotypes.

What is the typical clinical significance of Hemoglobin C?

Causes mild anemia and is not usually clinically significant

What is the significance of the SNP (g.27134T>G) in SMN1?

It is sometimes associated with a higher risk of having 2 SMN1 copies in cis.

What is the relationship between genotype and phenotype in cystic fibrosis?

The severity of pulmonary disease can vary among individuals with identical genotypes.

What are the potential outcomes if both partners are carriers for the same condition?

Prenatal diagnosis and advanced reproductive technologies may be discussed to reduce risk.

What causes Beta Thalassemia?

Not enough beta chains are produced, leading to an excess of unstable alpha chains.

What are the two types of Beta Thalassemia?

Beta Thalassemia minor (heterozygous) and Beta Thalassemia major (homozygous or compound heterozygous).

What are common features of Beta Thalassemia?

Severe anemia, often transfusion dependent, poor growth, jaundice, and splenomegaly.

What is the carrier frequency of Beta Thalassemia in Mediterranean populations?

1 in 20.

What is the primary cause of Alpha Thalassemia?

A shortage of alpha chains, leading to an excess of unstable beta tetramers (hemoglobin H).

What is the most common cause of Alpha Thalassemia?

Whole gene deletions in HBA1/HBA2 genes.

How many alpha globin gene copies can an individual be missing in Alpha Thalassemia?

From 1 to 4 copies.

What lab values may indicate suspicion of Beta Thalassemia?

Low MCV and high A2 levels.

What is the best test for diagnosing Alpha Thalassemia?

Sequencing is the best test for these conditions.

What is Fragile X Syndrome?

A genetic disorder caused by CGG repeats in the FMR1 gene, associated with intellectual disability.

What is the carrier frequency of Fragile X Syndrome?

Approximately 1 in 300.

What are the symptoms of Fragile X-associated tremor/ataxia syndrome (FXTAS)?

Intention tremor and progressive cerebellar ataxia after age 50.

What is Tay-Sachs Disease?

A lysosomal storage disorder leading to neurodegenerative changes, characterized by progressive weakness and loss of motor skills.

What gene is implicated in Tay-Sachs Disease?

HEXA gene, which is necessary for degradation of GM2 ganglioside.

What is the carrier frequency of Tay-Sachs Disease in Ashkenazi Jewish populations?

Approximately 1 in 30.

What is Gaucher Disease?

A lysosomal storage disorder leading to lipid buildup, particularly glucocerebroside, in bone marrow, spleen, and liver.

What are the three types of Gaucher Disease?

Type 1 (no CNS involvement), Type 2 (severe neurologic disease), Type 3 (slower progression of neurologic disease).

What gene is associated with Gaucher Disease?

GBA gene, which is implicated in glucosylceramidase enzyme activity.

What is the carrier frequency of Gaucher Disease in Ashkenazi Jewish populations?

1 in 15.

What is the recommended approach for carrier screening according to ACMG?

Carrier screening should be ethnic and population neutral, promoting equity and inclusion.

What is the difference between sequencing-based and genotype-based carrier screening?

Sequencing studies whole genes/sequence, while genotyping determines the presence of known variants.

What are the limitations of sequencing-based carrier screening?

Only reports pathogenic variants and may miss less common or characterized variants.

What is the importance of biochemical testing for Tay-Sachs Disease?

It measures HEXA enzyme activity, which is crucial for diagnosis.

What are the clinical features of Tay-Sachs Disease?

Progressive weakness, loss of motor skills, decreased visual attentiveness, and a cherry-red spot in the eye.

What is the typical age of onset for symptoms of Tay-Sachs Disease?

Symptoms typically appear in infancy.

What is the relationship between Gaucher Disease and Parkinson's Disease?

Carrier status for Gaucher may serve as a risk factor for Parkinson's Disease due to reduced penetrance.

What is the role of the LDLR gene in genetic conditions?

It is associated with Familial Hypercholesterolemia.

What is the Hardy-Weinberg principle used for?

To determine allele and genotype frequencies in a population under certain conditions.

What are the five conditions for Hardy-Weinberg equilibrium?

No natural selection, random mating, no mutations, a closed population, and a large population size.

What does the Hardy-Weinberg formula p2 + 2pq + q2 = 1 represent?

It represents the frequencies of homozygous dominant, heterozygous, and homozygous recessive individuals in a population.

How is the frequency of the recessive allele calculated in Hardy-Weinberg?

Using the formula q = √(q2), where q2 is the percentage of homozygous recessive individuals.

What is Bayesian analysis used for in genetic counseling?

To modify risk assessments based on additional family history or test results.

What is the chance of unaffected siblings being carriers of a recessive condition?

They have a 2/3 chance of being carriers.

What is the importance of ancestry in carrier screening?

Certain conditions should be offered based on specific ancestries, such as Tay-Sachs disease for French Canadian or Cajun ancestry.

What is the purpose of expanded carrier screening panels?

To test for multiple genetic conditions simultaneously, providing a broader assessment of genetic risks.

What is the estimated frequency of cystic fibrosis in the White population of the U.S.?

About 1 in 2,500 babies.

What is the relationship between Hardy-Weinberg equilibrium and population genetics?

It provides a model for understanding genetic variation and allele frequencies in populations.

What does the term 'penetrance' refer to in genetics?

The likelihood that a person with a specific genotype will exhibit the associated phenotype.

Why is it important to understand the differences between ancestry-based and expanded carrier screening?

To ensure appropriate testing and counseling based on individual and family genetic backgrounds.

What is the purpose of calculating residual risks in genetic counseling?

To assess the likelihood of a genetic condition in a pregnancy based on carrier screening results.

What does the term 'conditional probability' mean in the context of Bayesian analysis?

The probability of an event occurring given that another event has already occurred.

What is the residual carrier risk (RCR)?

The chance that an individual with a negative carrier screening result could still be a carrier of the disease.

Why is a negative carrier result not equivalent to 0% risk?

Because carrier frequencies and detection rates vary, and not all pathogenic variants may be detected.

What does the residual risk formula calculate?

Residual risk = carrier frequency x (1 - detection rate).

What is the prevalence of consanguinity in the Near/Middle East and Northern Africa?

20-50% of marriages are consanguineous

What are the increased prenatal risks associated with consanguineous couples?

Congenital abnormalities, intrauterine fetal demise, neonatal death, developmental delay, and autism spectrum disorder.

What is the coefficient of inbreeding (COI)?

The probability that an individual will inherit two identical alleles for a given gene.

What does the coefficient of relationship (COR) indicate?

It indicates the proportion of genes on average that consanguineous individuals would share by descent from common ancestors.

What is the formula for calculating the coefficient of inbreeding (COI)?

F = Σ(1/2)^n, where n is the number of generations to the common ancestor.

What is the minimum distance of kin allowed for marriage in Wisconsin?

Second cousins.

What is the effect of genotyping versus sequencing on residual carrier risk for non-European individuals?

Genotyping can lead to a greater RCR due to undetected pathogenic variants.

What is the significance of updating residual carrier risks (RCRs)?

RCRs need to be continually updated as new pathogenic variants are discovered or reclassified.

What is the role of genetic testing in prenatal risk assessment?

It provides information on the likelihood of fetal genetic conditions based on parental genotypes.

What is the significance of the term 'identical by descent' (IBD)?

It refers to alleles inherited from a common ancestor, which can increase the risk of recessive disorders.

What is consanguinity?

The genetic relationship between individuals who are closely related, such as first cousins.

What stigma is associated with incestual relationships in the U.S.?

It's illegal and there's a social stigma

What is Neu-Laxova syndrome (NLS)?

An autosomal recessive disorder characterized by severe intrauterine growth restriction (IUGR), microcephaly, and various malformations.

What are common clinical features of Neu-Laxova syndrome?

IUGR, microcephaly, CNS malformations, craniofacial anomalies, tissue edema, and limb deformities.

What is the significance of regions of homozygosity (ROH) in genetic counseling?

ROH can indicate increased risk for recessive genetic disorders in consanguineous couples.

What is a Robertsonian translocation?

A chromosomal rearrangement involving two acrocentric chromosomes that fuse at their centromeres.

What is a reciprocal translocation?

A chromosomal rearrangement where two non-homologous chromosomes exchange segments.

What percentage of the population is expected to have a balanced translocation?

About 0.1% to 0.3%.

How does the risk of balanced translocations change in individuals with recurrent pregnancy loss?

The risk increases to about 2-5%.

What genes are associated with NLS?

PHGDH, PSAT1, and PSPH

What are the implications of having a child with a rare condition for future pregnancies?

Parents may perceive risks differently, affecting their emotional response to new pregnancy risks.

What is the classic appearance of hands and feet in Neu-Laxova syndrome?

Described as an 'inflated rubber glove' appearance.

What is the significance of chromosome 1p13.2-p11.2 in NLS?

It contains the PHGDH gene, which is associated with Neu-Laxova syndrome.

What are the common findings in NLS regarding skin and limbs?

Ichthyotic skin and limb anomalies such as syndactyly and rocker bottom feet.

What are the challenges associated with reproductive risks in consanguineous couples?

Determining at-risk recessive conditions and managing parental guilt regarding relatedness.

What are the typical outcomes for a balanced translocation carrier?

They are usually unaffected phenotypically, but may have reproductive challenges.

What is a balanced reciprocal translocation?

A chromosomal rearrangement where segments from two different chromosomes are exchanged without any genetic material being lost.

What are the potential reproductive outcomes for parents with a balanced translocation?

They may have typical embryos, balanced translocations, or unbalanced translocations that could lead to health issues.

What are the two types of inversions in chromosomes?

Pericentric (includes the centromere) and paracentric (does not include the centromere).

What are the potential outcomes of crossing over in pericentric inversions?

It can lead to recombinant chromosomes that may be partially trisomic or monosomic.

What is the typical outcome for children of parents with paracentric inversions?

Most will have either the inversion or typical chromosomes, with some risk of miscarriages.