Genetics and Family Screening Flashcards
What is Noncompaction Cardiomyopathy (NCCM)?
NCCM is characterized by endocardial hypertrabeculation of the myocardium of the left ventricle.
What genetic mutation was first identified as a cause of NCCM?
A mutation in the X-linked TAZ gene.
In what year was the first genetic cause for NCCM identified?
1997.
What is the prevalence of mutations in sarcomere genes among NCCM patients?
Sarcomere genes are the most prevalent genetic causes of NCCM.
What percentage of NCCM patients have a mutation identified through next generation sequencing?
Around 35%.
What proportion of NCCM patients are considered to have a genetic cause?
Approximately 50%.
What is the recommendation for relatives of patients diagnosed with NCCM?
Referral for genetic counseling.
True or False: In 45% of familial NCCM, no mutation can be identified.
True.
What types of genetic causes are recognized for NCCM?
- Genetic NCCM
- Sporadic NCCM
- Benign LV hypertrabeculation.
What are the three main categories of genetic burden for noncompaction recognized?
- Patients with genetic NCCM
- Sporadic NCCM without a genetic cause
- Healthy individuals with benign LV hypertrabeculation.
What is the risk for first-degree relatives if a mutation is found in NCCM?
They are advised to undergo DNA testing for the familial mutation.
What percentage of NCCM patients have defects in sarcomere genes?
71%.
What is the inheritance pattern of defects in sarcomere genes causing NCCM?
Autosomal dominant.
Fill in the blank: Patients with two sarcomere gene mutations may have more severe clinical features than their relatives with _______.
single mutations.
What is Barth syndrome caused by?
Defects in the TAZ gene on the X chromosome.
What is the role of mitochondrial defects in NCCM?
They lead to insufficient energy production required in various organs.
What chromosomal defect is frequently reported in children presenting with NCCM?
1p36 deletion syndrome.
What does genetic counseling for NCCM involve?
Performing DNA analysis and detecting familial disease.
What is the purpose of genetic counseling in NCCM?
To estimate risk for relatives and convey information on the risks to index cases.
What are some mitochondrial genes linked to NCCM?
- MT-ATP6
- MT-ATP8
- MT-CO1
- MT-CO3
- MT-CYB
- MT-ND1
- MT-ND2
- MT-ND6.
What percentage of genetic NCCM patients may not show familial disease?
At least one third.
What is the primary role of genetic counselors in the context of NCCM?
To explain clinical features of the disease and the inheritance pattern, and organize informing and screening family members.
What is a key component of genetic counseling related to family members?
Helping index cases and their relatives handle information on heredity and discussing subsequent risks and consequences.
True or False: Genetic counseling aims to make scientific information accessible both intellectually and emotionally for patients and their families.
True
What emotional responses may patients or relatives experience during genetic counseling?
Distress, anxiety, or guilt.
What is the purpose of obtaining family history in genetic counseling for NCCM?
To determine if cardiomyopathy is familial and identify the mode of inheritance.
Fill in the blank: An uninformative family history cannot completely exclude a genetic cause for _______.
NCCM
What percentage of NCCM patients without affected relatives are known to have a mutation?
Approximately 20%
What factors may contribute to the underreporting of familial cardiomyopathy?
- Affected relatives may not have been diagnosed with NCCM.
- Family histories may not be informative due to small family size or little information on relatives.
What is the main goal of DNA testing for NCCM patients?
To identify the genetic cause for NCCM.
How does identifying a mutation in a family help in predictive testing?
It allows asymptomatic relatives to have a predictive DNA test identifying those at increased risk.
What is the significance of the genotype in NCCM patients?
It may help predict risk for ventricular systolic dysfunction and major cardiac adverse events.
What do NGS gene panels improve in genetic testing for NCCM?
The yield of genetic testing by allowing simultaneous analysis of multiple cardiomyopathy genes.
List three genes commonly included in cardiomyopathy gene panels.
- MYH7
- MYBPC3
- TTN
What classification system is used for interpreting DNA analysis results?
- Pathogenic variants (PV)
- Likely pathogenic variants (LPV)
- Variants of unknown clinical significance (VUS)
- Likely benign or benign variants
True or False: DNA testing of pre-symptomatic family members is indicated only when there is a PV or LPV in the family.
True
What percentage of NCCM patients have concomitant congenital heart defects?
Around 10%
What is the importance of family screening in NCCM?
To determine the risk of cardiomyopathy in relatives.
What factors influence the risk of cardiomyopathy in relatives of NCCM patients?
- Genetic defect in the index case
- Mode of inheritance
- Gene-specific penetrance
- Age at diagnosis of the index case
What is recommended for adult relatives of NCCM patients with a causative mutation?
Predictive DNA testing.
What psychological impact can regular hospital visits have on children undergoing screening for NCCM?
Adverse psychological effects like anxiety or depression.
What is a significant risk for women with NCCM during pregnancy?
Developing heart failure and/or arrhythmias.
What prenatal diagnostics can be discussed for women with NCCM?
- Prenatal DNA testing
- Prenatal cardiac ultrasound of the fetus
What is the risk for women with cardiomyopathy who have symptoms before pregnancy?
Increased risk and need for specialized obstetric care
Women with asymptomatic cardiomyopathies usually tolerate pregnancy well.
What is the likelihood of NCCM patients having a child with a cardiomyopathy?
Increased risk
Prenatal diagnosis can be discussed depending on mutation presence and risk estimates.
Why are prenatal diagnostics for NCCM rarely requested?
The risk of severe congenital NCCM in children is small
Symptoms of NCCM are age-related and may not be present in patients/carriers.
When is prenatal diagnosis for NCCM recommended?
When there is an affected child in the family
Individual options and limitations are discussed with NCCM patients with reproductive wishes.
What is a significant consideration for prenatal testing in NCCM?
Familial mutation
Prenatal DNA testing can be performed if a mutation is present in the family.
What are the two methods for prenatal DNA testing?
- Chorionic villus sampling (10–12 weeks)
- Amniocentesis (14–20 weeks)
Results are usually available within 2–3 weeks.
What should parents be informed about regarding prenatal testing interventions?
Risks for the mother and fetus, including miscarriage
Parents may choose to terminate the pregnancy if severe conditions are detected.
What does prenatal cardiac sonography allow for?
Detection of fetal cardiac malformations, cardiomyopathies, and arrhythmias
Performed in specialized tertiary prenatal centers.
What is a major limitation of prenatal sonography for NCCM?
Little is known about the onset and prenatal development of NCCM
Difficulty in predicting which patients will show signs of noncompaction prenatally.
What psychological impact may genetic testing have on patients and their families?
Increased burden and anxiety about risk transmission
The burden of cardiac symptoms often has a greater psychosocial impact than the genetic aspect.
What factor may lead to more distress in index cases undergoing genetic testing?
Having a cardiomyopathy
Relatives usually are asymptomatic, leading to less distress.
What is recommended for relatives from a family with a mutation?
Cardiologic screening
Also recommended for families without a mutation from age 10 onwards.
What does cardiologic screening include?
- Physical examination
- 12-lead electrocardiography
- Echocardiography
Expanded cardiac work-up may be needed if abnormalities are found.
What should be done for mutation carriers without a phenotype?
Cardiac examination every 5 years
They may develop a cardiomyopathy later in life due to age-related increase in penetrance.
What is the prevalence of cardiomyopathy identified in mutation carriers during first screening?
50–70%
About 30% of these patients are asymptomatic.
When should cardiologic follow-up occur for patients diagnosed with NCCM?
Every 1–2 years or sooner if new symptoms arise
Lifelong follow-up is required to monitor changes in symptoms and cardiac function.
