Carrier Screening For Genetic Conditions

Question 1

If a woman has unexplained ovarian insufficiency or failure or an elevated follicle-stimulating hormone level before age 40 years, fragile X carrier screening is recommended to determine whether she has an FMR1 premutation.

Answer 1

For fragile x

Question 2

A hemoglobin electrophoresis should be performed in addition to a complete blood count if there is suspicion of hemoglobinopathy based on ethnicity (African, Mediterranean, Middle Eastern, Southeast Asian, or West Indian descent). If red blood cell indices indicate a low mean corpuscular hemoglobin or mean corpuscular volume, hemoglobin electrophoresis also should be performed.

Answer 2

T

Question 3

Screening for Tay–Sachs disease should be offered when considering pregnancy or during pregnancy if either member of a couple is of Ashkenazi Jewish, French–Canadian, or Cajun descent. Those with a family history consistent with Tay–Sachs disease also should be offered screening.

Answer 3

Ashkenazi Jewish, French–Canadian, or Cajun descent

Question 4

There are several types of spinal muscular atrophy based on age at symptom onset. Earlier onset is correlated with more severe manifestations. The most severe and most common form of the disease, type I (Werdnig–Hoffman), has symptomatic onset before 6 months of age and causes death from respiratory failure within the first 2 years of life. Type II spinal muscular atrophy is of intermediate severity, with typical onset before 2 years of age. Affected children are able to sit, but few are able to stand or walk unaided. Respiratory insufficiency is a frequent cause of death during adolescence; however, the lifespan of patients with spinal muscular atrophy type II varies from age 2 years to the third decade of life. More than 80% of cases of spinal muscular atrophy are type I or type II, both of which are lethal forms. A milder form, type III (Kugelberg–Welander), has typical symptomatic onset after 18 months of age. However, the symptom profile is quite variable. Affected individuals typically reach all major motor milestones, but function ranges from requiring wheelchair assistance in childhood to completely unaided ambulation into adulthood with minor muscular weakness. Many patients have normal life expectancies. Type IV has onset in adulthood. There is an additional Type 0 proposed, which has onset in the prenatal period.

Answer 4

T

Question 5

SMN1 is considered the active gene for survival motor neuron protein production, and more than 98% of patients with spinal muscular atrophy have an abnormality in both SMN1 genes, which can be caused by a deletion (95%) of exon 7, or other mutation. There is generally one copy of SMN1 per chromosome, but occasionally two can be located on the same chromosome.

Answer 5

T

Question 6

goal of cystic fibrosis carrier screening is to identify individuals at risk of having a child with classic cystic fibrosis, which is defined by significant pulmonary disease and pancreatic insufficiency. Cystic fibrosis is more common among the non-Hispanic white population compared with other racial and ethnic populations; however, because of the increasing difficulty in assigning a single ethnicity to individuals, in 2005, the American College of Obstetricians and Gynecologists recommended offering cystic fibrosis carrier screening to all patients.

Answer 6

T

Question 7

Cystic fibrosis is the most common life-threatening, autosomal recessive condition in the ___ population

Answer 7

non-Hispanic white

Question 8

Cystic fibrosis is the most common life-threatening, autosomal recessive condition in the non-Hispanic white population. The disease incidence is 1 in 2,500 individuals in the non-Hispanic white population and considerably less in other ethnic groups. It is a progressive, multisystem disease that primarily affects the pulmonary, pancreatic, and gastrointestinal systems butdoes not affect intelligence. The current median predicted survival is approximately 42 years, with respiratory failure as the most common cause of death (7). More than 95% of males with cystic fibrosis have primary infertility with obstructive azoospermia secondary to congenital bilateral absence of the vas deferens. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, located on chromosome 7. Two copies of deleterious mutations in this gene cause cystic fibrosis.

Answer 8

T

Question 9

If both partners are carriers, diagnostic testing for cystic fibrosis can be performed on the chorionic villi or amniocytes.

Answer 9

Chorionic villi or

Amniocytes

Question 10

Asymptomatic individuals with heterozygous hemoglobin S genotypes (carriers) are said to have sickle cell trait. The most severe form of the disease, hemoglobin SS (homozygous hemoglobin S), is called sickle cell anemia.

Answer 10

T

Question 11

Sickle cell disease occurs most commonly in people of African origin. Approximately 1 in 10 African Americans has sickle cell trait

Answer 11

T

Question 12

The distorted red cells lead to increased viscosity, hemolysis, and anemia and a further decrease in oxygenation. When sickling occurs within small blood vessels, it can interrupt blood supply to vital organs (vasoocclusive crisis). Repeated vasoocclusive crises result in widespread microvascular obstruction with interruption of normal perfusion and function of several organs, including the spleen, lungs, kidneys, heart, and brain. These crises are extremely painful and typically require hospitalization and medical management. Over the course of their lifetimes, patients with sickle cell disease who have repeated crises often build up tolerance to opioid medications and may require large doses in order to achieve relief from the pain of an acute vasoocclusive crisis. Also, these patients often have an element of chronic pain and they may require daily pain medication even in the absence of an acute crisis. Adults with hemoglobin SS are functionally asplenic, having undergone autosplenectomy by adolescence. Absence of the spleen contributes to the increased incidence and severity of infection in patients with sickle cell disease.

Answer 12

T

Question 13

The most significant threat to patients with sickle cell disease is acute chest syndrome. Acute chest syndrome is characterized by a pulmonary infiltrate with fever that leads to hypoxemia and acidosis. The infiltrates are not infectious in origin but rather are due to vasoocclusion from sickling or embolization of marrow from long bones affected by sickling (13).

Answer 13

T

Question 14

Alpha-thalassemia usually results from a gene deletion of two or more copies of the four α-globin genes.

Deletion of one α-globin gene (α-/ αα) is clinically unrecognizable, and laboratory testing yields normal results.

Deletion of two α-globin genes causes α-thalassemia trait, a mild asymptomatic microcytic anemia.

The deletions can be on the same chromosome or in cis (αα/–),

or on each chromosome or in trans (α-/α-).

Answer 14

T

Question 15

Hemoglobin H disease, which is caused by the deletion of three α-globin genes, usually is associated with mild-to-moderate hemolytic anemia. Alpha-thalassemia major (hemoglobin Bart) results in the absence of α-globin (–/–), which is associated with hydrops fetalis, intrauterine death, and preeclampsia

Answer 15

hemoglobin bart

Question 16

ndividuals who are heterozygous for this mutation have β-thalassemia minor. Those who are homozygous have β-thalassemia major (Cooley’s anemia) or a milder form called thalassemia intermedia. There are numerous mutations associated with β-thalassemia, and each mutation can have a different effect on the amount of β-chain produced. Because of the many different mutations, many individuals with β-thalassemia major are actually compound heterozygotes carrying two different mutations. Beta-thalassemia major is characterized by severe anemia with resultant extramedullary erythropoiesis, delayed sexual development, and poor growth. Elevated levels of hemoglobin F in individuals with β-thalassemia major partially compensate for the absence of hemoglobin A; however, death usually occurs by age 10 years unless treatment is begun early with periodic blood transfusions. With transfusion, the severe anemia is reversed and extramedullary erythropoiesis is suppresse

Answer 16

t

Question 17

For some couples, preimplantation genetic diagnosis in combination with in vitro fertilization may be a desirable alternative to avoid termination of an affected pregnancy. Preimplantation genetic diagnosis has been successfully performed for sickle cell disease and most types of β-thalassemia

Answer 17

Preimplantation genetic diagnosis

Question 18

Fragile X syndrome is the most common inherited form of intellectual disability. The syndrome occurs in approximately 1 in 3,600 males and 1 in 4,000–6,000 females from a variety of ethnic backgrounds. Intellectual disability or impairment ranges from borderline, including learning disabilities, to severe, presenting with cognitive and behavioral disabilities, including autism with intellectual disability; attention deficit–hyperactivity disorder; or both. Most affected males have significant intellectual disability. Fragile X syndrome is a common known cause of autism or autism spectrum disorder behaviors with intellectual disability, with the diagnosis occurring in approximately 25% of affected individuals

Answer 18

most common inherited form of intellectual disability

Question 19

Fragile X syndrome is transmitted as an X-linked disorder

Answer 19

t

Question 20

If a woman has unexplained ovarian insufficiency or failure or an elevated follicle-stimulating hormone level before age 40 years, fragile X carrier screening is recommended to determine whether she has an FMR1 premutation.

Answer 20

t

Question 21

he American College of Obstetricians and Gynecologists has previously recommended offering carrier screening for four conditions in the Ashkenazi population:

Canavan disease is a severe degenerative neurologic disease. The phenotype is quite variable, but patients typically present in the first few months of life with delayed motor milestones (eg, head control and sitting). They will manifest macrocephaly, hypotonia, and intellectual disability. Life expectancy is variable, but many individuals die in childhood or adolescence. Treatment is primarily supportive because there is no cure. The disease is caused by mutations in the gene for aspartoacylase, which is involved in the metabolism of N-acetyl-L aspartic acid.
Cystic fibrosis is discussed elsewhere in this document.
Familial dysautonomia, a disorder of the sensory and autonomic nervous system, is associated with significant morbidity. Clinical features include abnormal suck and feeding difficulties, episodic vomiting, abnormal sweating, pain and temperature insensitivity, labile blood pressure levels, absent tearing, and scoliosis. Treatment is available that can improve the length and quality of life, but there currently is no cure. In 2001, the gene for familial dysautonomia was identified. At least two mutations in the familial dysautonomia gene, IKBKAP, have been identified in patients of Ashkenazi Jewish descent with familial dysautonomia. One of the mutations, IVS20(+6T->C), is found in more than 99% of patients with familial dysautonomia. It occurs almost exclusively in individuals of Ashkenazi Jewish descent; the carrier rate (1 in 32) is similar to Tay–Sachs disease and cystic fibrosis (22).
Tay–Sachs disease is discussed elsewhere in this document.

Answer 21

t

Question 22

ay–Sachs disease is a severe, progressive neurodegenerative disease. more prevalent in

Answer 22

ashkenazi jewish