ACOG has published two committee opinions on carrier screening. Committee Opinion 691 reviews the recommendations based on disorders. Committee Opinion 690 addresses the issues related to use of screening strategies such as expanded gene panel testing.
Key Highlights
Spinal Muscular Atrophy (SMA) has joined cystic fibrosis (CF) as a recommendation for all women who are pregnant or considering pregnancy
Hemoglobinopathies
Test all patients for CBC and RBC indices as part of antepartum care (ideally preconception)
Add Hgb electrophoresis if
Increased risk based on ethnicity: African, Middle Eastern, Southeast Asian, West Indian and Mediterranean ancestry
MCV is less than 80 fL with normal iron studies
Ashkenazi Jewish Testing (central and Eastern Europe descent)
Additional tests to ‘consider’ has been expanded to the following
Usher syndrome, Familial hyperinsulinism, Joubert and Maple syrup urine disease in addition to Bloom/Gaucher/Fanconi anemia/ML4/Neimann-Pick disease
Tay Sachs Disease
In addition to Ashkenazi Jews, offer if either partner is French-Canadian descent or Cajun
Screening can be performed using DNA-based testing (mutation analysis) or hexosaminidase enzyme in serum or leuckocytes (leukocyte only with oral contraceptives)
Enzyme testing picks up approximately 98% of carriers regardless of ethnicity
Mutation analysis is highly effective in at risk populations – detection rate is limited in other populations
Committee Opinion 690 reviews expanded carrier screening, including a discussion on counseling and what disorders should be included | Important summary statements include the following
Ethnic-specific, panethnic, and expanded carrier screening are acceptable strategies for prepregnancy and prenatal carrier screening. Each obstetrician–gynecologist or other health care provider or practice should establish a standard approach that is consistently offered to and discussed with each patient, ideally before pregnancy. After counseling, a patient may decline any or all carrier screening.
Expanded carrier screening does not replace previous risk-based screening recommendations. If obstetrician–gynecologists or other health care providers do not offer expanded carrier screening in their practice, screening recommendations for individual disorders should follow guidelines for carrier screening as outlined in Committee Opinion No. 691, Carrier Screening for Genetic Conditions.
Note: ACMG has published a document on preconception and prenatal carrier screening that includes a tiered approach to the selection of disorders | For the summary and links see ‘Related ObG Topics’ below)
In the US, all women who are considering or who are currently pregnant are offered a test that looks for whether a pregnancy may be at risk for a disorder called ‘spinal muscular atrophy’ (SMA). SMA is a severe progressive disorder caused by a loss of cells in the spinal cord, which leads to the loss of muscle strength and paralysis.
SMA is relatively common and affects all population groups
Childhood SMA is divided into 4 groups based on severity
Most severe type (Type 0) is present at birth with death by 6 months of age
Least severe type (Type III) appears after 18 months of age, and while life expectancy is that of the general population, most will lose their ability to walk with advancing age
Underlying Genetics
All people carry a few variants (changes or mutations in their DNA) that may impair the function of an important enzyme or protein
Thankfully, all genes come in pairs and as long as one copy of the gene that codes for SMA is working, enough protein is available to maintain health
The SMA test offered in pregnancy checks to see whether a parent is a ‘carrier’
A ‘carrier’ describes someone who has a serious change, but in only one copy of a gene pair
Because one gene copy is still working well, there is enough protein so that ‘carriers’ are healthy and the cells in the spinal cord will work normally
If one parent (usually the mother is tested first) is found to be a carrier, then the other parent will be offered testing as well
A baby will be ‘affected’ with SMA only if
Both parents are carriers and
Both of the baby’s gene copies are damaged (one non-working copy inherited from the mother and the other non-working copy from the father)
Because neither gene copy is making enough protein, the spinal cord cells will not work normally
In most cases, an entire piece of DNA, known as an exon, is missing from the gene (an exon is the section of a gene that instructs the cells to make protein – see ‘Related Topics’ below)
Note: Because the gene related to SMA is complicated, even expert laboratories may not be able to detect all ‘carriers’
KEY POINTS:
The SMA testing that is usually offered by obstetric providers during the routine pregnancy visit is meant for women with no personal or family history of SMA
Referral to genetic counseling services may be appropriate for
Individuals with a family history of SMA
A woman and/or her partner who are already known SMA carriers
If only one partner is an SMA carrier, the baby is not at risk for SMA
If both partners are SMA carriers, the risk to the baby of being affected with SMA is ¼ or 25%
Genetic testing usually does not need to be repeated in subsequent pregnancies if already on record
There are medications that are used to treat SMA
While they don’t provide a cure, they may help to improve symptoms
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Nusinersen: A Treatment for Spinal Muscular Atrophy (SMA) has Arrived
BACKGROUND AND PURPOSE:
Spinal Muscular Atrophy (SMA) is a serious autosomal recessive disorder
ACOG recommends offering SMA screening to all pregnant women or those considering pregnancy
SMA is caused by deletions or loss-of-function mutations in the SMN1 gene, causing insufficient expression of the SMN protein.
Another gene, SMN2 that is structurally very similar to SMN1, also produces SMN protein, but at only 5 to 10% of the SMN1 levels due to a splice-site variant excludes exon 7
A medication called nusinersen can alter RNA splicing of SMN2, potentially improving levels and function of the SMN protein
Mercuri et al. (NEJM, 2018) presents results from the phase 3 trial on the use of nusinersen in children with SMA
Participants: Children with SMA who had symptom onset after 6 months of age
Children were assigned at a 2:1 ratio to
Intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group)
Sham procedure (control group)
Treatment was administered on days 1, 29, 85, and 274
Primary outcome: Least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment
HFMSE scores range from 0 to 66 with higher scores meaning better motor function
Secondary outcomes
Percentage of children with a clinically meaningful increase from baseline in the HFMSE score, indicating an improvement in at least two motor skills
RESULTS:
When comparing the HFMSE score at month 15
There was a least-squares mean increase of 4.0 points from baseline compared to a decrease of 1.9 points in the control group
There was a significant between-group difference favoring nusinersen
Least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1 (P<0.001)
57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P<0.001)
The trial was terminated early due to significant improvement in the treatment arm
The overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively)
CONCLUSION:
Nusineren lead to clinically meaningful improvement in children with later-onset SMA
Spinal Muscular Atrophy: Genetic Concepts and Carrier Screening
WHAT IS IT?
ACOG recommends that screening for spinal muscular atrophy (SMA) be offered to all women who are considering or who are currently pregnant. SMA is a severe progressive neuromuscular disorder caused by loss of alpha motor neurons in the spinal cord, with the loss of muscle strength, leading to paralysis.
This disorder is common, with carrier frequencies in one study of 1/47 in Caucasians; 1/67 in Ashkenazi Jewish; 1/59 in Asian; 1/68 Hispanic; 1/52 Asian Indian; and 1/72 African American. In the overall US panethnic population, the carrier frequency was 1/54 with a detection rate of over 90%. SMA affects all population groups and is only second to cystic fibrosis as a cause of death from an autosomal recessive condition.
Childhood SMA is divided into 4 clinical groups but span a continuum without clear delineation
Type 0: Congenital SMA
Presents at birth
Death by 6 months of age
Type I: Severe SMA (Werdnig-Hoffmann disease)
Onset < 6 months
Median survival 2 years of age
Type II: Intermediate SMA (Dubowitz disease)
Onset 6-18 months
Children can sit but not stand unaided but lose ability by mid-teens
Life expectancy not known with certainty – adolescence to 3rd or 4th decade
Type III: Juvenile SMA (Kugelberg-Welander disease)
Onset > 18 months
Patients learn to walk unaided but most will lose ability with age
Life expectancy that of normal population
KEY POINTS:
Genetics
There are two related, almost identical genes on the long arm of chromosome 5, SMN1 and SMN2
SMN1 is the SMA-determining gene
Exon 7 in SMN1 is absent in both gene copies (maternal and paternal) in over 95% of affected individuals
In a few individuals, exon 7 is absent in one gene copy and there is a smaller mutation in the other gene copy
Some individuals have additional copies of SMN2 and their presence seem to lessen the severity of SMA
Limitations to Carrier Testing – False Negatives
De novo mutation: In 2% of cases, SMA results from a de novo mutation and therefore in this particular situation, screening parents will not detect the pathogenic variant (usually paternal)
Silent Carrier (2 + 0): Healthy individuals can carry 2 copies of SMN1 on a single chromosome and no copies on their other chromosome
The % of ‘silent carriers’ varies from approximately 30% in African Americans to 5% in Caucasians
The standard carrier screening tests are based on gene dosage and result in a false negative because 2 normal copies will be detected and therefore total amount of SMN1 will be interpreted as ‘normal’
The (2+0) individual is a carrier because there is a 50% chance he/she will pass the abnormal (missing SMN1) chromosome to the fetus
There are variants that track with silent carriers (i.e., found on chromosomes with duplications and not single-copy alleles) that can be incorporated into clinical carrier screening tests to improve residual risk estimates
Medication now available for SMA
Nusinersen
The FDA approved the first medication (nusinersen) in 2016, to treat children and adults with spinal muscular atrophy (SMA)
The FDA approval was based on a clinical trial in 121 patients with infantile-onset SMA who were diagnosed before 6 months of age and who were less than 7 months old at the time of their first dose
Patients were randomized to receive an injection of nusinersen into the fluid surrounding the spinal cord, or undergo a mock procedure without drug injection (a skin prick)
Forty percent of patients treated with nusinersen achieved improvement in motor milestones as defined in the study, whereas none of the control patients did
Onasemnogene abeparvovec-xioi
Indicated for the treatment of children with SMA <2 years
Gene therapy
Adeno-associated virus vector-based gene therapy
Vector delivers a fully functional copy of human SMN gene into the target motor neuron cells
One-time IV administration
Studies
Primary evidence of effectiveness from ongoing clinical trial
Compared to the natural history of patients with infantile-onset SMA patients in treatment arm demonstrated significant improvement in their ability to reach developmental motor milestones (e.g., head control and the ability to sit without support)
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