Ronald J. Wapner, MD

Screening for fetal chromosomal anomalies such as Down syndrome has become a routine part of prenatal care, but it is only possible during pregnancy. On the other hand, identifying pregnancies at risk for single-gene autosomal recessive disorders, or "Mendelian" disorders, is possible as part of preconception care.

Although Mendelian disorders are individually rare, some are more prevalent than we have thought. When considered collectively, Mendelian disorders are among the most common causes of admissions to pediatric hospitals, a significant cause of infant mortality, and a considerable public health concern.

Screening for carriers of Mendelian disorders has traditionally focused on a limited number of diseases, as determined by the parents’ ethnicity and race. For example, Tay Sachs disease has been seen primarily in the Ashkenazi Jewish community, and sickle cell disease occurs most frequently among African Americans. Until very recently, carrier screening was offered only to members of these groups.

The problem with this approach is that we have become a significantly intermixed population. There has been so much intermarriage among different racial and ethnic groups, and assimilation of different populations, that it has become increasingly difficult to discern a single ethnicity for individuals to determine who is "high risk." An increasing number of people report mixed ancestry, and many patients often prefer not to categorize themselves by race or ethnicity.

For example, an increasing number of carriers of a mutation for Tay Sachs disease do not report Ashkenazi Jewish ancestry. Similarly, the ethnic lines that have traditionally defined risk for cystic fibrosis have changed, and more widespread carrier screening has been increasingly encouraged over the past decade.

In 2011, the American College of Obstetricians and Gynecologists’ (ACOG) Committee on Genetics issued an update on carrier screening for cystic fibrosis, in which it stressed that, although cystic fibrosis is still more common among non-Hispanic white individuals and those of Ashkenazi Jewish ancestry, it "is reasonable to offer CF carrier screening to all patients" (Committee Opinion 486, Obstet. Gynecol. 2011;117:1028-31). Pan-ethnic screening for spinal muscular atrophy also has increasingly been incorporated into routine practice.

With newly available high-throughput genomic methods, we can now screen all patients, regardless of ethnicity, using a universal, pan-ethnic approach, which can identify 100-plus disease-causing mutations at a fraction of the cost of ethnic targeted screening.

Currently, the majority of carrier screening is performed as part of prenatal care; however, preconception carrier screening would allow patients and couples to consider all reproductive options. Knowledge that they carry the gene for a recessive disease, and thus have a 1-in-4 chance of having an affected child, gives parents the opportunity to consider their options before conception. These choices can include early prenatal diagnostic testing with or without pregnancy termination, use of donor gametes or election not to conceive their own child, or preimplantation genetic diagnosis (PGD), wherein a monogenetic disorder is diagnosed using only a few cells from the developing zygote.

In our practice at Columbia, we have been performing pan-ethnic screening for less than a year, and have already identified four couples at risk for having a child with severe genetic diseases. Two of these couples were both carriers for spinal muscular atrophy, and two were found to be carriers for rare genetic diseases that would not have been screened for were it not for our new pan-ethnic screening approach.

Carrier frequency

There are new options available for pan-ethnic carrier screening provided by a number of commercial companies. One of the more frequently used panels covers 417 disease-causing mutations associated with 108 recessive diseases, nearly all of which are considered to be severe, associated with progressive disease and reduced life span, or requiring significant intervention or treatment. This panel includes all of the currently recommended disorders recommended by ACOG for routine obstetrical care of individuals of Eastern European Jewish descent (i.e., Tay-Sachs disease, Canavan disease, familial dysautonomia, and cystic fibrosis) as well as the 10 disorders recommended for routine screening by the American College of Medical Genetics (ACMG).

A challenge of the expanded panels is that as many as 1 in 4 individuals who are screened will be identified as a carrier of at least one autosomal recessive disease. However, when both partners are screened, relatively few couples are found to be at risk of having an affected child. Overall, fewer than 1% of couples who take the test will turn out to be carriers of the same disease.

In a recent study of carrier frequencies, 24% of more than 23,400 individuals were found to be heterozygous for at least one non-mild condition. Approximately 5% were carriers for multiple disorders. Not surprisingly, carrier rates varied by ethnicity, ranging from 43.6% of Ashkenazi Jewish individuals to 8.5% of East Asians.

Across all ethnic groups, the most common carrier frequencies for clinically significant disorders were for cystic fibrosis, DFNB1 nonsyndromic hearing loss and deafness, spinal muscular atrophy, familial Mediterranean fever, Smith-Lemli-Opitz syndrome, sickle cell disease/beta-thalassemia, and Gaucher disease. Among the carrier states detected in the study, almost 77% and 70% were for diseases not included in ACOG carrier screening guidelines or in ACMG guidelines, respectively.

Investigators calculated that 433 of the individuals found to be carriers would not have learned their carrier status under conventional ethnicity-based screening paradigms. For example, approximately 26% of familial dysautonomia carriers in the study did not report Jewish ancestry. There also were multiple instances in the study of carrier frequencies being higher than expected for particular populations. For instance, the carrier frequency for cystic fibrosis was 1 in 40 among South Asians – a rate that is significantly higher than other reported rates (Genet. Med. 2013;15:178-186).

The study confirms a number of findings, the two most important being that there are numerous severe Mendelian conditions that are more prevalent than commonly understood, and that a significant proportion of Mendelian diseases are present in individuals outside the populations that have traditionally been characterized as high risk.

Clinical considerations

Usage of pan-ethnic expanded carrier screening is rapidly increasing, with many reproductive endocrinologists now recommending it prior to in vitro fertilization, and a growing number of obstetricians, other physicians, and patients using the tests both prenatally and in the preconception stage.

For ob.gyns., pan-ethnic screening is a significant paradigm shift which will impact our interactions with patients. For example, we will need to develop new ways of providing genetic counseling to our patients. Traditionally, we have spent significant time, prior to screening, describing each major genetic disease for which screening is performed. With the new screening paradigm, a broader, more generic consent process will be more practical – one in which we talk with patients and provide written or Web-based information about the benefits and limitations of the multidisease carrier screening panel, and then reserve in-depth discussions of specific risks and disorders for a later time, as needed.

Genetic counseling should be provided mainly on a post-test basis, and probably most often after both parents have been tested and found to be carriers. Ideally, both spouses/partners would be screened at the same time, but because most women visit their physicians by themselves, it is more practical overall to perform initial carrier screening for the woman first and then test her spouse/partner if she is found to be a carrier. Separate spouse/partner screening would require providers to contact carrier women quickly and reliably, and to obtain samples from their partners as soon as possible. The lab also should be made aware of the pre-identified carrier status of the patients before testing the spouses/partners.

A crucial message we should share with our patients during any counseling is that broader screening does not eliminate the risk of having an affected child, but reduces the risk. At present, many of the panels test only for established disease-causing mutations. There will always be patients who have a rare mutation that has not previously been described. This is particularly true as we begin screening populations not previously evaluated for Mendelian disorders. It is likely that the assortment of mutations causing specific diseases will be different in these groups, and that the residual risk of being a carrier will be higher than in well-studied populations.

With the cost for screening becoming more affordable, sequencing will become a major tool for determining carrier status of our patients. However, ob.gyns. must keep in mind that expanded screening should not substitute for obtaining a family history and referring a patient for genetic counseling when inheritable risk seems possible. Pan-ethnic screening may be able to identify patients’ risks for genetic disorders, minimizing the risk of having a child with a serious birth defect, but it has limitations. For example, not all pan-ethnic panels include analysis for premutation carriers, making it important to inquire about a history of unexplained mental retardation and autism in males, since this may stem from Fragile X syndrome.

Additionally, screening opens up the possibility of finding mutations with unknown or uncertain clinical significance. At present, when one parent is identified as a carrier of a disease-causing gene, the other can choose to have the disease-causing gene sequenced. This option should be offered to all carriers, but for many genes the additional information may be minimal and not worth the extra cost.

As we increase the frequency of carrier screening, we will identify individuals with mild forms of some diseases. For example, some mutations causing Gaucher disease are associated with a mild phenotype, and adults with these mutations may go undiagnosed for a lifetime. Patients should be made aware of this possibility and informed about the fact that some Mendelian disorders may only become evident in adulthood.

All of these issues must be carefully considered as expanded carrier screening moves into routine clinical care. The ACMG recently published a position statement on preconception and prenatal expanded carrier screening in which it listed criteria that must be met by a disorder to be included in a panel (Genet. Med. 2013;15:482-83). Presently, a work group composed of members of the obstetrical, maternal-fetal medicine, pediatric, genetics, and counseling communities is developing practice guidelines to advise the medical community on the use of expanded carrier screening panels.

Dr. Wapner, a professor in the department of obstetrics and gynecology at Columbia University Medical Center, New York, is recognized as an expert in reproductive genetics. He reported that he has no relevant disclosures.

Screening for fetal chromosomal anomalies such as Down syndrome has become a routine part of prenatal care, but it is only possible during pregnancy. On the other hand, identifying pregnancies at risk for single-gene autosomal recessive disorders, or "Mendelian" disorders, is possible as part of preconception care.

Although Mendelian disorders are individually rare, some are more prevalent than we have thought. When considered collectively, Mendelian disorders are among the most common causes of admissions to pediatric hospitals, a significant cause of infant mortality, and a considerable public health concern.

Screening for carriers of Mendelian disorders has traditionally focused on a limited number of diseases, as determined by the parents’ ethnicity and race. For example, Tay Sachs disease has been seen primarily in the Ashkenazi Jewish community, and sickle cell disease occurs most frequently among African Americans. Until very recently, carrier screening was offered only to members of these groups.

The problem with this approach is that we have become a significantly intermixed population. There has been so much intermarriage among different racial and ethnic groups, and assimilation of different populations, that it has become increasingly difficult to discern a single ethnicity for individuals to determine who is "high risk." An increasing number of people report mixed ancestry, and many patients often prefer not to categorize themselves by race or ethnicity.

For example, an increasing number of carriers of a mutation for Tay Sachs disease do not report Ashkenazi Jewish ancestry. Similarly, the ethnic lines that have traditionally defined risk for cystic fibrosis have changed, and more widespread carrier screening has been increasingly encouraged over the past decade.

In 2011, the American College of Obstetricians and Gynecologists’ (ACOG) Committee on Genetics issued an update on carrier screening for cystic fibrosis, in which it stressed that, although cystic fibrosis is still more common among non-Hispanic white individuals and those of Ashkenazi Jewish ancestry, it "is reasonable to offer CF carrier screening to all patients" (Committee Opinion 486, Obstet. Gynecol. 2011;117:1028-31). Pan-ethnic screening for spinal muscular atrophy also has increasingly been incorporated into routine practice.

With newly available high-throughput genomic methods, we can now screen all patients, regardless of ethnicity, using a universal, pan-ethnic approach, which can identify 100-plus disease-causing mutations at a fraction of the cost of ethnic targeted screening.

Currently, the majority of carrier screening is performed as part of prenatal care; however, preconception carrier screening would allow patients and couples to consider all reproductive options. Knowledge that they carry the gene for a recessive disease, and thus have a 1-in-4 chance of having an affected child, gives parents the opportunity to consider their options before conception. These choices can include early prenatal diagnostic testing with or without pregnancy termination, use of donor gametes or election not to conceive their own child, or preimplantation genetic diagnosis (PGD), wherein a monogenetic disorder is diagnosed using only a few cells from the developing zygote.

In our practice at Columbia, we have been performing pan-ethnic screening for less than a year, and have already identified four couples at risk for having a child with severe genetic diseases. Two of these couples were both carriers for spinal muscular atrophy, and two were found to be carriers for rare genetic diseases that would not have been screened for were it not for our new pan-ethnic screening approach.

Carrier frequency

There are new options available for pan-ethnic carrier screening provided by a number of commercial companies. One of the more frequently used panels covers 417 disease-causing mutations associated with 108 recessive diseases, nearly all of which are considered to be severe, associated with progressive disease and reduced life span, or requiring significant intervention or treatment. This panel includes all of the currently recommended disorders recommended by ACOG for routine obstetrical care of individuals of Eastern European Jewish descent (i.e., Tay-Sachs disease, Canavan disease, familial dysautonomia, and cystic fibrosis) as well as the 10 disorders recommended for routine screening by the American College of Medical Genetics (ACMG).

A challenge of the expanded panels is that as many as 1 in 4 individuals who are screened will be identified as a carrier of at least one autosomal recessive disease. However, when both partners are screened, relatively few couples are found to be at risk of having an affected child. Overall, fewer than 1% of couples who take the test will turn out to be carriers of the same disease.

In a recent study of carrier frequencies, 24% of more than 23,400 individuals were found to be heterozygous for at least one non-mild condition. Approximately 5% were carriers for multiple disorders. Not surprisingly, carrier rates varied by ethnicity, ranging from 43.6% of Ashkenazi Jewish individuals to 8.5% of East Asians.

Across all ethnic groups, the most common carrier frequencies for clinically significant disorders were for cystic fibrosis, DFNB1 nonsyndromic hearing loss and deafness, spinal muscular atrophy, familial Mediterranean fever, Smith-Lemli-Opitz syndrome, sickle cell disease/beta-thalassemia, and Gaucher disease. Among the carrier states detected in the study, almost 77% and 70% were for diseases not included in ACOG carrier screening guidelines or in ACMG guidelines, respectively.

Investigators calculated that 433 of the individuals found to be carriers would not have learned their carrier status under conventional ethnicity-based screening paradigms. For example, approximately 26% of familial dysautonomia carriers in the study did not report Jewish ancestry. There also were multiple instances in the study of carrier frequencies being higher than expected for particular populations. For instance, the carrier frequency for cystic fibrosis was 1 in 40 among South Asians – a rate that is significantly higher than other reported rates (Genet. Med. 2013;15:178-186).

The study confirms a number of findings, the two most important being that there are numerous severe Mendelian conditions that are more prevalent than commonly understood, and that a significant proportion of Mendelian diseases are present in individuals outside the populations that have traditionally been characterized as high risk.

Clinical considerations

Usage of pan-ethnic expanded carrier screening is rapidly increasing, with many reproductive endocrinologists now recommending it prior to in vitro fertilization, and a growing number of obstetricians, other physicians, and patients using the tests both prenatally and in the preconception stage.

For ob.gyns., pan-ethnic screening is a significant paradigm shift which will impact our interactions with patients. For example, we will need to develop new ways of providing genetic counseling to our patients. Traditionally, we have spent significant time, prior to screening, describing each major genetic disease for which screening is performed. With the new screening paradigm, a broader, more generic consent process will be more practical – one in which we talk with patients and provide written or Web-based information about the benefits and limitations of the multidisease carrier screening panel, and then reserve in-depth discussions of specific risks and disorders for a later time, as needed.

Genetic counseling should be provided mainly on a post-test basis, and probably most often after both parents have been tested and found to be carriers. Ideally, both spouses/partners would be screened at the same time, but because most women visit their physicians by themselves, it is more practical overall to perform initial carrier screening for the woman first and then test her spouse/partner if she is found to be a carrier. Separate spouse/partner screening would require providers to contact carrier women quickly and reliably, and to obtain samples from their partners as soon as possible. The lab also should be made aware of the pre-identified carrier status of the patients before testing the spouses/partners.

A crucial message we should share with our patients during any counseling is that broader screening does not eliminate the risk of having an affected child, but reduces the risk. At present, many of the panels test only for established disease-causing mutations. There will always be patients who have a rare mutation that has not previously been described. This is particularly true as we begin screening populations not previously evaluated for Mendelian disorders. It is likely that the assortment of mutations causing specific diseases will be different in these groups, and that the residual risk of being a carrier will be higher than in well-studied populations.

With the cost for screening becoming more affordable, sequencing will become a major tool for determining carrier status of our patients. However, ob.gyns. must keep in mind that expanded screening should not substitute for obtaining a family history and referring a patient for genetic counseling when inheritable risk seems possible. Pan-ethnic screening may be able to identify patients’ risks for genetic disorders, minimizing the risk of having a child with a serious birth defect, but it has limitations. For example, not all pan-ethnic panels include analysis for premutation carriers, making it important to inquire about a history of unexplained mental retardation and autism in males, since this may stem from Fragile X syndrome.

Additionally, screening opens up the possibility of finding mutations with unknown or uncertain clinical significance. At present, when one parent is identified as a carrier of a disease-causing gene, the other can choose to have the disease-causing gene sequenced. This option should be offered to all carriers, but for many genes the additional information may be minimal and not worth the extra cost.

As we increase the frequency of carrier screening, we will identify individuals with mild forms of some diseases. For example, some mutations causing Gaucher disease are associated with a mild phenotype, and adults with these mutations may go undiagnosed for a lifetime. Patients should be made aware of this possibility and informed about the fact that some Mendelian disorders may only become evident in adulthood.

All of these issues must be carefully considered as expanded carrier screening moves into routine clinical care. The ACMG recently published a position statement on preconception and prenatal expanded carrier screening in which it listed criteria that must be met by a disorder to be included in a panel (Genet. Med. 2013;15:482-83). Presently, a work group composed of members of the obstetrical, maternal-fetal medicine, pediatric, genetics, and counseling communities is developing practice guidelines to advise the medical community on the use of expanded carrier screening panels.

Dr. Wapner, a professor in the department of obstetrics and gynecology at Columbia University Medical Center, New York, is recognized as an expert in reproductive genetics. He reported that he has no relevant disclosures.

Screening for fetal chromosomal anomalies such as Down syndrome has become a routine part of prenatal care, but it is only possible during pregnancy. On the other hand, identifying pregnancies at risk for single-gene autosomal recessive disorders, or "Mendelian" disorders, is possible as part of preconception care.

Although Mendelian disorders are individually rare, some are more prevalent than we have thought. When considered collectively, Mendelian disorders are among the most common causes of admissions to pediatric hospitals, a significant cause of infant mortality, and a considerable public health concern.

Screening for carriers of Mendelian disorders has traditionally focused on a limited number of diseases, as determined by the parents’ ethnicity and race. For example, Tay Sachs disease has been seen primarily in the Ashkenazi Jewish community, and sickle cell disease occurs most frequently among African Americans. Until very recently, carrier screening was offered only to members of these groups.

The problem with this approach is that we have become a significantly intermixed population. There has been so much intermarriage among different racial and ethnic groups, and assimilation of different populations, that it has become increasingly difficult to discern a single ethnicity for individuals to determine who is "high risk." An increasing number of people report mixed ancestry, and many patients often prefer not to categorize themselves by race or ethnicity.

For example, an increasing number of carriers of a mutation for Tay Sachs disease do not report Ashkenazi Jewish ancestry. Similarly, the ethnic lines that have traditionally defined risk for cystic fibrosis have changed, and more widespread carrier screening has been increasingly encouraged over the past decade.

In 2011, the American College of Obstetricians and Gynecologists’ (ACOG) Committee on Genetics issued an update on carrier screening for cystic fibrosis, in which it stressed that, although cystic fibrosis is still more common among non-Hispanic white individuals and those of Ashkenazi Jewish ancestry, it "is reasonable to offer CF carrier screening to all patients" (Committee Opinion 486, Obstet. Gynecol. 2011;117:1028-31). Pan-ethnic screening for spinal muscular atrophy also has increasingly been incorporated into routine practice.

With newly available high-throughput genomic methods, we can now screen all patients, regardless of ethnicity, using a universal, pan-ethnic approach, which can identify 100-plus disease-causing mutations at a fraction of the cost of ethnic targeted screening.

Currently, the majority of carrier screening is performed as part of prenatal care; however, preconception carrier screening would allow patients and couples to consider all reproductive options. Knowledge that they carry the gene for a recessive disease, and thus have a 1-in-4 chance of having an affected child, gives parents the opportunity to consider their options before conception. These choices can include early prenatal diagnostic testing with or without pregnancy termination, use of donor gametes or election not to conceive their own child, or preimplantation genetic diagnosis (PGD), wherein a monogenetic disorder is diagnosed using only a few cells from the developing zygote.

In our practice at Columbia, we have been performing pan-ethnic screening for less than a year, and have already identified four couples at risk for having a child with severe genetic diseases. Two of these couples were both carriers for spinal muscular atrophy, and two were found to be carriers for rare genetic diseases that would not have been screened for were it not for our new pan-ethnic screening approach.

Carrier frequency

There are new options available for pan-ethnic carrier screening provided by a number of commercial companies. One of the more frequently used panels covers 417 disease-causing mutations associated with 108 recessive diseases, nearly all of which are considered to be severe, associated with progressive disease and reduced life span, or requiring significant intervention or treatment. This panel includes all of the currently recommended disorders recommended by ACOG for routine obstetrical care of individuals of Eastern European Jewish descent (i.e., Tay-Sachs disease, Canavan disease, familial dysautonomia, and cystic fibrosis) as well as the 10 disorders recommended for routine screening by the American College of Medical Genetics (ACMG).

A challenge of the expanded panels is that as many as 1 in 4 individuals who are screened will be identified as a carrier of at least one autosomal recessive disease. However, when both partners are screened, relatively few couples are found to be at risk of having an affected child. Overall, fewer than 1% of couples who take the test will turn out to be carriers of the same disease.

In a recent study of carrier frequencies, 24% of more than 23,400 individuals were found to be heterozygous for at least one non-mild condition. Approximately 5% were carriers for multiple disorders. Not surprisingly, carrier rates varied by ethnicity, ranging from 43.6% of Ashkenazi Jewish individuals to 8.5% of East Asians.

Across all ethnic groups, the most common carrier frequencies for clinically significant disorders were for cystic fibrosis, DFNB1 nonsyndromic hearing loss and deafness, spinal muscular atrophy, familial Mediterranean fever, Smith-Lemli-Opitz syndrome, sickle cell disease/beta-thalassemia, and Gaucher disease. Among the carrier states detected in the study, almost 77% and 70% were for diseases not included in ACOG carrier screening guidelines or in ACMG guidelines, respectively.

Investigators calculated that 433 of the individuals found to be carriers would not have learned their carrier status under conventional ethnicity-based screening paradigms. For example, approximately 26% of familial dysautonomia carriers in the study did not report Jewish ancestry. There also were multiple instances in the study of carrier frequencies being higher than expected for particular populations. For instance, the carrier frequency for cystic fibrosis was 1 in 40 among South Asians – a rate that is significantly higher than other reported rates (Genet. Med. 2013;15:178-186).

The study confirms a number of findings, the two most important being that there are numerous severe Mendelian conditions that are more prevalent than commonly understood, and that a significant proportion of Mendelian diseases are present in individuals outside the populations that have traditionally been characterized as high risk.

Clinical considerations

Usage of pan-ethnic expanded carrier screening is rapidly increasing, with many reproductive endocrinologists now recommending it prior to in vitro fertilization, and a growing number of obstetricians, other physicians, and patients using the tests both prenatally and in the preconception stage.

For ob.gyns., pan-ethnic screening is a significant paradigm shift which will impact our interactions with patients. For example, we will need to develop new ways of providing genetic counseling to our patients. Traditionally, we have spent significant time, prior to screening, describing each major genetic disease for which screening is performed. With the new screening paradigm, a broader, more generic consent process will be more practical – one in which we talk with patients and provide written or Web-based information about the benefits and limitations of the multidisease carrier screening panel, and then reserve in-depth discussions of specific risks and disorders for a later time, as needed.

Genetic counseling should be provided mainly on a post-test basis, and probably most often after both parents have been tested and found to be carriers. Ideally, both spouses/partners would be screened at the same time, but because most women visit their physicians by themselves, it is more practical overall to perform initial carrier screening for the woman first and then test her spouse/partner if she is found to be a carrier. Separate spouse/partner screening would require providers to contact carrier women quickly and reliably, and to obtain samples from their partners as soon as possible. The lab also should be made aware of the pre-identified carrier status of the patients before testing the spouses/partners.

A crucial message we should share with our patients during any counseling is that broader screening does not eliminate the risk of having an affected child, but reduces the risk. At present, many of the panels test only for established disease-causing mutations. There will always be patients who have a rare mutation that has not previously been described. This is particularly true as we begin screening populations not previously evaluated for Mendelian disorders. It is likely that the assortment of mutations causing specific diseases will be different in these groups, and that the residual risk of being a carrier will be higher than in well-studied populations.

With the cost for screening becoming more affordable, sequencing will become a major tool for determining carrier status of our patients. However, ob.gyns. must keep in mind that expanded screening should not substitute for obtaining a family history and referring a patient for genetic counseling when inheritable risk seems possible. Pan-ethnic screening may be able to identify patients’ risks for genetic disorders, minimizing the risk of having a child with a serious birth defect, but it has limitations. For example, not all pan-ethnic panels include analysis for premutation carriers, making it important to inquire about a history of unexplained mental retardation and autism in males, since this may stem from Fragile X syndrome.

Additionally, screening opens up the possibility of finding mutations with unknown or uncertain clinical significance. At present, when one parent is identified as a carrier of a disease-causing gene, the other can choose to have the disease-causing gene sequenced. This option should be offered to all carriers, but for many genes the additional information may be minimal and not worth the extra cost.

As we increase the frequency of carrier screening, we will identify individuals with mild forms of some diseases. For example, some mutations causing Gaucher disease are associated with a mild phenotype, and adults with these mutations may go undiagnosed for a lifetime. Patients should be made aware of this possibility and informed about the fact that some Mendelian disorders may only become evident in adulthood.

All of these issues must be carefully considered as expanded carrier screening moves into routine clinical care. The ACMG recently published a position statement on preconception and prenatal expanded carrier screening in which it listed criteria that must be met by a disorder to be included in a panel (Genet. Med. 2013;15:482-83). Presently, a work group composed of members of the obstetrical, maternal-fetal medicine, pediatric, genetics, and counseling communities is developing practice guidelines to advise the medical community on the use of expanded carrier screening panels.

Dr. Wapner, a professor in the department of obstetrics and gynecology at Columbia University Medical Center, New York, is recognized as an expert in reproductive genetics. He reported that he has no relevant disclosures.