Practical barriers to implementation prevent the promises of genetic medicine from being realized... more Practical barriers to implementation prevent the promises of genetic medicine from being realized across the U.S. healthcare system. Though new genetic technologies are introduced daily, the process of determining if, when, and how to use them can take decades. Last Fall, we convened a multi-stakeholder summit to address systemic barriers to delivering precision medicine at scale. In particular, we focused on digital infrastructure connecting genetic information in healthcare. Our group consists of stakeholders across the supply chain including health insurers, clinicians, hospital systems, researchers, policy makers, patient advocates, clinical laboratories, technology vendors, and drug developers. Through facilitated discussions, we identified barriers to ordering, performing, delivering, reimbursing, and regulating genetic tests and the information they provide, and generated proposals to overcome these barriers. In a series of in-depth panel discussions and solution-oriented bre...
Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes in... more Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes including heterogeneous genetic defects. While mutations in the bone morphogenetic protein receptor type II (BMPR2) gene are the single most common causal factor for hereditary cases, pathogenic mutations have been observed in approximately 25% of idiopathic PAH patients without a prior family history of disease. Additional defects of the transforming growth factor beta (TGF-β) pathway have been implicated in disease pathogenesis. Specifically, studies have confirmed activin A receptor type II-like 1 (ACVRL1), endoglin (ENG) and members of the SMAD family as contributing to PAH both with and without associated clinical phenotypes. Most recently, next-generation sequencing has identified novel, rare genetic variation implicated in the PAH disease spectrum. Of importance, several identified genetic factors converge on related pathways and provide significant insight into the development, mai...
Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome... more Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited. We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented. Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had café-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p<0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive. CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children.
Laboratory genetic counselors work in many different laboratory settings that can represent a var... more Laboratory genetic counselors work in many different laboratory settings that can represent a variety of clinical specialties. This chapter explores the various types of laboratories and their resulting business relationships. Genetic counselors working in a laboratory will build important relationships with colleagues from within their own company as well as competitors, clients, and others they work with externally. The laboratory’s specialty and its setting will determine who their clients are and is also directly related to their business model. CPT codes and billing and reimbursement issues are also reviewed in this chapter. The size and success of different billing and reimbursement strategies will ultimately affect the services a laboratory offers as well as how the counselor’s roles will develop in that setting.
We are approaching our 30th year anniversary in 2009 and now is the perfect time to start thinkin... more We are approaching our 30th year anniversary in 2009 and now is the perfect time to start thinking of where genetic counseling is going and where we want the NSGC to move over the next 30 years. Before we get to tomorrow I think we can learn a little from looking back at our history. In Audrey Heimler’s Oral History of the NSGC (Journal of Genetic Counseling, Vol. 6, No. 3, 1997), she talks about the formation of the society about 30 years ago. During early discussions some counselors maintained “we are gaining ground as professionals, let’s not be too aggressive right now”. In April of 1978 a committee was formed to write the by laws of this new society. This task took 14 months. Why so long? Luba Djurdjinovic was quoted as saying “How we do this will determine how we will be perceived. We are charged with the responsibility of defining the profession of genetic counseling and the professional who is a genetic counselor. The by-laws of the proposed society will set the tone for the profession”. And so they did. The first NSGC business meeting was held this month in 1979. The Board had been alerted about physicians who were contemplating action against the Society. Possible outcomes included confrontation at the pending NSGC Business Meeting, legal action, and, worst-case scenario, demise of the fledgling society. It was decided that Board members would present brief reports and avoid discussion. The Board believed that genetic counselors would have a mandate to guide their own future if the plans for the proposed society were intact at the conclusion of the meeting. About 100 members and other interested genetic counselors were seated facing the Board. Unobserved by most of the audience, but visible to the Board, were about 20 grim-faced physicians standing in the rear of the room. The meeting proceeded as planned. This unusual meeting lasted 1 hour after which the physicians exited without comment. The cost of survival was high. At the first public business meeting, the ad hoc Board had been compelled to project the impression that it did not value communication among members. Following this meeting, Audrey received a thoughtful letter from Gillian Ingall stating she was disturbed that there had been no forum for discussion at the recent business meeting. She suggested that the Board consider a more open format for future business meetings. In Perspectives Vol. 2, No. 3, the announcement of the Annual Business Meeting the following year includes an implied apology and acknowledgment: “The theme of this year’s business meeting is ‘Discussion’. From that time to the present, communication has been an NSGC priority”. Looking back over the last 10 years, Wendy Uhlmann spoke about the importance of billing and reimbursement as an issue for our membership. In 2000, Vivian Weinblatt spoke of how genetic counselors right here in California will soon have the ability to apply for licensure. However she cautioned that this success needed to be tempered by the tasks we have yet to accomplish, namely obtaining reimbursement for services. Kathy Schneider spoke about the journey genetic counselors had taken during the first 20 years of our society and focused on our need to strengthen our presence in Washington. Robin Bennett spoke of how the one voice of the NSGC is comprised of the individual voices of our J Genet Counsel (2009) 18:105–108 DOI 10.1007/s10897-008-9211-y
Single-gene disorders have a straightforward inheritance pattern, and the genetic causes can be t... more Single-gene disorders have a straightforward inheritance pattern, and the genetic causes can be traced to changes in specific individual genes. A particular disorder could be rare; however, as a group, single-gene disorders are responsible for a significant percentage of pediatric diseases. Autosomes refer to the numbered chromosomes (chromosome 1‐22), as opposed to the sex chromosomes, X and Y. Every individual carries two copies of each autosome and, therefore, also has two copies of every gene carried on those chromosomes, one inherited from each parent. Based on the location of the relevant genes, single-gene traits can be divided into autosomal inheritance and sex-linked. Autosomal inheritance, depending onwhetherone or two mutant alleles arerequired to cause a phenotype, can be divided into autosomal dominant or autosomal recessive. Based on Mendel’s laws, the two alleles segregate and pass to different offspring, as shown in >Fig. 2.1; A and A’ will pass to different indiv...
We developed a rules-based scoring system to classify DNA variants into five categories including... more We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies collected from internal and external sources. Scores were calculated by trained scientists using a quantitative framework that assigned differential weighting to these five types of data. We performed descriptive and comparative statistics on the dataset and tested inter-observer concordance among the trained scientists. Private variants defined as variants found within single families (n = 5,182), were either VUS (80.5%; n = 4,169) or likely pathogenic (19.5%; n = 1,013). The remaining variants (n = 6,712) were VUS (38.4%; n = 2,577) or likely benign/benign (34.7%; n = 2,327) or likely pa...
Chronic pancreatitis is a progressive inflammatory disorder leading to irreversible exocrine and/... more Chronic pancreatitis is a progressive inflammatory disorder leading to irreversible exocrine and/or endocrine impairment. It is well documented that mutations in the cationic trypsinogen (PRSS1) gene can cause hereditary pancreatitis. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) and the serine protease inhibitor Kazal type 1 (SPINK1) genes are also associated with pancreatitis. We analyzed 381 patients with a primary diagnosis of chronic or recurrent pancreatitis using the Ambry Test: Pancreatitis to obtain comprehensive genetic information for the CFTR, SPINK1, and PRSS1 genes. The results identified 32% (122/381) of patients with 166 mutant CFTR alleles, including 12 novel CFTR variants: 4375-20 A>G, F575Y, K598E, L1260P, G194R, F834L, S573C, 2789 + 17 C>T, 621+83 A>G, T164S, 621+25 A>G, and 3500-19 G>A. Of 122 patients with CFTR mutations, 5.5% (21/381) also carried a SPINK1 mutation, and 1.8% (7/381) carried a PRSS1 mutation. In addi...
The most common disease-causing mutation in the cystic fibrosis transmembrane conductance regulat... more The most common disease-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is the out-of-frame deletion of 3 nucleotides (CTT). This mutation leads to the loss of phenylalanine-508 (ΔF508) and a silent codon change (SCC) for isoleucine-507 (I507-ATC→ATT). ΔF508 CFTR is misfolded and degraded by endoplasmic reticulum-associated degradation (ERAD). We have demonstrated that the I507-ATC→ATT SCC alters ΔF508 CFTR mRNA structure and translation dynamics. By comparing the biochemical and functional properties of the I507-ATT and I507-ATC ΔF508 CFTR, we establish that the I507-ATC→ATT SCC contributes to the cotranslational misfolding, ERAD, and to the functional defects associated with ΔF508 CFTR. We demonstrate that the I507-ATC ΔF508 CFTR is less susceptible to the ER quality-control machinery during translation than the I507-ATT, although 27°C correction is necessary for sufficient cell-surface expression. Whole-cell patch-clamp recordings indicate sustained, thermally stable cAMP-activated Cl(-) transport through I507-ATC and unstable function of the I507-ATT ΔF508 CFTR. Single-channel recordings reveal improved gating properties of the I507-ATC compared to I507-ATT ΔF508 CFTR (NPo=0.45±0.037 vs. NPo=0.09±0.002; P<0.001). Our results signify the role of the I507-ATC→ATT SCC in the ΔF508 CFTR defects and support the importance of synonymous codon choices in determining the function of gene products.
Practical barriers to implementation prevent the promises of genetic medicine from being realized... more Practical barriers to implementation prevent the promises of genetic medicine from being realized across the U.S. healthcare system. Though new genetic technologies are introduced daily, the process of determining if, when, and how to use them can take decades. Last Fall, we convened a multi-stakeholder summit to address systemic barriers to delivering precision medicine at scale. In particular, we focused on digital infrastructure connecting genetic information in healthcare. Our group consists of stakeholders across the supply chain including health insurers, clinicians, hospital systems, researchers, policy makers, patient advocates, clinical laboratories, technology vendors, and drug developers. Through facilitated discussions, we identified barriers to ordering, performing, delivering, reimbursing, and regulating genetic tests and the information they provide, and generated proposals to overcome these barriers. In a series of in-depth panel discussions and solution-oriented bre...
Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes in... more Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes including heterogeneous genetic defects. While mutations in the bone morphogenetic protein receptor type II (BMPR2) gene are the single most common causal factor for hereditary cases, pathogenic mutations have been observed in approximately 25% of idiopathic PAH patients without a prior family history of disease. Additional defects of the transforming growth factor beta (TGF-β) pathway have been implicated in disease pathogenesis. Specifically, studies have confirmed activin A receptor type II-like 1 (ACVRL1), endoglin (ENG) and members of the SMAD family as contributing to PAH both with and without associated clinical phenotypes. Most recently, next-generation sequencing has identified novel, rare genetic variation implicated in the PAH disease spectrum. Of importance, several identified genetic factors converge on related pathways and provide significant insight into the development, mai...
Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome... more Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited. We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented. Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had café-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p<0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive. CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children.
Laboratory genetic counselors work in many different laboratory settings that can represent a var... more Laboratory genetic counselors work in many different laboratory settings that can represent a variety of clinical specialties. This chapter explores the various types of laboratories and their resulting business relationships. Genetic counselors working in a laboratory will build important relationships with colleagues from within their own company as well as competitors, clients, and others they work with externally. The laboratory’s specialty and its setting will determine who their clients are and is also directly related to their business model. CPT codes and billing and reimbursement issues are also reviewed in this chapter. The size and success of different billing and reimbursement strategies will ultimately affect the services a laboratory offers as well as how the counselor’s roles will develop in that setting.
We are approaching our 30th year anniversary in 2009 and now is the perfect time to start thinkin... more We are approaching our 30th year anniversary in 2009 and now is the perfect time to start thinking of where genetic counseling is going and where we want the NSGC to move over the next 30 years. Before we get to tomorrow I think we can learn a little from looking back at our history. In Audrey Heimler’s Oral History of the NSGC (Journal of Genetic Counseling, Vol. 6, No. 3, 1997), she talks about the formation of the society about 30 years ago. During early discussions some counselors maintained “we are gaining ground as professionals, let’s not be too aggressive right now”. In April of 1978 a committee was formed to write the by laws of this new society. This task took 14 months. Why so long? Luba Djurdjinovic was quoted as saying “How we do this will determine how we will be perceived. We are charged with the responsibility of defining the profession of genetic counseling and the professional who is a genetic counselor. The by-laws of the proposed society will set the tone for the profession”. And so they did. The first NSGC business meeting was held this month in 1979. The Board had been alerted about physicians who were contemplating action against the Society. Possible outcomes included confrontation at the pending NSGC Business Meeting, legal action, and, worst-case scenario, demise of the fledgling society. It was decided that Board members would present brief reports and avoid discussion. The Board believed that genetic counselors would have a mandate to guide their own future if the plans for the proposed society were intact at the conclusion of the meeting. About 100 members and other interested genetic counselors were seated facing the Board. Unobserved by most of the audience, but visible to the Board, were about 20 grim-faced physicians standing in the rear of the room. The meeting proceeded as planned. This unusual meeting lasted 1 hour after which the physicians exited without comment. The cost of survival was high. At the first public business meeting, the ad hoc Board had been compelled to project the impression that it did not value communication among members. Following this meeting, Audrey received a thoughtful letter from Gillian Ingall stating she was disturbed that there had been no forum for discussion at the recent business meeting. She suggested that the Board consider a more open format for future business meetings. In Perspectives Vol. 2, No. 3, the announcement of the Annual Business Meeting the following year includes an implied apology and acknowledgment: “The theme of this year’s business meeting is ‘Discussion’. From that time to the present, communication has been an NSGC priority”. Looking back over the last 10 years, Wendy Uhlmann spoke about the importance of billing and reimbursement as an issue for our membership. In 2000, Vivian Weinblatt spoke of how genetic counselors right here in California will soon have the ability to apply for licensure. However she cautioned that this success needed to be tempered by the tasks we have yet to accomplish, namely obtaining reimbursement for services. Kathy Schneider spoke about the journey genetic counselors had taken during the first 20 years of our society and focused on our need to strengthen our presence in Washington. Robin Bennett spoke of how the one voice of the NSGC is comprised of the individual voices of our J Genet Counsel (2009) 18:105–108 DOI 10.1007/s10897-008-9211-y
Single-gene disorders have a straightforward inheritance pattern, and the genetic causes can be t... more Single-gene disorders have a straightforward inheritance pattern, and the genetic causes can be traced to changes in specific individual genes. A particular disorder could be rare; however, as a group, single-gene disorders are responsible for a significant percentage of pediatric diseases. Autosomes refer to the numbered chromosomes (chromosome 1‐22), as opposed to the sex chromosomes, X and Y. Every individual carries two copies of each autosome and, therefore, also has two copies of every gene carried on those chromosomes, one inherited from each parent. Based on the location of the relevant genes, single-gene traits can be divided into autosomal inheritance and sex-linked. Autosomal inheritance, depending onwhetherone or two mutant alleles arerequired to cause a phenotype, can be divided into autosomal dominant or autosomal recessive. Based on Mendel’s laws, the two alleles segregate and pass to different offspring, as shown in >Fig. 2.1; A and A’ will pass to different indiv...
We developed a rules-based scoring system to classify DNA variants into five categories including... more We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies collected from internal and external sources. Scores were calculated by trained scientists using a quantitative framework that assigned differential weighting to these five types of data. We performed descriptive and comparative statistics on the dataset and tested inter-observer concordance among the trained scientists. Private variants defined as variants found within single families (n = 5,182), were either VUS (80.5%; n = 4,169) or likely pathogenic (19.5%; n = 1,013). The remaining variants (n = 6,712) were VUS (38.4%; n = 2,577) or likely benign/benign (34.7%; n = 2,327) or likely pa...
Chronic pancreatitis is a progressive inflammatory disorder leading to irreversible exocrine and/... more Chronic pancreatitis is a progressive inflammatory disorder leading to irreversible exocrine and/or endocrine impairment. It is well documented that mutations in the cationic trypsinogen (PRSS1) gene can cause hereditary pancreatitis. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) and the serine protease inhibitor Kazal type 1 (SPINK1) genes are also associated with pancreatitis. We analyzed 381 patients with a primary diagnosis of chronic or recurrent pancreatitis using the Ambry Test: Pancreatitis to obtain comprehensive genetic information for the CFTR, SPINK1, and PRSS1 genes. The results identified 32% (122/381) of patients with 166 mutant CFTR alleles, including 12 novel CFTR variants: 4375-20 A>G, F575Y, K598E, L1260P, G194R, F834L, S573C, 2789 + 17 C>T, 621+83 A>G, T164S, 621+25 A>G, and 3500-19 G>A. Of 122 patients with CFTR mutations, 5.5% (21/381) also carried a SPINK1 mutation, and 1.8% (7/381) carried a PRSS1 mutation. In addi...
The most common disease-causing mutation in the cystic fibrosis transmembrane conductance regulat... more The most common disease-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is the out-of-frame deletion of 3 nucleotides (CTT). This mutation leads to the loss of phenylalanine-508 (ΔF508) and a silent codon change (SCC) for isoleucine-507 (I507-ATC→ATT). ΔF508 CFTR is misfolded and degraded by endoplasmic reticulum-associated degradation (ERAD). We have demonstrated that the I507-ATC→ATT SCC alters ΔF508 CFTR mRNA structure and translation dynamics. By comparing the biochemical and functional properties of the I507-ATT and I507-ATC ΔF508 CFTR, we establish that the I507-ATC→ATT SCC contributes to the cotranslational misfolding, ERAD, and to the functional defects associated with ΔF508 CFTR. We demonstrate that the I507-ATC ΔF508 CFTR is less susceptible to the ER quality-control machinery during translation than the I507-ATT, although 27°C correction is necessary for sufficient cell-surface expression. Whole-cell patch-clamp recordings indicate sustained, thermally stable cAMP-activated Cl(-) transport through I507-ATC and unstable function of the I507-ATT ΔF508 CFTR. Single-channel recordings reveal improved gating properties of the I507-ATC compared to I507-ATT ΔF508 CFTR (NPo=0.45±0.037 vs. NPo=0.09±0.002; P<0.001). Our results signify the role of the I507-ATC→ATT SCC in the ΔF508 CFTR defects and support the importance of synonymous codon choices in determining the function of gene products.
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Papers by Steven Keiles