By Deborah Levenson
RESEARCH UPDATE MARFAN SYNDROME DATABASE INFORMATION UNRELIABLE FOR DIAGNOSES Incomplete, inaccurate clinical information; inconsistent diagnostic terminology key concerns nformation about variants that cause Marfan syndrome (MFS) in some genetic databases is best used only for research, not actual diagnosis of the disorder, a recent paper says. MFS is an autosomal dominant disorder caused by variants in FBN1, which expresses a protein important to connective tissue. An analysis by researchers from Aarhus University Hospital in Denmark found that none of the 23 variants listed as causing MFS in four commonly used genetic databases were clearly associated with the disease, according to a recent paper in Genetics in Medicine (Groth et al., 2015). The researchers evaluated both database information and papers cited in the databases against defined clinical diagnostic criteria for MFS known as the Ghent nosology. They found that many papers that included references to phenotypic data associated with specific variants lacked evidence that patients had an accurate MFS diagnosis, the researchers write. “Be careful in using the databases when analyzing variants,” says Kristian Groth, MD, a PhD student at the Department of Cardiology at Aarhus University Hospital in Denmark and first author of the Genetics in Medicine study. “The databases are only as good as the data that are put into them.”
Impetus for Research Dr. Groth and his colleagues examined information about the 23 variants because a previous study by another research group produced populationbased exome data that questioned the same variants’ pathogenicity (Yang et al., 2014). “When I read the paper of Yang et © 2015 Wiley Periodicals, Inc.
© tossi66 / Fotolia.com
I
Inaccurate, inconsistent clinical information about genetic variants that cause Marfan syndrome may complicate patients’ diagnoses, say geneticists.
al., I was not surprised of their findings but quickly realized that the problem is a general problem that not all are aware of,” Dr. Groth says. For their own research, Dr. Groth and his team examined information about the same 23 variants contained in four databases: the Human Gene Mutation Database, maintained by the Institute of Medical Genetics in the U.K.; the Universal Mutation Database, run by the French National Institute of Health and Medical Research; the ClinVar database, maintained by the federal National Institutes of Heath (NIH); and the UniProt database, a collaboration of the European Bioinformatics Institute, the SIB Swiss Institute of Bioinformatics, and the U.S.-based Protein Information Resource.
Incorrect or incomplete clinical data, especially about aortic disease, in databases can lead to inaccurate diagnoses of MFS, says Anne De Paepe, MD, PhD, senior author of the Ghent nosology, head of the Department of Medical Genetics at Ghent University Hospital, and Vice-Chancellor of Ghent University in Belgium. Dr. De Paepe points out that diagnosis of MFS still relies mainly on identification of clinical manifestations, which can change as children grow. Suspected MFS should also spur testing for mutations in other genes, such as TGFBR2, that cause similar phenotypes but are not MFS, she adds.
Addressing a Larger Problem Inaccurate databases can affect diagnoses vii
RESEARCH UPDATE CONTINUED of all types of genetic diseases, notes Sherri Bale, PhD, Managing Director of GeneDX in Gaithersburg, Maryland, and co-author of recently updated standards for interpretation of sequence variants jointly issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP). “Many databases are uncurated,” says Dr. Bale, who also cochairs a workgroup that develops variant classification and curation standards for ClinVar. Among the ways the standards seek to remedy poor quality of database information is to establish consistent meanings for genetic terminology, according to Dr. Bale. For example, the standards aim to replace the term “mutation,” which carries a negative
connotation, with the word “variant,” described as pathogenic, likely pathogenic, of uncertain significance, likely benign, or benign. The standards also establish criteria for the correct use of these descriptive terms. In addition, the standards emphasize the important role clinical information plays in the interpretation of genomic data and encourage geneticists to include clinical information in genomic sequencing orders. In the standards, the ACMG and AMP also stress that molecular findings are not the final word on genetic diagnoses, and they urge geneticists to avoid using genetic test results as sole evidence of a disease. “Variant analysis is, at present, imperfect, and the variant category
reported does not imply 100% certainty,” write the ACMG and AMP in their standards.
References Groth KA, Gaustadnes M, Thorsen K, Østergaard JR, Jensen UB, Gravholt CH, Andersen NH. 2015. Difficulties in diagnosing Marfan syndrome using current FBN1 databases. Genet Med DOI: 10.1038/gim.2015.32. [Epub ahead of print] Yang RQ, Jabbari J, Cheng XS, Jabbari R, Nielsen JB, Risgaard B, Chen X, Sajadieh A, Haunsø S, Svendsen JH, Olesen MS, Tfelt-Hansen J. 2014. New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome. BMC Genet 15:74. DOI: 10.1002/ajmg.a.37195 2015 Wiley Periodicals, Inc.
TESTING UPDATE RESPECTFUL COMMUNICATION BY GENETICISTS IMPORTANT FOR PARENTS OF CHILDREN WITH UNDIAGNOSED DISORDERS Parents explain preferences for talking with geneticists, physicians about diagnoses, treatment, management plans for children
M
ultiple medical, logistic, and social challenges are facts of life for all families affected by genetic disorders, but having a child with an undiagnosed condition is an especially isolating experience. Without that diagnosis, parents don’t have an opportunity to connect with communities of other parents grappling with the same malady. For this reason, geneticists should pay extra attention to how they communicate with families lacking a diagnosis and treat their relationships with families as partnerships, say parents. They want to be engaged in open communication that fully discloses facts about the diagnostic process, testing, and research. Parents raised their concerns during a panel discussion at a March 2015 meeting of the American College of Medical Genetics and Genomics (ACMG) in Salt Lake City, which addressed ways researchers and families could partner to viii
diagnose and care for children with rare diseases. The panel was part of a session, Community Conversation: The Journey of the Undiagnosed and the Rare. During the meeting, clips were shown from an upcoming documentary, Undiagnosed: Medical Refugees. This film was co-directed by Nick Miller and produced by Crystal Shearman, who were at the meeting to answer questions from the audience. The film, which was also co-directed by undiagnosed patient and psychologist Katia Moritz, PhD, deals with the plight of patients with perplexing medical symptoms. In interviews with AJMG Sequence, three mothers who participated in the panel offered geneticists tips on improving communication and building productive relationships with families.
Communication and Partnership Good
communication
stems
from
treating families as equal partners in a child’s diagnosis and care, the mothers say. Especially important is sharing all pertinent information, says mother Amy Clugston, President and Founder of Syndromes Without a Name (SWAN), based in Ostego, Michigan. After a 17-year diagnostic odyssey, Ms. Clugston learned that a DYRK1A mutation caused her 18-year-old daughter Lorna’s microcephaly, heart defect, and developmental impairments. The answer from research-based whole-genome sequencing (WGS) came after visits with more than 43 specialists including geneticists. Ms. Clugston advises geneticists to offer explanations in layman’s terms but to make sure families have the proper medical terminology and get written reports after appointments. Parents desperate for diagnoses keep close tabs on research, a process made easier with
RESEARCH UPDATE MARFAN SYNDROME DATABASE INFORMATION UNRELIABLE FOR DIAGNOSES Incomplete, inaccurate clinical information; inconsistent diagnostic terminology key concerns nformation about variants that cause Marfan syndrome (MFS) in some genetic databases is best used only for research, not actual diagnosis of the disorder, a recent paper says. MFS is an autosomal dominant disorder caused by variants in FBN1, which expresses a protein important to connective tissue. An analysis by researchers from Aarhus University Hospital in Denmark found that none of the 23 variants listed as causing MFS in four commonly used genetic databases were clearly associated with the disease, according to a recent paper in Genetics in Medicine (Groth et al., 2015). The researchers evaluated both database information and papers cited in the databases against defined clinical diagnostic criteria for MFS known as the Ghent nosology. They found that many papers that included references to phenotypic data associated with specific variants lacked evidence that patients had an accurate MFS diagnosis, the researchers write. “Be careful in using the databases when analyzing variants,” says Kristian Groth, MD, a PhD student at the Department of Cardiology at Aarhus University Hospital in Denmark and first author of the Genetics in Medicine study. “The databases are only as good as the data that are put into them.”
Impetus for Research Dr. Groth and his colleagues examined information about the 23 variants because a previous study by another research group produced populationbased exome data that questioned the same variants’ pathogenicity (Yang et al., 2014). “When I read the paper of Yang et © 2015 Wiley Periodicals, Inc.
© tossi66 / Fotolia.com
I
Inaccurate, inconsistent clinical information about genetic variants that cause Marfan syndrome may complicate patients’ diagnoses, say geneticists.
al., I was not surprised of their findings but quickly realized that the problem is a general problem that not all are aware of,” Dr. Groth says. For their own research, Dr. Groth and his team examined information about the same 23 variants contained in four databases: the Human Gene Mutation Database, maintained by the Institute of Medical Genetics in the U.K.; the Universal Mutation Database, run by the French National Institute of Health and Medical Research; the ClinVar database, maintained by the federal National Institutes of Heath (NIH); and the UniProt database, a collaboration of the European Bioinformatics Institute, the SIB Swiss Institute of Bioinformatics, and the U.S.-based Protein Information Resource.
Incorrect or incomplete clinical data, especially about aortic disease, in databases can lead to inaccurate diagnoses of MFS, says Anne De Paepe, MD, PhD, senior author of the Ghent nosology, head of the Department of Medical Genetics at Ghent University Hospital, and Vice-Chancellor of Ghent University in Belgium. Dr. De Paepe points out that diagnosis of MFS still relies mainly on identification of clinical manifestations, which can change as children grow. Suspected MFS should also spur testing for mutations in other genes, such as TGFBR2, that cause similar phenotypes but are not MFS, she adds.
Addressing a Larger Problem Inaccurate databases can affect diagnoses vii
RESEARCH UPDATE CONTINUED of all types of genetic diseases, notes Sherri Bale, PhD, Managing Director of GeneDX in Gaithersburg, Maryland, and co-author of recently updated standards for interpretation of sequence variants jointly issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP). “Many databases are uncurated,” says Dr. Bale, who also cochairs a workgroup that develops variant classification and curation standards for ClinVar. Among the ways the standards seek to remedy poor quality of database information is to establish consistent meanings for genetic terminology, according to Dr. Bale. For example, the standards aim to replace the term “mutation,” which carries a negative
connotation, with the word “variant,” described as pathogenic, likely pathogenic, of uncertain significance, likely benign, or benign. The standards also establish criteria for the correct use of these descriptive terms. In addition, the standards emphasize the important role clinical information plays in the interpretation of genomic data and encourage geneticists to include clinical information in genomic sequencing orders. In the standards, the ACMG and AMP also stress that molecular findings are not the final word on genetic diagnoses, and they urge geneticists to avoid using genetic test results as sole evidence of a disease. “Variant analysis is, at present, imperfect, and the variant category
reported does not imply 100% certainty,” write the ACMG and AMP in their standards.
References Groth KA, Gaustadnes M, Thorsen K, Østergaard JR, Jensen UB, Gravholt CH, Andersen NH. 2015. Difficulties in diagnosing Marfan syndrome using current FBN1 databases. Genet Med DOI: 10.1038/gim.2015.32. [Epub ahead of print] Yang RQ, Jabbari J, Cheng XS, Jabbari R, Nielsen JB, Risgaard B, Chen X, Sajadieh A, Haunsø S, Svendsen JH, Olesen MS, Tfelt-Hansen J. 2014. New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome. BMC Genet 15:74. DOI: 10.1002/ajmg.a.37195 2015 Wiley Periodicals, Inc.
TESTING UPDATE RESPECTFUL COMMUNICATION BY GENETICISTS IMPORTANT FOR PARENTS OF CHILDREN WITH UNDIAGNOSED DISORDERS Parents explain preferences for talking with geneticists, physicians about diagnoses, treatment, management plans for children
M
ultiple medical, logistic, and social challenges are facts of life for all families affected by genetic disorders, but having a child with an undiagnosed condition is an especially isolating experience. Without that diagnosis, parents don’t have an opportunity to connect with communities of other parents grappling with the same malady. For this reason, geneticists should pay extra attention to how they communicate with families lacking a diagnosis and treat their relationships with families as partnerships, say parents. They want to be engaged in open communication that fully discloses facts about the diagnostic process, testing, and research. Parents raised their concerns during a panel discussion at a March 2015 meeting of the American College of Medical Genetics and Genomics (ACMG) in Salt Lake City, which addressed ways researchers and families could partner to viii
diagnose and care for children with rare diseases. The panel was part of a session, Community Conversation: The Journey of the Undiagnosed and the Rare. During the meeting, clips were shown from an upcoming documentary, Undiagnosed: Medical Refugees. This film was co-directed by Nick Miller and produced by Crystal Shearman, who were at the meeting to answer questions from the audience. The film, which was also co-directed by undiagnosed patient and psychologist Katia Moritz, PhD, deals with the plight of patients with perplexing medical symptoms. In interviews with AJMG Sequence, three mothers who participated in the panel offered geneticists tips on improving communication and building productive relationships with families.
Communication and Partnership Good
communication
stems
from
treating families as equal partners in a child’s diagnosis and care, the mothers say. Especially important is sharing all pertinent information, says mother Amy Clugston, President and Founder of Syndromes Without a Name (SWAN), based in Ostego, Michigan. After a 17-year diagnostic odyssey, Ms. Clugston learned that a DYRK1A mutation caused her 18-year-old daughter Lorna’s microcephaly, heart defect, and developmental impairments. The answer from research-based whole-genome sequencing (WGS) came after visits with more than 43 specialists including geneticists. Ms. Clugston advises geneticists to offer explanations in layman’s terms but to make sure families have the proper medical terminology and get written reports after appointments. Parents desperate for diagnoses keep close tabs on research, a process made easier with
