RESEARCH UPDATE CONTINUED or ordinary photographs, a scanner, and a computer, he adds.
Face2Gene Technology Available Another facial analysis program known as Face2Gene, launched recently by New York–based FDNA Accessible Genetics, is a genetic search and reference mobile application that has capabilities similar to the approach developed by the Oxford researchers. It can be downloaded for free to Apple devices. Face2Gene is the result of several years of research, development, and validation by a group of geneticists led by Michael R. Hayden, MD, PhD, Chairman of FDNA’s Scientific Advisory Board and Steering Committee and Senior Scientist at the Centre for Molecular Medicine and Therapeutics in Vancouver, Canada. The application, based on processing tens of thousands of facial images, creates and uses facial meshes to identify particular facial phenotypes through learning algorithms and a crowdsourcing method. “The more clinicians upload cases into Face2Gene, the better the technology becomes for everyone in the network,” says Dekel Gelbman, LL.B, MBA, Chief Executive Officer of FDNA. Face2Gene refers users to both genetic databases and other clinicians whose patients have similar facial
meshes and can share information about particular cases within the wider network of users. “If there’s a case you’re struggling with, you can upload images into the application [and] others can comment if they have seen something similar,” Mr. Gelbman says. This sort of communication previously occurred mostly at annual conferences, he notes. Users are enthusiastic about Face2Gene. “It gives confidence that you are ordering the right test,” says Karen W. Gripp, MD, Division Chief, Genetics Director, and Costello Program Chief in the Division of Medical Genetics at Alfred I. duPont Hospital for Children in Wilmington, Delaware. The feature that connects users to genetic databases is useful to “see if I’m missing something,” she adds. Omar Abdul-Rahman, MD, Professor of Pediatrics and Neurology at the University of Mississippi Medical Center in Jackson, says he uses Face2Gene as a reference when he suspects a genetic condition. He says the application provides a list of possible conditions, which is useful when a child lacks distinctive facial features but has other key features of a particular disease. Dr. Abdul-Rahman says the application was recently useful in his decision to test, and ultimately diagnose,
a child with Mowat-Wilson syndrome [see “Importance of Facial Features in Mowat-Wilson Syndrome Highlighted,” p. X], which he had suspected but previously had never seen in practice. He has also used Face2Gene to help identify a spectrum of diagnoses associated with alcohol exposure. “You have to recognize that facial analysis technology is still a new tool and that it has limitations,” Dr. AbdulRahman emphasizes. “It is useful in the hands of a geneticist who still must rely on clinical judgment.” “Absolutely, these types of technology are tools to aid the work of clinician experts and to narrow the search space for possible diagnoses,” agrees Dr. Nellåker. “Both our and the FDNA approach are machine-learning methods and with more images will become better at accounting for ethnic, gender, and age variation.”
Reference Ferry Q, Steinberg J, Webber C, FitzPatrick DR, Ponting CP, Zisserman A, Nellåker C. 2014. Diagnostically relevant facial gestalt information from ordinary photos. eLife Jun 24; 3:e02020; http://dx.doi.org/10.7554/eLife.02020 [ePub ahead of print]. DOI 10.1002/ajmg.a.36755 2014 Wiley Periodicals, Inc.
OPITZ AWARD OPITZ AWARD WINNERS FOCUS ON HEMIHYPERPLASIA, KABUKI SYNDROME Winning papers detail array testing for hemihyperplasia, genotype-phenotype differences in KS
T
he work of two researchers—one involved in studying hemihyperplasia and the other concerned with causative genetic mutation of Kabuki syndrome (KS)—has earned each of them the 2014 John M. Opitz Young Investigator Award. Investigator Jennifer Kalish, MD, PhD, Instructor in Genetics and Pediatrics at The Children’s Hospital of Pennsylvania and Perelman School of Medicine at the University of Pennsylvania, both in Philadelphia, earned the honor for her
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paper that suggests having two copies of the gene 11p15 from one parent—a situation known as paternal uniparental isodisomy (UPD)—may be an underdetected cause of a rare adrenal gland tumor known as pheochromocytoma [Kalish et al., 2013]. Researcher Noriko Miyake, MD, Associate Professor at Yokohama City University Graduate School of Medicine in Yokohama, Japan, won the award for her paper detailing phenotypic differences in patients with KS who have mutations
in two of the genes associated with the disorder [Miyake et al., 2013]. Given annually since 2002, the Opitz award recognizes work by researchers who are younger than 40 or who have completed doctoral training within the past 10 years. The award honors Dr. Opitz, the founding Editor-in-Chief of the American Journal of Medical Genetics and a pioneer in recognizing and correlating specific groups of pediatric anomalies with heredity.
Photos courtesy of Dr. Jennifer Kalish and Dr. Noriko Miyake
Arrays Help Spot the Problem For her paper, Dr. Kalish focused on an 18-month-old girl who was previously diagnosed with hemihyperplasia, also known as asymmetric overgrowth, of the arm. Such overgrowth is often associated with well-defined syndromes, including Beckwith-Wiedemann syndrome, but can also be isolated. Dr. Kalish did a single nucleotide polymorphism (SNP) array analysis of the girl’s pheochromocytoma tissue and found that deletions of 8p12pter, 21q21.1qter, 22q11.23qter—commonly seen in pheochromocytomas—did not occur in all the tumor cells, a situation known as mosaicism. More interestingly, Dr. Kalish found that the girl had two copies of part of chromosome 11 from her father. This homozygosity was the girl’s primary problem, because molecular testing for other causes of pheochromocytomas returned normal results, Dr. Kalish noted. Subsequent SNP array analysis of skin fibroblasts demonstrated 5% of cells also had two copies of 11p15.3 from the father. Dr. Kalish and her colleagues subsequently used SNP array analysis to identify four patients with subtle hemihyperplasia with low-level mosaic UPD that methylation analysis did not detect. She says her findings can help inform researchers about testing for tumor risk around hemihyperplasia. “When you see subtle hemihyperplasia like we did with our first patient, there is a tumor risk, and you need to screen for tumors,” she emphasizes. Dr. Kalish says she plans further research into how the genetic changes she saw can cause tumors to form.
Kabuki Syndrome Facial Phenotypes Better Described Dr. Miyake’s study identified 50 MLL2 and five KDM6A mutations among 81 patients with KS, which is characterized by developmental delay, intellectual disability, and specific facial features. She found non-protein, truncatingtype MLL2 mutations mainly around functional domains and truncating-type mutations scattered throughout the entire
Opitz award winners Dr. Jennifer Kalish (l) and Dr. Noriko Miyake
coding region. Facial features of patients with truncating-type MLL2 mutations were typical of those previously reported in KS patients. High-arched eyebrows, short fifth fingers, and decreased muscle tone in infancy were more frequent among patients with MLL2 mutations than those with KDM6A mutations. Meanwhile, short stature and slow postnatal growth occurred in all individuals with KDM6A mutations but in only half of those with MLL2 mutations, her research showed. Noting that many cases of KS never receive a molecular diagnosis, Dr. Miyake says she wants to find other genes associated with the disorder.
Help from Mentors Both winners acknowledged the important role mentors can play in supporting the work of young scientists. “This is absolutely fantastic and the first international award for me,” says Dr. Miyake, whose mentors include her current supervisor, Naomichi Matsumoto, MD, PhD, Professor of Human Genetics at Yokohama City University Graduate School of Medicine; Elizabeth C. Engle, MD, Professor of Neurology and Ophthalmology at Harvard Medical School and a Senior Associate in neurology, ophthalmology, and medicine at Boston Children’s Hospital, both in Boston; and Norio Niikawa, MD, PhD, President of Health Sciences University of Hokkaido in Tobetsu, Japan. Dr. Niikawa “led me to this genetic research field and has given me a lot of good chances since I was a medical student,” Dr. Miyake notes. “It is a true honor to be recognized for my work on 11p overgrowth detection
and tumor formation,” says Dr. Kalish. “As my mentors have always told me, it all begins with a patient. There is so much we do not know about how these patients develop tumors. It is my goal to understand how these genetic changes lead to cancer in these patients and in other isolated cancers [and] to use these findings to improve the clinical care for patients with rare and common disorders.” Dr. Kalish, who was nominated by Dr. Matthew A. Deardorff, offers advice to other young geneticists: “It is important to try and understand as much as possible about every patient; when unique features appear, it is imperative to query further. Find excellent mentors and colleagues to help you. Together, we can develop methods and technology to better care for our patients,” she says.
References Kalish JM, Conlin LK, Mostoufi-Moab S, Wilkens AB, Mulchandani S, Zelley K, Kowalski M, Bhatti TR, Russo P, Mattei P, Mackenzie WG, LiVolsi V, Nichols KE, Biegel JA, Spinner NB, Deardorff MA. 2013. Bilateral pheochromocytomas, hemihyperplasia, and subtle somatic mosaicism: The importance of detecting low-level uniparental disomy. Am J Med Genet A 161A(5):993-1001. Miyake N, Koshimizu E, Okamoto N, Mizuno S, Ogata T, Nagai T, Kosho T, Ohashi H, Kato M, Sasaki G, Mabe H, Watanabe Y, Yoshino M, Matsuishi T, Takanashi J, Shotelersuk V, Tekin M, Ochi N, Kubota M, Ito N, Ihara K, Hara T, Tonoki H, Ohta T, Saito K, Matsuo M, Urano M, Enokizono T, Sato A, Tanaka H, Ogawa A, Fujita T, Hiraki Y, Kitanaka S, Matsubara Y, Makita T, Taguri M, Nakashima M, Tsurusaki Y, Saitsu H, Yoshiura K, Matsumoto N, Niikawa N. 2013. MLL2 and KDM6A mutations in patients with Kabuki syndrome. Am J Med Genet A 161(9):2234-2243. DOI 10.1002/ajmg.a.36756 2014 Wiley Periodicals, Inc.
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Face2Gene Technology Available Another facial analysis program known as Face2Gene, launched recently by New York–based FDNA Accessible Genetics, is a genetic search and reference mobile application that has capabilities similar to the approach developed by the Oxford researchers. It can be downloaded for free to Apple devices. Face2Gene is the result of several years of research, development, and validation by a group of geneticists led by Michael R. Hayden, MD, PhD, Chairman of FDNA’s Scientific Advisory Board and Steering Committee and Senior Scientist at the Centre for Molecular Medicine and Therapeutics in Vancouver, Canada. The application, based on processing tens of thousands of facial images, creates and uses facial meshes to identify particular facial phenotypes through learning algorithms and a crowdsourcing method. “The more clinicians upload cases into Face2Gene, the better the technology becomes for everyone in the network,” says Dekel Gelbman, LL.B, MBA, Chief Executive Officer of FDNA. Face2Gene refers users to both genetic databases and other clinicians whose patients have similar facial
meshes and can share information about particular cases within the wider network of users. “If there’s a case you’re struggling with, you can upload images into the application [and] others can comment if they have seen something similar,” Mr. Gelbman says. This sort of communication previously occurred mostly at annual conferences, he notes. Users are enthusiastic about Face2Gene. “It gives confidence that you are ordering the right test,” says Karen W. Gripp, MD, Division Chief, Genetics Director, and Costello Program Chief in the Division of Medical Genetics at Alfred I. duPont Hospital for Children in Wilmington, Delaware. The feature that connects users to genetic databases is useful to “see if I’m missing something,” she adds. Omar Abdul-Rahman, MD, Professor of Pediatrics and Neurology at the University of Mississippi Medical Center in Jackson, says he uses Face2Gene as a reference when he suspects a genetic condition. He says the application provides a list of possible conditions, which is useful when a child lacks distinctive facial features but has other key features of a particular disease. Dr. Abdul-Rahman says the application was recently useful in his decision to test, and ultimately diagnose,
a child with Mowat-Wilson syndrome [see “Importance of Facial Features in Mowat-Wilson Syndrome Highlighted,” p. X], which he had suspected but previously had never seen in practice. He has also used Face2Gene to help identify a spectrum of diagnoses associated with alcohol exposure. “You have to recognize that facial analysis technology is still a new tool and that it has limitations,” Dr. AbdulRahman emphasizes. “It is useful in the hands of a geneticist who still must rely on clinical judgment.” “Absolutely, these types of technology are tools to aid the work of clinician experts and to narrow the search space for possible diagnoses,” agrees Dr. Nellåker. “Both our and the FDNA approach are machine-learning methods and with more images will become better at accounting for ethnic, gender, and age variation.”
Reference Ferry Q, Steinberg J, Webber C, FitzPatrick DR, Ponting CP, Zisserman A, Nellåker C. 2014. Diagnostically relevant facial gestalt information from ordinary photos. eLife Jun 24; 3:e02020; http://dx.doi.org/10.7554/eLife.02020 [ePub ahead of print]. DOI 10.1002/ajmg.a.36755 2014 Wiley Periodicals, Inc.
OPITZ AWARD OPITZ AWARD WINNERS FOCUS ON HEMIHYPERPLASIA, KABUKI SYNDROME Winning papers detail array testing for hemihyperplasia, genotype-phenotype differences in KS
T
he work of two researchers—one involved in studying hemihyperplasia and the other concerned with causative genetic mutation of Kabuki syndrome (KS)—has earned each of them the 2014 John M. Opitz Young Investigator Award. Investigator Jennifer Kalish, MD, PhD, Instructor in Genetics and Pediatrics at The Children’s Hospital of Pennsylvania and Perelman School of Medicine at the University of Pennsylvania, both in Philadelphia, earned the honor for her
viii
paper that suggests having two copies of the gene 11p15 from one parent—a situation known as paternal uniparental isodisomy (UPD)—may be an underdetected cause of a rare adrenal gland tumor known as pheochromocytoma [Kalish et al., 2013]. Researcher Noriko Miyake, MD, Associate Professor at Yokohama City University Graduate School of Medicine in Yokohama, Japan, won the award for her paper detailing phenotypic differences in patients with KS who have mutations
in two of the genes associated with the disorder [Miyake et al., 2013]. Given annually since 2002, the Opitz award recognizes work by researchers who are younger than 40 or who have completed doctoral training within the past 10 years. The award honors Dr. Opitz, the founding Editor-in-Chief of the American Journal of Medical Genetics and a pioneer in recognizing and correlating specific groups of pediatric anomalies with heredity.
Photos courtesy of Dr. Jennifer Kalish and Dr. Noriko Miyake
Arrays Help Spot the Problem For her paper, Dr. Kalish focused on an 18-month-old girl who was previously diagnosed with hemihyperplasia, also known as asymmetric overgrowth, of the arm. Such overgrowth is often associated with well-defined syndromes, including Beckwith-Wiedemann syndrome, but can also be isolated. Dr. Kalish did a single nucleotide polymorphism (SNP) array analysis of the girl’s pheochromocytoma tissue and found that deletions of 8p12pter, 21q21.1qter, 22q11.23qter—commonly seen in pheochromocytomas—did not occur in all the tumor cells, a situation known as mosaicism. More interestingly, Dr. Kalish found that the girl had two copies of part of chromosome 11 from her father. This homozygosity was the girl’s primary problem, because molecular testing for other causes of pheochromocytomas returned normal results, Dr. Kalish noted. Subsequent SNP array analysis of skin fibroblasts demonstrated 5% of cells also had two copies of 11p15.3 from the father. Dr. Kalish and her colleagues subsequently used SNP array analysis to identify four patients with subtle hemihyperplasia with low-level mosaic UPD that methylation analysis did not detect. She says her findings can help inform researchers about testing for tumor risk around hemihyperplasia. “When you see subtle hemihyperplasia like we did with our first patient, there is a tumor risk, and you need to screen for tumors,” she emphasizes. Dr. Kalish says she plans further research into how the genetic changes she saw can cause tumors to form.
Kabuki Syndrome Facial Phenotypes Better Described Dr. Miyake’s study identified 50 MLL2 and five KDM6A mutations among 81 patients with KS, which is characterized by developmental delay, intellectual disability, and specific facial features. She found non-protein, truncatingtype MLL2 mutations mainly around functional domains and truncating-type mutations scattered throughout the entire
Opitz award winners Dr. Jennifer Kalish (l) and Dr. Noriko Miyake
coding region. Facial features of patients with truncating-type MLL2 mutations were typical of those previously reported in KS patients. High-arched eyebrows, short fifth fingers, and decreased muscle tone in infancy were more frequent among patients with MLL2 mutations than those with KDM6A mutations. Meanwhile, short stature and slow postnatal growth occurred in all individuals with KDM6A mutations but in only half of those with MLL2 mutations, her research showed. Noting that many cases of KS never receive a molecular diagnosis, Dr. Miyake says she wants to find other genes associated with the disorder.
Help from Mentors Both winners acknowledged the important role mentors can play in supporting the work of young scientists. “This is absolutely fantastic and the first international award for me,” says Dr. Miyake, whose mentors include her current supervisor, Naomichi Matsumoto, MD, PhD, Professor of Human Genetics at Yokohama City University Graduate School of Medicine; Elizabeth C. Engle, MD, Professor of Neurology and Ophthalmology at Harvard Medical School and a Senior Associate in neurology, ophthalmology, and medicine at Boston Children’s Hospital, both in Boston; and Norio Niikawa, MD, PhD, President of Health Sciences University of Hokkaido in Tobetsu, Japan. Dr. Niikawa “led me to this genetic research field and has given me a lot of good chances since I was a medical student,” Dr. Miyake notes. “It is a true honor to be recognized for my work on 11p overgrowth detection
and tumor formation,” says Dr. Kalish. “As my mentors have always told me, it all begins with a patient. There is so much we do not know about how these patients develop tumors. It is my goal to understand how these genetic changes lead to cancer in these patients and in other isolated cancers [and] to use these findings to improve the clinical care for patients with rare and common disorders.” Dr. Kalish, who was nominated by Dr. Matthew A. Deardorff, offers advice to other young geneticists: “It is important to try and understand as much as possible about every patient; when unique features appear, it is imperative to query further. Find excellent mentors and colleagues to help you. Together, we can develop methods and technology to better care for our patients,” she says.
References Kalish JM, Conlin LK, Mostoufi-Moab S, Wilkens AB, Mulchandani S, Zelley K, Kowalski M, Bhatti TR, Russo P, Mattei P, Mackenzie WG, LiVolsi V, Nichols KE, Biegel JA, Spinner NB, Deardorff MA. 2013. Bilateral pheochromocytomas, hemihyperplasia, and subtle somatic mosaicism: The importance of detecting low-level uniparental disomy. Am J Med Genet A 161A(5):993-1001. Miyake N, Koshimizu E, Okamoto N, Mizuno S, Ogata T, Nagai T, Kosho T, Ohashi H, Kato M, Sasaki G, Mabe H, Watanabe Y, Yoshino M, Matsuishi T, Takanashi J, Shotelersuk V, Tekin M, Ochi N, Kubota M, Ito N, Ihara K, Hara T, Tonoki H, Ohta T, Saito K, Matsuo M, Urano M, Enokizono T, Sato A, Tanaka H, Ogawa A, Fujita T, Hiraki Y, Kitanaka S, Matsubara Y, Makita T, Taguri M, Nakashima M, Tsurusaki Y, Saitsu H, Yoshiura K, Matsumoto N, Niikawa N. 2013. MLL2 and KDM6A mutations in patients with Kabuki syndrome. Am J Med Genet A 161(9):2234-2243. DOI 10.1002/ajmg.a.36756 2014 Wiley Periodicals, Inc.
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