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CLINICAL MEDICAL GENETICS GENETICS 202 Jon Bernstein Department of Pediatrics October 29, 2015 Session Goals Gain familiarity with the field of clinical medical genetics ◦ A developmental biology, biochemistry and genetics clinic Understand the meaning of “dysmorphology” and its role in clinical diagnosis ◦ Relating genotypes to phenotypes ◦ Introduction to the identification of zebras (or precision medicine) Lecture Outline The rapidly changing landscape of medical genetics Dysmorphology/Systematic phenotyping ◦ Major and minor anomalies ◦ Categories of anomalies Malformation, deformation, disruption ◦ Constellations of anomalies Association, sequence, syndrome Clinical cases ◦ Modern clinical genetics ◦ Bioinformatics support for matchmaking – precision medicine Genetics from a Medical Education Perspective Learned in Pre-clinical curriculum Clinical Curriculum Residency, Fellowship…. Learned in Pre-clinical curriculum Clinical Curriculum Residency, Fellowship…. Learned in Pre-clinical curriculum (mostly fall quarter) and occasionally thereafter. Genotype Environment Phenotype Genetic testing and family history The medical history Assessing the patient (Physical Exam, Lab Tests, Imaging, Pathology, Physiologic studies) Clinical Genetics •Obstetrics •Pulmonology •Cardiology •Hematology •Oncology •Gastroenterology/Hepatology •Psychiatry •Immunology •Neurology •Otolaryngology •Endocrinology •Primary Care •Medical Genetics • Biochemical genetics • Dysmorphology Clinical Medical Genetics Dysmorphology Biochemical genetics ◦ Inborn errors of metabolism ◦ Lysosomal disorders ◦ Mitochondrial disease Allusions to dysmorphology in GENE202 Filamin A related disorders in molecular genetics Teratology segment of reproductive genetics lecture ◦ Warfarin embryopathy Allusions to dysmorphology in DBIO Hereditary hearing loss ◦ Waardenburg syndrome Skeletal dysplasias ◦ Achondroplasia ◦ Cleidocranial dysplasia Ectodermal dysplasia ◦ Ectodermal dysplasia, anhidrotic Disorders of sex development ◦ Campomelic dysplasia Teratology ◦ Fetal alcohol syndrome Situations Prompting Consideration of Syndromes that May Have Recognizable Dysmorphic Features One or more anomalies Growth aberration Cranial size/contour abnormalities Neurologic problems Ectodermal defects Orthopedic problems Abnormal genitalia/sexual development Unusual behavior, activity or speech Phenotype variation from family Hearing/vision loss A clinical case – from lecture #1 18 year old young woman with a long, complicated medical history including bone marrow failure and pulmonary disease. http://www.genereviews.org http://www.wheelessonline.com Making the diagnosis Search OMIM for bone marrow, lung, skin, nails Three out of the top 5 results are forms of dyskeratosis congenita. One phenotype/disease multiple modes of inheritance Dyskeratosis congenita can show the following modes of inheritance ◦ Autosomal dominant ◦ Autosomal recessive ◦ X-linked recessive At GeneReviews.org , originally from Macmillan Publishers Ltd: Nature Genetics, Savage SA, Connecting complex disorders through biology, 44:238-40, copyright 2012 Dysmorphology The study of abnormal form The medical specialty of evaluating patients with abnormal physical features What is a dysmorphic feature Normal structure of abnormal size, proportion or shape ◦ Smooth philtrum ◦ Variant palmar creases ◦ Upslanting palpebral fissures Feature not normally present ◦ Ear tag ◦ Extra digit ◦ Supernummerary nipple Elements of Morphology http://elementsofmorphology.nih.gov/ Categories of dysmorphic features Minor anomaly ◦ Features that differ from family, racial/ethnic background or the general population Most found as “low frequency normals” in general population (e.g. Down syndrome- small ears, epicanthal folds, upslanting eyes, transverse palmar crease, incurved 5th fingers) ◦ No major surgical or cosmetic importance Major anomaly ◦ Indication for medical or surgical intervention, or cosmetic importance ◦ Cleft lip, cleft palate, structural heart disease, microtia Importance of Minor Anomalies Specific minor anomalies may be markers for occult major malformations ◦ Sacral tags, birthmarks Many syndromes are defined by a pattern of specific minor anomalies ◦ Fetal alcohol syndrome ◦ Marfan syndrome Three or more minor anomalies associated with increased risk of a major malformation (congenital heart defect, cleft palate for example) Identification of anomalies Careful physical examination required Found more frequently in areas of the body that are more variable and complex ◦ 70% found on either the hands or face Variant palmar creases “Hockey Stick Crease” as seen in Fetal Alcohol Syndrome Single transverse crease as seen in Down syndrome Stanford Medical Genetics http://elementsofmorphology.nih.gov/ Decreased creases as seen in fetal hypokinesia http://elementsofmorphology.nih.gov/ The Lip-Philtrum Guide • Microcephaly, short stature, small weight for age (all < 5th %ile) Hoyme, 2006, Pediatrics, Diagnosis of FAS by 1996 IOM Criteria, PMID: 15629980 Making a diagnosis Sifting through information to find a unifying explanation(s) for ◦ History ◦ Exam ◦ Studies Radiology EKG Sweat test ◦ Laboratory Tests Clinical case #1: Dysmorphology/Phenotyping in the era of whole genome sequencing A newborn boy is noted to be small for gestational age. He experiences episodes of low blood sugar in the nursery. With age he is short for age, has delayed tooth eruption, frequent sinopulmonary infections and hearing loss Has array CGH, a variety of single gene tests and eventually whole exome sequencing Facial dysmorphology Avila, Magali, et al. Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: towards recommendation for molecular testing and management. Clinical Genetics (2015). Dyment DA et al. Mutations in PIK3R1 Cause SHORT Syndrome. Am J Hum Genet. 2013 Jul 11;93(1):158-66. Epub 2013 Jun 27. PMID: 23810382 Revisiting the exome c.1945C>T variant in PIK3R1 ◦ Not reported on initial analysis Not predicted to be deleterious Mutation was not yet in databases Review -- Factors to consider / actions to take in establishing a genetic diagnosis ◦ Does phenotype match that in other affected individuals ◦ Mode of inheritance ◦ Number of mutations/variants identified (2 for recessive) Confidence in designating variants as mutation Informatics, segregation, literature/databases ◦ Configuration/phase of mutations (cis vs trans for recessive) If not enough mutations found – is there more testing that should be done Multiple lines of evidence to support a diagnosis The clinical history, physical exam and other findings should match the diagnosis supported by genetic information. Categorizing congenital anomalies/dysmorphic features Malformation Deformation Disruption Considering congenital differences in a developmental context can be helpful in developing a differential diagnosis. Cause/mechanism and timing Malformation Congenital heart defect or cleft lip and palate Structural defects arising form an intrinsically abnormal developmental process More likely to have a genetic component to etiology www.cdc.gov Deformation Abnormality of structure arising from mechanical forces on an otherwise normally formed structure or tissue Club foot, overlapping toes, unusual head shape Positional plagiocephaly http://www.nlm.nih.gov/medlineplus http://www.springerimages.com Disruption Structural defects resulting from the destruction or interruption of intrinsically normal tissue Affect a group of tissues in a specific anatomic distribution that does not follow usual pattern of embryologic development ◦ Limb reduction anomalies from amniotic bands ◦ Intestinal atresia caused by vascular insufficiency Constellations of anomalies and their origins Association Sequence Syndrome ◦ Genetic ◦ Epigenetic ◦ Teratogenic Origins of congenital anomalies Association ◦ Nonrandom occurrence of multiple anomalies that cannot be explained by chance alone and for which no consistent etiology can be established ◦ 6 to 8 anomalies comprise core features; rarely are all anomalies present in 1 individual Origins of congenital anomalies Sequence ◦ Anomalies due to single problem in morphogenesis that leads to cascade of subsequent events Syndrome ◦ Recognizable recurring pattern of multiple anomalies; all cases due to a single identifiable etiology The story of CHARGE Sanlaville and Verloes, EJHG, 2007 www.chargesyndrome.org Case #2 A young man is noted to have spontaneous keloids and a history of mitral valve disease Exome sequencing reveals a variant of unknown significance in the FLNA gene, c.4726G>A (p.G1576R) Pedigree Case #3 Brachydactyly and bronchomalacia Newborn boy requires intubation for respiratory failure ◦ Has a very pliable bronchial tree that essentially collapses on itself ◦ His father was hospitalized for several weeks as an infant for similar, but milder findings ◦ Both the child and the father have short digits and hallux valgus Matchmaking Making matches – and discoveries Data Sharing from Stanford The Autism Spectrum Autism Fragile X Isolated or syndromic / Essential or complex An emerging map of autism spectrum disorders 16p11.2 Deletion 22q13 Deletion 22q11 Deletion Timothy Syndrome 15q13 Deletion Fragile X Idiopathic Autism? PTEN Lecture Summary Genetic understanding of diverse disease processes is rapidly increasing Dysmorphology refers to the study of abnormal form and the application of this study to medical care Major and minor anomalies ◦ Malformations, deformations, disruptions ◦ Associations, sequences and syndromes Human phenotype ontology Lecture Summary Clinical lessons – thinking about syndromes and diagnoses in general ◦ Critically assess all of the available information Consider that each piece of information may or may not be accurate and may or may not be related to an underlying etiology for the patient’s condition Importance of the basic sciences ◦ Analogous to planning and interpreting the results of an experiment Lecture Summary Careful observation can lead to ◦ Diagnosis ◦ Improved therapy ◦ New discoveries The role of clinical description/phenotyping in the interpretation of genomic information Value of systematic sharing of high quality data Medical Genetics – The Medical Specialty At Stanford ◦ Clinical Clerkship – Pediatrics 301A Dysmorphology, biochemical genetics, cancer genetics, clinical laboratory genetics ◦ Medical Genetics Residency Program Entry after one year of training in any primary specialty ◦ Clinical laboratory fellowships ◦ Center for Undiagnosed Diseases Beyond Stanford ◦ The American Board of Medical Genetics www.abmg.org ◦ The American College of Medical Genetics (and Genomics) www.acmg.net (Video on Genetics Residency http://youtu.be/oh_S6zmMcm8) ◦ The American Society of Human Genetics www.ashg.org Review Question Which of the following is expected to arise most consistently in the first trimester of pregnancy A. Malformation B. Deformation C. Disruption D. Sequence