5 la genetica clínica en pediatria

5 la genetica clínica en pediatria
Dismorfología y Genética Clínica en Pediatría Mesa Redonda S.V.P. Amparo Sanchis Calvo, Graciela Pi Castán, Salvador Climent Alberola, Antonio Martínez Carrascal. Hospital Dr. Peset (Valencia), Hospital La Ribera (Alzira), Hospital de Ontinyent, Hospital de Requena. eso Interdisciplinar e ética Humana Soci Fa Fa Sociedad Española de Asesoramiento Genético Asociación Española en Diagnóstico Prenatal AEDP Sección de Genética Clínica y Dismorfología A.E.P tus genes, tu herencia, tu futu
El Diagnóstico en el Área de la Genética Clínica y Dismorfología Enfoque práctico
Soc Fa F Sociedad Española de Asesoramiento Genético Asociación Española en Diagnóstico Prenatal AEDP Sección de Genética Clínica y Dismorfología A.E.P
La Medicina Clínica es un proceso básicamente intelectual: todos los datos se integran formando un perfil con significado Jean Aicardi
¿Cómo diagnosticar en Dismorfología? El Paciente con una enfermedad poco frecuente suele ser un gran reto por: 1. La dificultad en su diagnóstico. 2. La complejidad en su tratamiento y manejo. Jürgen W. Spranger
¿Para qué un diagnóstico etiológico? Impacto Ventajas Inconvenientes Pone una “etiqueta” * Hace descansar a los padres sobre la búsqueda de causas. * Evita estudios o tratamientos innecesarios * * Le “marca” al paciente. Etiología *Permite una prevención primaria y un consejo genético. * Permite una prevención secundaria (diagnóstico prenatal, feticidio si los padres pueden asumirlo éticamente). * Evita sentimientos de culpabilidad * Puede crear sentimientos de culpabilidad. * Posibilita la manipulación genética. * Puede disminuir el número de pacientes afectos y sus consecuencias. Pronóstico *Posibilita prevención terciaria (incluyendo aumento expectativa de vida). *Formulación de expectativas realistas. * Puede hacer desaparecer la esperanza en una cura, incluso saber la expectativa de vida reducida.
Primer enfoque: • La premonición, el olfato,…
Segundo enfoque: El Tamizado de muchos datos *Primera regla básica: Antes de valorar al paciente, recoge datos de la anamnesis, árbol genealógico y exploración. * Selecciona: convierte los datos groseros y complejos… en… Datos con relevancia: signos esenciales + datos fundamentales = patrón de un síndrome o enfermedad.
Segunda regla básica:Tener una hipótesis que apoye los datos y patrones conseguidos OMIM POSSUM LondonMedicalDatabase Face2Gene Los padres pueden saber más de lo que piensas… Introducir los datos más importantes = hallazgos principales Si todo falla… contactar con un nivel superior Segundo enfoque: El Tamizado de muchos datos Siri: ¡Tenemos un problema!. Robin Winter and Michale Baraister
Pediatra de Atención Primaria Neonatólgo Neuropediatra Endocrinólogo Infantil Gastro, Nutrición y Metabolismo “No relegar la dismorfología en una torre de marfil”
Piensa en verde… Piensa en dismorfología.
Pediatra de Atención Primaria Pediatra de Hospital Nivel I y II: Neonatólogo, Neuropediatra, Endocrino Infantil,… Hospital de Referencia: Pediatra integrado en Servicio de Genética Trabajo en equipo: todos somos………necesariosmuy
Motivos para pensar en una valoración dismorfológica • Retardo crecimiento intrauterino. • Microcefalia, macrocefalia, craneosinóstosis (no plagiocefalia aislada). • Hipotonía, hipertonía. • Genitales anómalos. • Retardo psicomotor. • Desmedro. • Crecimiento somático alterado. • Baja talla, talla alta • Asimetría corporal o crecimiento disarmónico. • Cuadro regresivo. • Trastornos del neurodesarrollo asociados a cualquier malformación. • Familiares de primer grado con patología similar. • Patología metabólico, olor corporal anómalo. • Discrasias sanguíneas. • Vómitos sin causa aparente.
CytoScan® Dx Assay To aid in the diagnosis of developmental delay and intellectual disability Unrivaled performance. Results that matter. For In Vitro Diagnostic Use
The prevalence of developmental disabilities in US children is 13.87%,1 and they occur across all racial, ethnic, and socioeconomic groups. Recently, it has been reported that 1 in 33 babies is born with congenital anomalies in the US.2 Frequently, developmental delay and/or intellectual disability (DD/ID) is accompanied with one or more congenital anomalies or dysmorphic features. The affected individuals have lifelong challenges, including various medical conditions and difficulties with physical movement, learning, and social interaction. Early intervention is key to providing better outcomes for children with special needs. Despite this, on average, diagnosis of developmental delay in children does not occur until they have reached the age of four years old.3 Often, certain intellectual disabilities are diagnosed much later, as late as when the child has entered elementary school. Establishing an underlying diagnosis early can provide physicians and families with knowledge of which disorder is affecting the child, prognosis, and comorbidity information, all of which have implications beyond medical treatment. However, finding a diagnosis can be a lengthy journey, and opportunities for taking early action are often lost during this so-called “diagnostic odyssey.” While environmental factors and nutritional deficiencies are known causative factors, the largest specific etiology of ID is genetic.4 According to the American Academy of Neurology (AAN), the Child Neurology Society (CNS), the American College of Medical Results that matter for the best in patient care
karyotyping and more comprehensive coverage than FISH. n This example illustrates two interstitial duplications: in blue, a 5 Mb duplication in 15q11.2->15q13.1; in red, a 1 Mb hemizygous gain in 16p13.11- >16p13.11. n Due to the high density of non-polymorphic (copy number) probes and polymorphic (SNP) markers in the array, the copy number changes can be visualized in the Log2 ratio track as well as confirmed in the allelic difference track. n These microarray findings, in conjunction with clinical evaluation, led to a diagnosis of 15q11 microduplication syndrome. References 1. Boyle C. A., et al. Trends in the prevalence of developmental disabilities in US children. Pediatrics 127(6):1034–1042 (2011). 2. Heron M. P., et al. Deaths: Final data for 2006. National Vital Statistics Reports 57(14):1–136 (2009). 3. Mann J. R., et al. Does race influence age of diagnosis for children with developmental delay? Disability and Health Journal 1(3):157−162 (2008). 4. Leonard H., Wen X. The epidemiology of mental retardation: challenges and opportunities in the new millennium. Mental Retardation and Developmental Disabilities Intellectual disability might be present as the only manifestation of a disease or may be associated with other manifestations causing a clinical syndrome.8 Some syndromes are genetically heterogeneous and may be caused by aberrations in several genes with distinct roles in common biological pathways like Rubinstein-Taby Syndrome (RTS).9 CytoScan Dx Assay detects chromosomal aberrations across the whole genome
Buen enfoque: Árbol Genealógico Exploración Clínica “con ojos de dismorfólogo” y resto de hallazgos Piedra angular
55 cm; 90th percentile), frontal bossing, hypertelorism (inner canthal distance 3.5 cm; 497th percentile – outer canthal distance 11 cm; 497th percentile), down slant of palpebral fissures, short nose with anteverted nostrils, wide philtrum and thin upper lip. In the past, the chromosomal analysis in peripheral blood lymphocytes had revealed a 46,XY(90%)/47,XYY(10%) mosaic. Molecular analysis revealed a missense mutation in exon 3 (614 G4T) that causes a change in the residue 205 from Ser to Ile. The same mutation was found in his mother and in her three sisters, who have mild phenotypical signs (hypertelorism, widow’s peak). The patients in whom a mutation was not found (37 individuals) present with various combinations of short stature, facial appearance (hypertelorism, small nose with anteverted nares, broad nasal bridge, ptosis, strabismus), hand abnormalities and genitourinary manifestations (Table 2). Most clinical signs were concordant with the males is characterised by genital anomalies (shawl scrotum, cryptorchidism), short stature, distinct craniofacial abnormalities, brachydactyly with interdigital webbing and joint laxity. A broad range of mild developmental delay or learning difficulty has occasionally been reported. Never- theless, in affected males the phenotype is variable as they may exhibit different combinations of associated features. In general, carrier females may have a milder phenotype than males, showing minor and mild clinical signs, possibly depending on the pattern of X-chromosome inactivation. Despite the presence of clinical inclusion criteria and the advances in the molecular pathogenesis of AAS, disease-causing mutations have been identified in only a small number of patients. Possibly, both the variability of phenotype and the genetic heterogeneity account for a clinical overdiagnosis. Short stature with hypertelorism and brachydactyly represent a relatively frequent association in clinical dysmorphology. Moreover, AAS patients are often referred with various degrees of mental handicap (mild mental retardation, learning disabilities, attention-deficit disorders) and, as the majority of cases are sporadic, X-linked inheritance may be question- able. In the present study, we performed mutation screening of the FGD1 gene in 46 male patients referred with the clinical diagnosis of AAS. This is the largest series reported to date. We identified eight mutations, all novel, including four deletions, one insertion and three missense mutations. The majority of the mutations identified were found to be unique to a single family. The only exception is the 528insC, occurring in exon 3, which was detected in two independent families (Belgian and Italian). The deletions and the insertion mutations are all predicted to result in a frameshift, which leads to a truncation of the protein. The three missense mutations, S205I, E380A and R443H, occur in exons 3, 5 and 6, respectively. They all occur at the N-terminal half of the protein, encompassing the proline- rich region and the SRC domains, upstream from the first PH domain. The 614 G4T mutation, detected as a single observation in patient 25, changes the S205 residue (S205I) located in the proline-rich N-terminal region, a protein- Figure 2 Front and profile of patient 25 (a and b), over- riding scrotum (c) and interdigital webbing (d). Genotype–phenotype correlation in AAS A Orrico et al 21 Problemas diagnósticos en Dismorfología 1. Problemas “achacables” al Pediatra o al clínico: *Por una evaluación incompleta. *Por falta de conocimiento. Las áreas del cuerpo más importantes son: * la cara * las manos También pies y genitales la capacidad del observador está directamente relacionada por su conocimiento y experiencia YVES LACASSIE, 2015
Problemas diagnósticos en Dismorfología 2. Problemas por el paciente o la familia: * aportan información incompleta o errónea. * óvulo, espermatozoide o embrión * de donante. * paternidad falsa no conocida. * evaluar dismorfias en otros miembros de la familia Caso especial de un mortinato: * guardar ADN, Rx,… YVES LACASSIE, 2015
Problemas diagnósticos en Dismorfología 3. Problemas en el área de la genética I * heterogeneidad genética: * diferentes genes * diferentes tipos de herencia: AD,AR,.. Fenotipo común o muy similar Interacción entre genes y genes de regulación Genes contiguos no solo por la disposición lineal sino tridimensional
a) Mecanismos epigenéticos: cambios heredables en la expresión génica o en el fenotipo celular causado por diferentes mecanismos sin cambiar la secuencia de ADN: *Metilación del ADN. *Deacetilación de las histonas Problemas diagnósticos en Dismorfología 3. Problemas en el área de la genética II: b) Pleiotropismo c) Abiotropismo d) Mecanismos ambientales que simulan mecanismo genético e) de herencia no tradicional f) Mosaicismo gonadal
Problemas diagnósticos en Dismorfología 4. Problemas ambientales: Dos vertientes a) Factores ambientales intraútero p.e. teratógenos (alcohol, talidomida,…) o a nivel gonadal b)Posibilidad de acceso al diagnóstico: Depende de la sociedad o país. POBREZA. increased fasting glucose, impaired glucose tolerance, and altered in- sulin signaling compared to natu- rally conceived controls (9). More rapid postnatal growth and fat de- position after IVF conception are associated with altered gene expression in liver, adipose tissue, pancreatic islets, and muscle (10), plus vascular stiffness, higher arte- rial blood pressure, and signs of en- dothelial dysfunction (11). Notably, adverse effects are retained if embryos are transferred to healthy recipients at the two-cell stage, impli- cating disruption of very early developmental events. Thus, at least in mice, conception by IVF alters later placental and fetal development, growth trajectory after birth, and metabolic parameters and behav- ior in adult life. In vitro–cultured embryos show changes to blastocysts and fetal growth that mimic many aspects of in vivo dietary and inflammatory insults (12), suggesting that endogenous cell stress may be a common pathway driving adverse impacts on offspring. Although the protocols implemented in ani- mals are more aggressive than clinical IVF, emerging data suggest that in IVF-conceived children, blood pressure and fasting glucose are higher (13), and vascular dysfunction can be evident (14). Epigenetic reprogramming at conception The periconception influences on development are believed to occur through environment-induced modification of the embryo’s epigenome. A dynamic phase of epigenetic remodeling begins at fertilization, when most epigenetic marks are cleared from the oocyte and sperm genomes before fusion of the chromatin at syn- gamy, and is completed just before implantation when remethylation of the embryonic genome occurs (15). Altered methylation of cytosine res- idues, or loss of parental-specific imprinted marks, may be attenuated by the chromatin structure, including nucleosome positioning, and altered histone acetylation or assembly, which modulate the availability of DNA for transcription. Epige- netic marks are carried forward into daughter cells, where despite further modification by the developmental program, they permanently affect gene expression in resulting adult tissues (15). Maternal nutrition at conception is a major influence on resetting of the epigenome in the early embryo—a compelling example is epigenetic control of the agouti viable yellow (Avy ) locus, which determines coat color in mice and is highly sensitive to methyl groups in the diet (3, 16). DNA methylation in human infants was recently associated with seasonal variation in diet (17); similar epigenetic marks were present in different tissues, indicating that persistent systemic changes were established at conception. Altered methylation patterns are also evident in embryos conceived by IVF or exposed to stress- inducing culture conditions (16, 18, 19). After IVF, mouse blastocysts show disrupted expression of the epigenetic regulator Txnip and enriched histone acetylation at its promoter, which are main- tained into adulthood (10). Vascular dysfunction evident in IVF-conceived mice is associated with altered methylation of genes in the aorta (11)— but causal relationships betweenepigeneticchanges and phenotypic alterations have not been dem- onstrated and are difficult to prove. Specific classes of elements in the genome appear particularly sensitive to epigenetic dysregulation, including transposons (which control expression of the Avy locus) and genomically imprinted genes, which normally survive the global erasure of epigenetic marks at conception (16). Although the impact of IVF on transposons is not known, there is an increased incidence of imprinting disorders in IVF children, suggesting that maintenance of imprinted genes may be disturbed (20). However, genome-wide analysis of methylation shows no epigenetic changes attributable to IVF (21). Intriguingly, males are consistent- ly more vulnerable to most dietary, culture-induced, and physiochemical models of metabolic programming (2, 5, 6, 8, 12). Female embryos con- sume relatively more glucose, and male embryos develop more quickly to the blastocyst stage (22). Sex- dependent transcriptional differences in molecular pathways controlling glucose metabolism, protein metabolism, DNA methylation, and epigenetic regulation (23) likely cause sex-specific differential responses to environmental insults. Ex ovo omnia: All things come from eggs Effects on oocytes contribute to the effects of maternal environment on offspring phenotype. Studies to iso- late preconception effects from later pregnancy demonstrate that maternal nutrition during oocyte maturation influences offspring phenotype (Fig. 2). In sheep, maternal over- feeding generates offspring that ac- cumulate fat (24), while in mice, a protein-deficient diet for 3.5 days before conception leads to hyperten- sion (25). Developing oocytes are suspended in follicular fluid that provides a unique nutritional environment which reflects maternal physiological states— for instance, adiposity (26). As the oocyte matures, it accumulates epigenetic marks, both on histones and DNA, until the final phases of maturation before ovulation. Although gen- erally these marks are erased at conception, there is evidence that at some loci, oocyte epigenetic marks are not cleared, allowing the possibility of transgenerational inheritance. As well as maternally imprinted loci, epigenetic marks established in response to environmental cues may also be resistant (3, 27). This is difficult to definitively demonstrate, because the complex- ity of the human genome makes it impossible to clearly distinguish genetic and epigenetic hered- ity (27). Attributing effects to transgenerational inheritance requires experiments in inbred genetic backgrounds, and the use of oocyte transfer or cross-fostering to ensure that effects are truly transmitted through the germ line (28). Evi- dence from mice exposed to preconception zinc SCIENCE sciencemag.org 15 AUGUST 2014 • VOL 345 ISSUE 6198 757 modifications Micronutients impact DNA Lipid & sugars alter mitochondrial activity Dietary fat increases lipid droplet size & composition B A Altered diet, inflammation, toxins Lipid droplets Chromatin Mitochondria Fig. 2. Maternal nutrition affects oocyte provisioning. (A) The maternal environment influences oocyte stores of mitochondria and metabolites. Lipid droplets are stained green with BODIPY 493/503 in a mouse oocyte, and mitochondria are stained with MitoTracker Orange. Chromosomal DNA aligned at metaphase II is stained blue with Hoescht dye. (B) Cyto- plasmic constituents respond to maternal nutrition and in turn alter con- ceptus development. mice fed a zinc-deficient diet for just 5 days before conception generated smaller fetuses prone to neural tube defects even after embryo transfer (29), and methylation of histones and chromatin was decreased in oocytes and retained in the maternal pronucleus after fertilization (30). Increased oocyte lipid content and cellular stress are also evident in mouse studies showing poor embryo and fetal development after maternal preconception diabetes or obesity (31, 32). Maternal nutritional influences on oocyte mitochondria are emerging as a pathway of lasting consequence to offspring (33). Embryogenesis is an energy-demanding process, and oocyte-derived mitochondria are required to support blastocyst formation (34). Alterations in maternal dietary protein affect mitochondrial localization and dampen mitochondrial activity in two-cell embryos (35) associated with later disturbances to fetal brain gene expression (36). In diabetic or obese mice, oocyte mitochondria fail to support normal embryo development (31, 32). Promis- ingly, these defects are modifiable by diet—oocyte quality, mitochondrial function, and fertility in aged mice can be restored by caloric restriction (37) or an omega-3–enriched diet (38). Paternal programming—a new consideration Paternal smoking, age, and occupational chem- ical exposure are well known to be linked with increased risk of cancer and neurological disorders in children (39, 40). It is less well appre- ciated that the father’s body mass has a greater impact than the mother’s on body fat and metabolic measures in prepubertal children (41). As well as sperm DNA damage, in some instances there is accumulating evidence for pathways of paternal transgenerational epigenetic effects, attributable to sperm and seminal fluid (42, 43). Interest in paternal epigenetic contributions stems grandfather’s food availability to mortality in grandsons (44) and associating paternal smoking with increased body mass index in male children (44). Paternal obesity is associated with changes to methylation in cord blood from offspring, at the demethylated region of IGF2 and possibly other imprinted genes (45). Although this can be interpreted as evidence for an epigenetic pathway, as for all human cohort studies, the possibility of shared genetic or nongenetic programming contributions cannot be discounted (27). Rodent models have been developed to assess epigenetic transmission of metabolic and other phenotypes via the paternal line (42). For example, male mice fed a low-protein diet fathered offspring with decreased hepatic cholesterol esters and altered hepatic expression of lipid and cholesterol biosynthesis genes, associated with altered epigenetic marks (46). Male mice born to undernourished mothers sired offspring with reduced birthweight and impaired glucose tolerance (47). Other rat studies showed that nutritional cues from the father result in female offspring with impaired metabolic health (48), associated with altered gene methylation and transcriptome changes within pancreas and adipose tissues (48, 49). Rats exposed to the environmental toxin vinclozolin during development in utero have impaired spermatogenesis, which is transferred to male offspring (50). When male mice were conditioned to respond to a specific odor associated with a fear stimulus and then mated, their offspring inherited increased behav- ioral responses to the same odor (51). Similar transmissible effects are seen in the offspring of fathers exposed in early life to stress imposed by maternal separation (52). These intriguing studies raise the exciting prospect of specificity in paternal transmission and the possibility of tar- geted transmission of acquired characteristics; has emerged. Fathers transmit DNA modifications to offspring Genetic and epigenetic transmission mechanisms may be intertwined in sperm to transmit environmental exposures to the next generation (Fig. 3). Sperm development involves extensive DNA strand repair and chromatin remodeling in which histones are largely, but not completely, replaced by protamines (43). Both sperm nucleosome and histone-bound regions are conserved among mammalian species at loci of developmental importance—including promoters for early embryo development and imprinted regions (53). Compared with protamine-bound regions, genes in histone-bound regions appear more susceptible to DNA damage (54) due to smoking, obesity, and aging (55), compounded by the incapacity of sperm to repair DNA damage due to oxidative stress (56). Histone-bound regions appear vital for paternal DNA replication following fertilization as well as activation of paternal genome transcription in the early embryo. Whereas the paternal protamines are replaced by maternal histones in the first 4 to 6 hours after fertilization, the retained paternal histones are not replaced; therefore, epigenetic marks to these histones are likely inherited by the embryo (57). Expression of SIRT6, a class III histone deacety- lase, is regulated by metabolic state and is decreased in the testes germ cells of mice with diet-induced obesity, associated with increased DNA damage in transitional spermatids as well as mature sperm (58). This may explain why sperm from obese fathers can alter the developmental capacity of the embryo in vitro, alter- ing rates of mitosis and early differentiation events (59), resulting in reduced pluripotency and metabolic function. 758 15 AUGUST 2014 • VOL 345 ISSUE 6198 sciencemag.org SCIENCE Environment/lifestyle insult Toxins Endocrine disrupters Smoking Obesity Altered gene expression in zygote Impaired embryo growth and health of offspring Insult affects sperm during development in testes or during maturation in the epididymis Histone-bound DNA MicroRNA DNA breaks Fig. 3. Environmental effects on paternal nongenetic contributions. Postulated modes of action of environment or lifestyle factors on sperm function, imparted either during spermatogenesis or epididymal transit, and pathways for impact on the development of the embryo.
Problemas diagnósticos en Dismorfología 5. Problemas tecnológicos- herramientas informáticas Problemas en la interpretación de resultados “hallazgos de significado incierto” Validación de modelos “in silico” (modelo de simulación computacional) Incompleto conocimiento de la correlación fenotipo - genotipo
14 Fig. 2.1 Schematic of the next-generation–sequencing workflow. Following DNA isolation, t sequences are enriched by amplification (RainDance) or capture-based methods, sequenced next-generation platform (HiSeq 2500), and analyzed by open source or commercial soft package, such as NextGENe from Softgenetics, to obtain the variants that will then be filter p tized to identify the potentially causative gene(s) 2 A Survey of Next-Generation–Sequencing Technolo 80 Fig. 8.1 Whole exome sequencing workflow. The DNA is fragmented, library is prepared, and reads are generated by NGS instrument (i.e., HiSeq2500). Determining nucleotide calls (A,C,G,T or N) along with error probabilities (Q score) is performed via a proprietary base calling algorithm during the sequencing run. The FASTQ file is the raw data which contains the base calls and qual- 8 Exome Sequencing as a Discovery and Diagnostic Tool
El niño de la enfermedad sin nombre
La Estación Experimental Aula Dei (también denominada por el acrónimo EEAD) es un centro de investigación agronómica dependiente del Consejo Superior de Investigaciones Científicas.1 Está situada a unos 13 km de la ciudad de Zaragoza, muy cerca de la Cartuja de Aula Dei (de la que toma el nombre).2
Jérôme LejeuneMartha Gautier Raimond Turpin ¿Papel de los Pediatras? “Solo tengo una manera de ahorrar y es curar” Cultivo de fibroblastos Análisis cromosómico Plan de estudio Sd. Down
(A) (A) (B) (C) (D) FIGURE 11–2 Pioneers of modern clinical dysmorphology: (A) Robert Gorlin (1923–2006) (see Cohen, 2006, for an obituary; Cohen, 2007), (B) John Opitz (born 1935), (C) Judith Hall (born 1939), and (D) Robin Winter (1956–2004) (see Nance, The focus of dysmorphologists on delineation and nosology was not without its critics, particularly from more general clinicians, including some pediatricians. Rarity and lack of immediate potential for treatment or (A) (B) (C) (D) - t y f d s n f e h l . s - s , s , r - o d s s , h - t cular defects associated with prenatal onset growth deficiency and developmental delay in 8 unrelated children of 3 ethnic groups, all born to mothers who were alcoholics. The Workshop’s Beginning The Smith Workshop emerged during a 1979 teratology meeting and was inspired by frustration over the lack of attention to malformation, Dr. Graham recalls. At a gathering in an airport bar, Dr. Smith away by then.” The first workshop and the 30 subse- quent ones have been opportunities for clinicians, researchers, and trainees “to bring the most important thing they are doing related to understanding abnormalities of structure to others in the field,” says Dr. Jones. “We comment and learn from each other in an informal way.” Limiting partic- ipation to 125–130 people allows for such interaction. “This gathering isn’t meant to be about passive listening,” he adds, explaining that the term “workshop” underscores the central importance of all attendees’ contributions. The chairs of the 2010 meeting emphasize this point. The meeting is unique because all participants present their work and debate, says Sonja Rasmussen, MD, Senior Scientist at the Centers for Disease Control and Prevention, and Michael Bamshad, MD, Professor of Pediatrics at the University of Washington. “At other meetings, you’re often there either to learn or just to present,” Dr. Rasmussen explains. “The Smith meeting is small so people can feel com- fortable discussing controversial topics that non-Smith attendees aren’t interested in.” The meeting has developed a reputa- tion for mentoring fellows and younger people in the field. “The meeting in general is good for fellows because of its interac- tivity. New fellows eat with authors of key books on genetic disorders,”Dr.Rasmussen explains. Praising the way the meeting pro- eting is small so people can le discussing controversial on-Smith attendees aren’t David W. Smith, MD John M Opitz Robert J Gorlin John CareyKen Jones Judith Hall Jaime Frias Roger E Stevenson Raoul C.M. Hennekam Giovanni Neri
[Dr. Smith] didn’t want to relegate dysmorphology to some ivory tower. Roger E. Stevenson, MD “Every Pediatrician should be a dysmorphologist”
Herramientas Para Pediatras en el área de la Genética Clínica y Dismorfología
¿Porqué perder tiempo en la confección de un árbol genealógico en pediatría? hay motivos…. Se puede considerar la primera prueba diagnóstica previo a plantearse cualquier estudio genético
Proband is a free iPad application designed to enable counselors and clinicians to quickly and efficiently capture a patient’s genetic family history during the clinical encounter. Users create the pedigree using a series of gestures similar to drawing. All data is stored in a structured format, with diagnoses annotations available from ICD-10 and the Human Phenotype Ontology. Completed pedigrees can be exported to PDF, PNG, or structured XML file. The Department of Biomedical and Health Informatics at The Children’s Hospital of Philadelphia developed and tested the app with genetic counselors in actual clinical settings. https://probandapp.com/tutorials/ ventricular nodular heterotopia) is both pheno- typically and genetically heterogeneous30 and is present in 40% of patients with an FLNA mutation (Online Mendelian Inheritance in Man [OMIM] number, 300049; chromosome-map location, Xq28). Much less common than this X-linked dominant form is an autosomal recessive mutation in ARFGEF2 (OMIM number, 608097; chro- Figure 3. Three-Generation Pedigree. The family history shows affected females in three generations — a pedigree that is consistent with inheritance in an X-linked autosomal dominant manner. Squares represent male family members, and circles female family members. As the key illustrates, the shading in each quadrant represents the presence of a certain feature; open symbols represent unaffected members. The arrow indicates the patient, who had growth retardation, heterotopia, and pulmonary and cardiac abnormalities. Heart murmur (echocardiogram not performed) Respiratory failure Polyvalvular dysplasia and aortic dilatation Hypermobility Periventricular heterotopia (dark gray) or seizures only (light gray) I II III
Identify Rare Diseases with a Selfie How Machine Learning Is Revolutionizing the Diagnosis of Rare Diseases Dekel Gelbman Moti Shniberg
Human Phenotype Ontology Title: ... Abstract ... MeSH terms: D012261 D019851 SNPGene HP:0003463 HP:0007265 PMID HPO Annotations MeSH Disorder / Trait Common disorder Rare disorder Common disorder Common disorder Gene | Rare disorder | Phenotype associations Bio-LarK CR 1 2 3 4 5 Figure 2. Overview of CR and Bioinformatic Analysis The analysis was performed in several major steps. (1) Bio-LarK was used to analyze the PubMed-MEDLINE 2014 corpus, which resulted in a total of 5,136,645 abstracts annotated with MeSH terms and phenotypic features. (2) For each of 3,145 resulting diseases, the fre- quency and specificity of HPO terms found in the abstract were used for inferring phenotypic annotations. (3) These annotations were used for producing disease models for each of the diseases. (4) Medical validation of the annotations was performed on the basis of disease, phenotype, and SNP annotations in GWAS Central for phenotype sharing in common disease. (5) Validation with OMIM, Orphanet, and DO was used for assessing phenotype sharing between rare and common diseases linked to the same locus. ARTICLE The Human Phenotype Ontology: Semantic Unification of Common and Rare Disease Tudor Groza,1,2,25 Sebastian Ko¨hler,3,25 Dawid Moldenhauer,3,4 Nicole Vasilevsky,5 Gareth Baynam,6,7,8,9,10 Tomasz Zemojtel,3,11 Lynn Marie Schriml,12,13 Warren Alden Kibbe,14 Paul N. Schofield,15,16 Tim Beck,17 Drashtti Vasant,18 Anthony J. Brookes,17 Andreas Zankl,2,19,20 Nicole L. Washington,21 Christopher J. Mungall,21 Suzanna E. Lewis,21 Melissa A. Haendel,5 Helen Parkinson,18 and Peter N. Robinson3,22,23,24,* The Human Phenotype Ontology (HPO) is widely used in the rare disease community for differential diagnostics, phenotype-driven analysis of next-generation sequence-variation data, and translational research, but a comparable resource has not been available for common disease. Here, we have developed a concept-recognition procedure that analyzes the frequencies of HPO disease annotations as identified in over five million PubMed abstracts by employing an iterative procedure to optimize precision and recall of the identified terms. We derived disease models for 3,145 common human diseases comprising a total of 132,006 HPO annotations. The HPO now comprises over 250,000 phenotypic annotations for over 10,000 rare and common diseases and can be used for examining the phenotypic overlap among common diseases that share risk alleles, as well as between Mendelian diseases and common diseases linked by genomic location. The annotations, as well as the HPO itself, are freely available. Introduction The Human Phenotype Ontology (HPO) provides a structured, comprehensive, and well-defined set of over 11,000 classes (terms) that describe phenotypic abnormalities seen in human disease.1,2 The HPO has been used for developing algorithms and computational tools for clinical differential diagnostics,3–5 for the prioritization of candi- date disease-associated genes,6–11 in exome sequencing studies,6–10 and for diagnostics in clinical exome sequencing.11 In addition, the HPO has been used for translational research, including inferring novel drug indications,12 characterizing the proteome of the human postsynaptic density,13 analyzing Neandertal exomes,14 and other topics.15–22 The HPO currently provides over 116,000 annotations to over 7,000 rare diseases; for instance, the disease Marfan syndrome (MIM: 154700) is annotated with the HPO terms ‘‘arachnodactyly’’ (HP: 0001166), ‘‘ectopia lentis’’ (HP: 0001083), and 46 others. The patterns and specificity of the annotations allow the information content (IC) of each term to be calculated; the IC reflects the clinical specificity of the term and represents a key component of most of the aforementioned algorithms.23 Additionally, computational logical definitions are provided for HPO terms. For instance, the HPO term ‘‘hypoglycemia’’ is defined on the basis of ‘‘decreased concentration’’ (PATO: 0001163) in ‘‘blood’’ (UBERON: 0000178) with respect to ‘‘glucose’’ (CHEBI: 17234); this definition uses terms from the ontologies PATO24 for describing qualities, UBERON for Peter N Robinson Michael Baraister
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Smart Phenotyping. Better Genetics. Phenotyping apps that facilitate comprehensive and precise genetic evaluations. APPS SUITE INTRODUCTION UI_book_v11.indd 1 9/15/16 4:19 PM
https:// app.face2gene.com www.fdna.com
Caso 1 • Nacida a las 39 semanas con 1900 gr. small for gestation age • Movimientos fetales escasos decreased fetal movements • Retraso en de desarrollo neuroevolutivo. global developmental delay • Desmedro failure to thrive • Baja talla short stature • Al año inicia convulsiones afebriles seizures • Microcefalia al nacer congenital microcephaly
Caso 2 • Niña sudamericana adoptada. • retraso desarrollo moderado. Cognitive Impairment • retraso del lenguaje delayed speech and language development • baja talla, no se conocen datos familiares short stature • prominencia de los pulpejos de los dedos prominent finger tip pads • clinodactilia del 5º dedo. Clinodactyly • Of The 5th Finger • riñón en herradura. Horseshoe Kidney
4 www.FDNA.com We Take Pa2ent Privacy Seriously
Face2Gene uses advanced technologies to protect patient information. • All patient photos are converted into a de-identified mathematical facial descriptor (phenotype sequencing). This de-identified sequence is used for the Face2Gene analysis while the original photo is encrypted and stored on separate disk volume, accessible only to you and other healthcare providers whom you actively approve. See data sharing policy for more information • Compliant with HIPAA and all European Union (EU) privacy rules and standards • No need to change your patient consent form SECURITY AND PATIENT PRIVACY SECURITY
Detect Dysmorphic Features & Reveal Related Traits • Detection of dysmorphic features from facial photos • Automatic calculation of anthropometric growth charts • Suggestion of likely phenotypes to assist in feature annotation Discover Relevant Genetic Disorders • Matching of phenotypes to genetic disorders based on gestalt • Refine relevance of genetic disorders based on deep phenotyping • Supports over 7,500 genetic disorders Access Best-in-class Resources • Fully integrated London Medical Database • Unique visualization tools for phenotype analysis • Comprehensive real-world phenotype- genotype data Enhanced patient evaluation with deep phenotyping CLINIC 4 Analysis 100%Carrier 2 2 , MLL3, KDM6a SSSSSSSWWWWWWWWIIIIIIPPPPPPPEEEEEEE TTTTTTTOOOOOO MMMMMMMMMMMMMMMMOOOOOOVVVVVVVEEEEEEE SSSSSSSPPPPPPPLLLLLLIIIIIITTTTTTT UI_book_v11.indd 4 9/15/16 4:19 PM
Set Up Enhanced Case Reviews with Your Team • Define your own review teams • Collaborate on cases • Increases visibility to diagnostic dilemmas Give & Receive Clinical Feedback • Share cases in secure group forums • Comment on other cases and receive feedback on your cases • Community created solely for health care professionals Submit Cases to the Unknown Forum’s Expert Review Panel • Easily submit cases from Face2Gene Clinic • Get feedback from the top experts in the field • Submitted cases can be considered for molecular testing grants Collaborative case review for diagnostic dilemmas FORUMS 5 100% HIPAA & EU COMPLIANT UI_book_v11.indd 5 9/15/16 4:19 PM
Review Photos & Features • Access detailed feature photos and descriptions • Review syndromes most relevant for each feature • Over 20,000 feature photos Search for Syndromes • Easy access to detailed syndrome descriptions • Review syndromes most relevant for each feature • Over 10,000 syndromes with detailed references Up-to-date Content Through Genetics Community Curation • Updated by respected members of the genetics community • Easily contribute relevant updates • Integrated with the Face2Gene community Trusted dysmorphology RY|LMD UNLIMITED ACCESS for $71/mo $10/mo
Communicate Efficiently with Clinicians • Easily integrated APIs (Plug & Play) • Two-way digital correspondence channel with clinicians Access Patients’ Phenotype Data—Securely • Obtain a rich phenotype with your patient’s detected and annotated HPO features • Review a short list of plausible syndromes with OMIM IDs • Sift through a list of the most clinically relevant genes Improve Variant Prioritization & Filtering • Phenotype sequencing adds a dimension to variant filtering • Prioritize variants using HPO terms provided directly from clinicians • Supports most ontologies NEW DOB AGE GEST. AGE GENDER ETHNICITY Better variant analysis through deep phenotyping
Teach Your Students Dysmorphology • Share real cases with your team or students • Help your students learn to recognize dysmorphic traits • Create your own curriculum by sharing your cases Learn to Recognize Dysmorphic Features & Syndromes • Learn from hundreds of real cases • Master feature and gestalt identification • Access additional educational content through Face2Gene Library | London Medical Databases Test your Dysmorphology Skills • Put your dysmorphology skills to the test with dozens of challenges • Create tests for your team and students • Ideal for workshops, schools and teams Interactive dysmorphology training on any device ACADEMY

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