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.

25 al 28 ABRILMADRID 2017

Congreso Interdisciplinar enGenética Humana

SECRETARÍA TÉCNICAT 34 93 221 22 42 F 34 932217005 www.geyseco.es [email protected]ÓN DE CONGRESOS Y SOCIEDADES

www.geneticahumana2017.org

Sociedad Española de Farmacogenética y Farmacogenómica

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 futuro

El Diagnóstico en el Área de la Genética Clínica y

Dismorfología

Enfoque práctico

25 al 28 ABRILMADRID 2017

Congreso Interdisciplinar enGenética Humana

SECRETARÍA TÉCNICAT 34 93 221 22 42 F 34 932217005 www.geyseco.es [email protected]ÓN DE CONGRESOS Y SOCIEDADES

www.geneticahumana2017.org

Sociedad Española de Farmacogenética y Farmacogenómica

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 futuro

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

OMIMPOSSUM

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 unproblema!.

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 enServicio 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 Genetics (ACMG), and the International Collaboration for Clinical Genomics (ISCA/ICCG), a chromosomal microarray analysis (CMA) is considered the first-line genetic test to aid in the diagnostic evaluation of ID when patient history and physical examination do not provide an obvious syndrome diagnosis.5, 6, 7

These guidelines for CMA to replace traditional karyotype and fluorescence in situ hybridization (FISH) as first-line genetic testing for unexplained ID are due to its greater sensitivity, higher resolution, genome-wide capability, and greater diagnostic yield.6 CytoScan Dx Assay is the first CMA to receive FDA clearance and CE mark.

Results that matter for the best in patient care

CytoScan® Dx Assay is the first FDA-cleared whole-genome

diagnostic test to aid physicians in identifying the underlying

genetic cause of developmental delay, intellectual disability,

congenital anomalies, or dysmorphic features in children.

2

Whole-genome coverage for today and tomorrow

The high-density, whole-genome CytoScan® Dx Array includes 2.69 million markers for copy number (CN) analysis, with 750,000 bi-allelic SNP probes and 1.9 million non-polymorphic markers. CytoScan Dx Assay with its whole-genome coverage delivers higher resolution than karyotyping and more comprehensive coverage than FISH.

3

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 Research Review 8(3):117–134 (2002).

5. Michelson D. J., et al. Evidence report: genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 77(17):1629–1635 (2011).

6. Miller D. T., et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. American Journal of Human Genetics 86(5):749–764 (2010).

7. Manning M., Hudgins L. Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genetics in Medicine 12(11):742–745 (2010).

8. Chelly H., et al. Genetics and pathophysiology of mental retardation. European Journal of Human Genetics 14:701–713 (2006).

9. Roelfsema J. H., et al. Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. American Journal of Human Genetics 76(4):572–580 (2005).

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 – outercanthal distance 11 cm; 497th percentile), down slant ofpalpebral fissures, short nose with anteverted nostrils, widephiltrum and thin upper lip. In the past, the chromosomalanalysis in peripheral blood lymphocytes had revealed a46,XY(90%)/47,XYY(10%) mosaic. Molecular analysis re-vealed a missense mutation in exon 3 (614 G4T) thatcauses a change in the residue 205 from Ser to Ile. The samemutation was found in his mother and in her three sisters,who have mild phenotypical signs (hypertelorism, widow’speak).

The patients in whom a mutation was not found (37individuals) present with various combinations of shortstature, facial appearance (hypertelorism, small nose withanteverted nares, broad nasal bridge, ptosis, strabismus),hand abnormalities and genitourinary manifestations(Table 2). Most clinical signs were concordant with thediagnosis. Short stature (34 out of 37 patients), hypertelor-ism (36 out of 37), hand abnormalities (short and broadhands, clinodactyly, camptodactyly) (28 out of 37) and thepeculiar scrotal morphology (28 out of 37) were displayedby most of patients. Cryptorchidism was found in eightindividuals and hernias in five. Interphalangeal webbingwas recorded in 19 out of 37 patients. Only six hadpalpebral ptosis. A total of 12 patients presented severemental retardation.

DiscussionAt present, the diagnosis of AAS is primarily based onclinical criteria. In typical cases, the phenotype of affected

males is characterised by genital anomalies (shawl scrotum,cryptorchidism), short stature, distinct craniofacial ab-normalities, brachydactyly with interdigital webbing andjoint laxity. A broad range of mild developmental delay orlearning difficulty has occasionally been reported. Never-theless, in affected males the phenotype is variable as theymay exhibit different combinations of associated features.In general, carrier females may have a milder phenotypethan males, showing minor and mild clinical signs,possibly depending on the pattern of X-chromosomeinactivation. Despite the presence of clinical inclusioncriteria and the advances in the molecular pathogenesis ofAAS, disease-causing mutations have been identified inonly a small number of patients. Possibly, both thevariability of phenotype and the genetic heterogeneityaccount for a clinical overdiagnosis. Short stature withhypertelorism and brachydactyly represent a relativelyfrequent association in clinical dysmorphology. Moreover,AAS patients are often referred with various degrees ofmental handicap (mild mental retardation, learning dis-abilities, attention-deficit disorders) and, as the majority ofcases are sporadic, X-linked inheritance may be question-able.

In the present study, we performed mutation screeningof the FGD1 gene in 46 male patients referred with theclinical diagnosis of AAS. This is the largest series reportedto date. We identified eight mutations, all novel, includingfour deletions, one insertion and three missense muta-tions. The majority of the mutations identified were foundto be unique to a single family. The only exception is the528insC, occurring in exon 3, which was detected in twoindependent families (Belgian and Italian). The deletionsand the insertion mutations are all predicted to result in aframeshift, which leads to a truncation of the protein. Thethree missense mutations, S205I, E380A and R443H, occurin exons 3, 5 and 6, respectively. They all occur at theN-terminal half of the protein, encompassing the proline-rich region and the SRC domains, upstream from the firstPH domain. The 614 G4T mutation, detected as a singleobservation in patient 25, changes the S205 residue (S205I)located in the proline-rich N-terminal region, a protein-interaction module involved in the localisation of FGD1protein to the subcortical cytoskeleton and Golgi com-plex.14 Notably, in the context of proline-rich regions,serine residues frequently flank proline, and are consideredto represent, through phosphorylation, a structure formodulation of the protein function.15 The E380A andR443H changes were found in patients 26 and 63,respectively, and subsequently detected in other affectedand carrier family members. These two amino-acid changesoccur in the conserved Rho/RacGEF domain. In particular,E380 is a residue that resides within the predicted SRC1and R443 is adjacent to the predicted SRC2 regions.3 Boththese residues were conserved at a comparative sequenceanalysis of the FGD1-related protein.16 All the base

Figure 2 Front and profile of patient 25 (a and b), over-riding scrotum (c) and interdigital webbing (d).

Genotype–phenotype correlation in AASA Orrico et al

21

European Journal of Human Genetics

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 manosTambién pies y genitales

la capacidad del observador está directamente relacionada por su conocimiento y experiencia

YVES LACASSIE, 2015

Problemas diagnósticos en Dismorfología2. 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


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


3. Problemas en el área de la genética II:

b) Pleiotropismo c) Abiotropismod) Mecanismos ambientales que simulan mecanismo genéticoe) de herencia no tradicionalf) Mosaicismo gonadal

Problemas diagnósticos en Dismorfología4. 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, impairedglucose tolerance, and altered in-sulin signaling compared to natu-rally conceived controls (9). Morerapid postnatal growth and fat de-position after IVF conception areassociated with altered gene ex-pression 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 em-bryos are transferred to healthyrecipients at the two-cell stage, impli-cating disruption of very early devel-opmental events. Thus, at least inmice, conception by IVF alters laterplacental and fetal development,growth trajectory after birth, andmetabolic parameters and behav-ior in adult life. In vitro–culturedembryos show changes to blasto-cysts and fetal growth that mimicmany aspects of in vivo dietary andinflammatory insults (12), suggest-ing that endogenous cell stress maybe a common pathway driving ad-verse impacts on offspring. Althoughthe protocols implemented in ani-mals are more aggressive than clin-ical IVF, emerging data suggest thatin IVF-conceived children, blood pres-sure and fasting glucose are higher(13), and vascular dysfunction canbe evident (14).

Epigenetic reprogrammingat conception

The periconception influences ondevelopment are believed to occurthrough environment-induced modi-fication of the embryo’s epigenome.A dynamic phase of epigenetic re-modeling begins at fertilization,when most epigenetic marks arecleared from the oocyte and spermgenomes before fusion of the chromatin at syn-gamy, and is completed just before implantationwhen remethylation of the embryonic genomeoccurs (15). Altered methylation of cytosine res-idues, or loss of parental-specific imprintedmarks,may be attenuated by the chromatin structure,including nucleosome positioning, and alteredhistone acetylation or assembly, whichmodulatethe availability of DNA for transcription. Epige-netic marks are carried forward into daughtercells, where despite further modification by thedevelopmental program, they permanently affectgene expression in resulting adult tissues (15).Maternal nutrition at conception is a major

influence on resetting of the epigenome in theearly embryo—a compelling example is epige-netic control of the agouti viable yellow (Avy)locus, which determines coat color in mice andis highly sensitive to methyl groups in the diet(3, 16). DNA methylation in human infants was

recently associated with seasonal variation indiet (17); similar epigenetic marks were presentin different tissues, indicating that persistentsystemic changeswere 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 ofthe epigenetic regulator Txnip and enriched his-tone acetylation at its promoter, which are main-tained into adulthood (10). Vascular dysfunctionevident in IVF-conceived mice is associated withaltered methylation of genes in the aorta (11)—but causal relationships betweenepigenetic changesand phenotypic alterations have not been dem-onstrated and are difficult to prove.Specific classes of elements in the genomeappear

particularly sensitive to epigenetic dysregulation,including transposons (which control expressionof the Avy locus) and genomically imprinted genes,

which normally survive the globalerasure of epigenetic marks at con-ception (16). Although the impact ofIVF on transposons is not known,there is an increased incidence ofimprinting disorders in IVF children,suggesting that maintenance of im-printed genes may be disturbed (20).However, genome-wide analysis ofmethylation shows no epigeneticchanges attributable to IVF (21).Intriguingly, males are consistent-

ly more vulnerable to most dietary,culture-induced, and physiochemicalmodels of metabolic programming(2, 5, 6, 8, 12). Female embryos con-sume relatively more glucose, andmale embryos develop more quick-ly to the blastocyst stage (22). Sex-dependent transcriptional differencesin molecular pathways controllingglucose metabolism, protein metab-olism, DNA methylation, and epige-netic regulation (23) likely causesex-specific differential responses toenvironmental insults.

Ex ovo omnia: All things comefrom eggs

Effects on oocytes contribute to theeffects of maternal environment onoffspring phenotype. Studies to iso-late preconception effects from laterpregnancy demonstrate that mater-nal nutrition during oocyte matura-tion influences offspring phenotype(Fig. 2). In sheep, maternal over-feeding generates offspring that ac-cumulate fat (24), while in mice, aprotein-deficient diet for 3.5 days be-fore conception leads to hyperten-sion (25).Developing oocytes are suspended

in follicular fluid that provides aunique nutritional environment whichreflectsmaternal physiological states—for instance, adiposity (26). As the

oocytematures, it accumulates epigeneticmarks,both on histones and DNA, until the final phasesof maturation before ovulation. Although gen-erally these marks are erased at conception,there is evidence that at some loci, oocyte epi-genetic marks are not cleared, allowing the pos-sibility of transgenerational inheritance. As wellas maternally imprinted loci, epigenetic marksestablished in response to environmental cuesmay also be resistant (3, 27). This is difficult todefinitively demonstrate, because the complex-ity of the human genome makes it impossible toclearly distinguish genetic and epigenetic hered-ity (27).Attributing effects to transgenerational inher-

itance requires experiments in inbred geneticbackgrounds, and the use of oocyte transfer orcross-fostering to ensure that effects are trulytransmitted 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

Micronutientsimpact DNA

Lipid & sugars altermitochondrial

activity

Dietary fat increaseslipid droplet size

& composition

B

A

Altered diet, inflammation, toxins

Lipid droplets

Chromatin

Mitochondria

Fig. 2. Maternal nutrition affects oocyte provisioning. (A) The maternalenvironment 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. ChromosomalDNA 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.

deficiency is convincing, because embryos frommice fed a zinc-deficient diet for just 5 daysbefore conception generated smaller fetuses proneto neural tube defects even after embryo transfer(29), and methylation of histones and chromatinwas decreased in oocytes and retained in the ma-ternal pronucleus after fertilization (30). Increasedoocyte lipid content and cellular stress are alsoevident in mouse studies showing poor embryoand fetal development after maternal precon-ception diabetes or obesity (31, 32).Maternal nutritional influences on oocyte

mitochondria are emerging as a pathway of lastingconsequence to offspring (33). Embryogenesis is anenergy-demanding process, and oocyte-derivedmitochondria are required to support blastocystformation (34). Alterations in maternal dietaryprotein affect mitochondrial localization anddampen mitochondrial activity in two-cell em-bryos (35) associated with later disturbances tofetal brain gene expression (36). In diabetic orobese mice, oocyte mitochondria fail to supportnormal embryo development (31, 32). Promis-ingly, these defects are modifiable by diet—oocytequality, mitochondrial function, and fertility inaged mice can be restored by caloric restriction(37) or an omega-3–enriched diet (38).

Paternal programming—anew consideration

Paternal smoking, age, and occupational chem-ical exposure are well known to be linked withincreased risk of cancer and neurological disor-ders in children (39, 40). It is less well appre-ciated that the father’s body mass has a greaterimpact than the mother’s on body fat and meta-bolic measures in prepubertal children (41). Aswell as sperm DNA damage, in some instancesthere is accumulating evidence for pathways ofpaternal transgenerational epigenetic effects, at-tributable to sperm and seminal fluid (42, 43).Interest in paternal epigenetic contributions stems

from human epidemiological studies, relating agrandfather’s food availability to mortality ingrandsons (44) and associating paternal smok-ing with increased body mass index in malechildren (44). Paternal obesity is associatedwith changes to methylation in cord blood fromoffspring, at the demethylated region of IGF2andpossibly other imprinted genes (45). Althoughthis can be interpreted as evidence for anepigenetic pathway, as for all human cohortstudies, the possibility of shared genetic ornongenetic programming contributions cannotbe discounted (27).Rodent models have been developed to assess

epigenetic transmission of metabolic and otherphenotypes via the paternal line (42). For exam-ple, male mice fed a low-protein diet fatheredoffspring with decreased hepatic cholesterol estersand altered hepatic expression of lipid and cho-lesterol biosynthesis genes, associated with al-tered epigenetic marks (46). Male mice born toundernourished mothers sired offspring withreduced birthweight and impaired glucose toler-ance (47). Other rat studies showed that nutri-tional cues from the father result in femaleoffspring with impaired metabolic health (48),associated with altered gene methylation andtranscriptome changes within pancreas and adi-pose tissues (48, 49). Rats exposed to the environ-mental toxin vinclozolin during development inutero have impaired spermatogenesis, which istransferred to male offspring (50). When malemice were conditioned to respond to a specificodor associated with a fear stimulus and thenmated, their offspring inherited increased behav-ioral responses to the same odor (51). Similartransmissible effects are seen in the offspring offathers exposed in early life to stress imposed bymaternal separation (52). These intriguing studiesraise the exciting prospect of specificity inpaternal transmission and the possibility of tar-geted transmission of acquired characteristics;

but to date, no biologically plausible mechanismhas emerged.

Fathers transmit DNA modificationsto offspring

Genetic and epigenetic transmissionmechanismsmay be intertwined in sperm to transmit envi-ronmental exposures to the next generation (Fig.3). Sperm development involves extensive DNAstrand repair and chromatin remodeling in whichhistones are largely, but not completely, replacedby protamines (43). Both sperm nucleosome andhistone-bound regions are conserved amongmammalian species at loci of developmentalimportance—including promoters for early em-bryo development and imprinted regions (53).Compared with protamine-bound regions, genesin histone-bound regions appear more susceptibletoDNAdamage (54) due to smoking, obesity, andaging (55), compounded by the incapacity ofsperm to repair DNA damage due to oxidativestress (56).Histone-bound regions appear vital for pa-

ternal DNA replication following fertilizationas well as activation of paternal genome tran-scription in the early embryo. Whereas thepaternal protamines are replaced by maternalhistones in the first 4 to 6 hours after fertil-ization, the retained paternal histones are notreplaced; therefore, epigenetic marks to thesehistones are likely inherited by the embryo (57).Expression of SIRT6, a class III histone deacety-lase, is regulated by metabolic state and isdecreased in the testes germ cells of mice withdiet-induced obesity, associated with increasedDNA damage in transitional spermatids as wellas mature sperm (58). This may explain whysperm from obese fathers can alter the devel-opmental capacity of the embryo in vitro, alter-ing rates of mitosis and early differentiationevents (59), resulting in reduced pluripotencyand metabolic function.

758 15 AUGUST 2014 • VOL 345 ISSUE 6198 sciencemag.org SCIENCE

Environment/lifestyle insultToxins

Endocrine disruptersSmokingObesity

Altered geneexpressionin zygote

Impaired embryo growthand health of offspring

Insult affectssperm duringdevelopment 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 spermfunction, imparted either during spermatogenesis or epididymal transit, and pathways for impact on the development of the embryo.


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

2.2 Fundamentals of NGS Platforms

Generally, NGS is composed of four steps; DNA isolation, target sequences enrich-ment, sequencing by an NGS platform, and bioinformatic analysis (Fig. 2.1 ). During the analysis, fragment sequences are aligned and variant calls are obtained and pri-oritized by applying various fi lters to identify the potentially causative gene(s). An optional report generation step exists in clinical laboratories after potential caus-ative variants are Sanger-confi rmed. A detailed description of the principles and platforms of NGS is mentioned in the next sections.

Massively parallel sequencing is one common feature shared by almost all cur-rent NGS platforms, following clonally amplifi ed single DNA molecules, sepa-rated in a defi ned microchamber (called fl ow cells, fl owchips, or picotiter plate; Voelkerding et al. 2009 ). One exception to this is Pacifi c Biosciences which uses single-molecule sequencing technology without clonal amplifi cation (Eid et al. 2009 ). In contrast, Sanger sequencing has orders of magnitude lower throughput by sequencing products produced in individual sequencing reactions. NGS is fi rst carried out by fragmenting the genomic DNA into small pieces, usually in the range of 300–500 bps (Borgström et al. 2011 ). Then, platform-specifi c adapters are ligated to the ends of the DNA segments, permitting their attachment and sequencing. In the NGS execution, sequencing results are obtained by reading optical signals during repeated cycles from either polymerase-mediated fl uores-cent nucleotide extensions of four different colors (e.g., Illumina’s HiSeq system), or from iterative cycles of fl uorescently labeled oligonucleotide ligation (e.g., ABI

Fig. 2.1 Schematic of the next-generation–sequencing workfl ow. Following DNA isolation, target sequences are enriched by amplifi cation (RainDance) or capture-based methods, sequenced by a next-generation platform (HiSeq 2500), and analyzed by open source or commercial software package, such as NextGENe from Softgenetics, to obtain the variants that will then be fi lter priori-tized to identify the potentially causative gene(s)

2 A Survey of Next-Generation–Sequencing Technologies

80

Fig. 8.1 Whole exome sequencing workfl ow. 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 fi le is the raw data which contains the base calls and qual-ity score per base. The major step in the analysis is the process of aligning the reads to the human genome, which often takes few hours to complete. To assess the quality of exome sequencing QC parameters, which include the number of reads aligned successfully and the depth of coverage percentage on specifi c target region, are checked. The alignment procedure yields multi-sequence alignments in BAM format. Next, variants are determined by comparison to an indexed reference sequence. Statistical scores are computed to reduce false positive errors due to false alignments and sequence homology artifacts. This is followed by variant annotation-based frequency, muta-tion type, and other functional criteria. The combination fi ltering parameters along with inheri-tance modeling (if available) is then performed to narrow the number of causative mutations to a manageable number for further investigation. Knowledge databases (HGMD, OMIM) provide functional information that is helpful for interpretation. In clinical laboratories, potential causative variants are Sanger-confi rmed and a report is generated after review

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

https://es.wikipedia.org/wiki/EEAD

https://es.wikipedia.org/wiki/Consejo_Superior_de_Investigaciones_Cient%C3%ADficas

https://es.wikipedia.org/wiki/Zaragoza

https://es.wikipedia.org/wiki/Cartuja_de_Aula_Dei

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

The Elements of Medical Genetics 317

Gorlin (1923−2006), M. M. Cohen (1935−2007), John Opitz and Judith Hall from the United States and Canada, and Robin Winter (1950−2004)and Dian Donnai from Britain (Fig. 11−2).

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)

F I G U R E 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, 2004, for an obituary). ([A] courtesy of the American Journal of Medical Genetics/Elsevier; [B] and [C] courtesy of Judith Hall; [D] courtesy of Marcus Pembrey.)




(A) (B)

(C) (D)





(A) (B)

(C) (D)


understand something about the morphol-ogy of structures they see. “He didn’t wantto relegate dysmorphology to some ivorytower,” Dr. Stevenson recalls.

A compendium on short stature, ofwhich Dr. Smith was an author, appearedin the Journal of Pediatrics [1965]. It wasthe forerunner to his many well-knownbooks, including Recognizable Patterns ofHuman Malformation, RecognizablePatterns of Human Deformation, Growthand Its Disorders, Introduction to ClinicalPediatrics, and Biologic Ages of Man.Another book, The Child with Down’sSyndrome (Mongolism): Causes, Char-acteristics and Acceptance for PersonsConcerned with His Education and Care,was written specifically for parents. Thisbook was also innovative, recalls Dr. Jones,because “there wasn’t much written forparents back then.”

Dr. Smith was the first to recognize tri-somy 13 and the second researcher toreport on trisomy 18. He was also involvedin discovery of a number of conditionsassociated with birth defects, lending hisname to several, including Aase-Smith,Smith-Lemli-Opitz, and Marshall-Smithsyndromes.“Smith typically put other peo-ple first, so many other conditions he first

described do not bear his name,” notesJohn Graham, MD, Director of ClinicalGenetics and Dysmorphology at Cedars–Sinai Medical Center in Los Angeles,California, and another of Dr. Smith’s fel-lows. These conditions include Klinefeltersyndrome and Turner syndrome. Severalother syndromes were discovered using Dr.Smith’s methodology, Dr. Graham adds.

Together, Drs. Smith and Jones werethe first North Americans to describe fetalalcohol syndrome in 1973, after identifyinga pattern craniofacial, limb, and cardiovas-

cular defects associated with prenatal onsetgrowth deficiency and developmental delayin 8 unrelated children of 3 ethnic groups,all born to mothers who were alcoholics.

The Workshop’s BeginningThe Smith Workshop emerged during a1979 teratology meeting and was inspiredby frustration over the lack of attention tomalformation, Dr. Graham recalls. At agathering in an airport bar, Dr. Smith

lamented the dearth of such discussion andinvited both Dr. Graham and Dr. Jones toenvision their ideal meeting. He handed anotepad to Dr. Jones, Dr. Graham notes.

“What we came up with was a work-shop in which all attendees submitabstracts and participate in discussion.There would be only 100 participants whowould meet for about 4 days to think aboutmorphogenesis and malformation,” Dr.Graham recalls. “Dave asked Ken to organ-ize the first meeting, and I agreed to do itthe following year. Dave had already passed

away by then.”The first workshop and the 30 subse-

quent ones have been opportunities for cli-nicians, researchers, and trainees “to bringthe most important thing they are doingrelated to understanding abnormalities ofstructure to others in the field,” says Dr.Jones. “We comment and learn from eachother in an informal way.” Limiting partic-ipation to 125–130 people allows for suchinteraction. “This gathering isn’t meant tobe about passive listening,” he adds,explaining that the term “workshop”underscores the central importance of allattendees’ contributions.

The chairs of the 2010 meetingemphasize this point. The meeting isunique because all participants presenttheir work and debate, says SonjaRasmussen, MD, Senior Scientist at theCenters for Disease Control andPrevention, and Michael Bamshad, MD,Professor of Pediatrics at the University ofWashington. “At other meetings, you’reoften there either to learn or just to pres-ent,” Dr. Rasmussen explains. “The Smithmeeting is small so people can feel com-fortable discussing controversial topics thatnon-Smith attendees aren’t interested in.”

The meeting has developed a reputa-tion for mentoring fellows and youngerpeople in the field. “The meeting in gener-al is good for fellows because of its interac-tivity. New fellows eat with authors of keybooks on genetic disorders,”Dr. Rasmussenexplains. Praising the way the meeting pro-motes mentorship, she recalls her firstworkshop, at which she sat between theauthors of 2 texts that she had used in herfellowships. “I still turn to them for guid-ance,” Dr. Rasmussen notes. “This sort ofthing honors the legacy of David Smith. It’san example of how we carry on his work.”

The 2010 LineupEach year, the workshop’s organizers iden-tify “hot topics” as themes for the meeting.For 2010, the themes were race, ethnicity,and birth defects; disorders of sensory per-ception; novel strategies to understand thecauses and mechanisms of birth defects;and adults with dysmorphic syndromes.

viii

RESEARCH UPDATE CONTINUED

The Smith meeting is small so people canfeel comfortable discussing controversial

topics that non-Smith attendees aren’tinterested in.—Sonja Rasmussen, MD

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 Pediatrasen el área de la Genética Clínica y Dismorfología

¿Porqué perder tiempo en la confección de un árbol genealógico en pediatría?

hay motivos….

XXXIICONGRESO

DE LA SOCIEDAD

VALENCIANADE

PEDIATRÍA

ALICANTE28 Y 29 DE ABRIL DE 2016

PALACIO DE CONGRESOS DE ALICANTECOLEGIO OFICIAL DE MÉDICOS DE ALICANTE

“El niño con patología crónica”

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/

n engl j med 376;6 nejm.org February 9, 2017570

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

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 muta-tion in ARFGEF2 (OMIM number, 608097; chro-mosome-map location, 20q13). Thoracic aortic dilatation is uncommon in infancy; it is reported most frequently in Marfan’s syndrome associat-ed with an FBN1 mutation (an abnormality that is often associated with severe mitral and tricuspid valve regurgitation) and in the Loeys–Dietz syn-drome, which is caused by mutations in TGFBR1and TGFBR2 (typically accompanied by arterial tortuosity).31 Most of the other syndromes asso-ciated with genetically triggered aortic disease, including Beals’ syndrome (also known as con-genital contractural arachnodactyly, associated with an FBN2 mutation), the vascular Ehlers–Danlos syndrome (associated with COL3A1 mutations), Turner’s syndrome, and the 22q11.2 deletion syndrome, occur in adults and older children. Depending on the severity of the mutation, there are rare cases of familial thoracic aortic dilata-tion in infants, although in all these conditions, the true rate of aortic dilatation among infants is poorly understood. As is the case in older children

and adults, aortic dilatation can occur in infants with bicuspid aortic valve.

Polyvalvular dysplasia, a striking feature of this case, is nearly always seen in patients with tri-somy 18 and is less common in patients with trisomy 13. The feature is consistently present in disorders of the Ras–mitogen-activated protein kinase (MAPK) pathway, which include Noonan’s syndrome, Costello’s syndrome, and the cardio-faciocutaneous syndrome,32 and is also present in neonatal Marfan’s syndrome and the Loeys–Dietz syndrome. Mutations in FLNA are also in-creasingly appreciated as a cause of thoracic aortic aneurysm and dissection and myxomatous poly-valvulopathy.23

Another geneticist had evaluated the patient’s mother for periventricular heterotopia, seizures, academic challenges, hypermobility, and a heart murmur, although echocardiography was not per-formed. The patient’s maternal grandmother and maternal half-aunt had seizures; the grandmother (but not the half-aunt) underwent MRI of the head, but neither family member underwent imaging of the heart. This familial pattern is highly sup-portive of X-linked dominant inheritance; how-ever, in the absence of male fetuses that died in utero or male infants that had severe disease, we cannot confirm this inheritance pattern.

Dr . T. Ber na r d K ina ne’s Di agnosis

Periventricular heterotopia due to an FLNA muta-tion and congenital alveolar dysplasia.

Dr . A ngel a E . Lin’s Di agnosis

X-linked periventricular heterotopia caused by an FLNA mutation.

Pathol o gic a l Discussion

Dr. Eugene J. Mark: A thoracoscopic biopsy of the lung was performed to obtain a diagnosis for the pulmonary disease. Histopathological examination of the lung tissue revealed areas of relatively normal cellularity alternating with areas of ab-normally high cellularity, which was apparent at low magnification (Fig. 4A). Interstitial thicken-ing was caused by proliferation of capillaries, which formed tortuous structures (Fig. 4B). Cap-illaries in alveolar walls at times lay parallel one

Figure 3. Three-Generation Pedigree.

The family history shows affected females in three generations — a pedi-gree 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 mem-bers. The arrow indicates the patient, who had growth retardation, hetero-topia, and pulmonary and cardiac abnormalities.

Heart murmur(echocardiogram not performed)

Respiratoryfailure

Polyvalvular dysplasia and

aortic dilatationHypermobility

Periventricularheterotopia (dark gray)or seizures only (light gray)

I

II

III

The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF NEWCASTLE on February 8, 2017. For personal use only. No other uses without permission.

Copyright © 2017 Massachusetts Medical Society. All rights reserved.

https://probandapp.com/tutorial/

Identify Rare Diseases with a Selfie

How Machine Learning Is Revolutionizing the Diagnosis of Rare Diseases

Dekel Gelbman

Moti Shniberg

https://news.developer.nvidia.com/identify-rare-diseases-with-a-selfie/

for the estimation of the true- and false-positive and thefalse-negative rates. We note that it is not informative tocalculate a true-negative rate across the entire HPO becauseeven if the CR process flags several hundred terms, the greatmajority of the over 10,000 HPO terms will be true nega-tives. We found that maximizing the overall F-score (i.e.,the harmonic mean of precision and recall) led to a meanF-score of 45.1% (i.e., a mean precision of around 60%accompanied by a mean recall of around 40%). In separateexperiments, we found that a CR run with parameters de-signed tomaximize theprecision ineachof the13categoriesachieved ameanprecisionof 66.8% (datanot shown).How-ever, we chose to use the annotations derived from theF-score procedure for the remainder of the analysis. Thecomplete setof annotations associatedwith the41commondiseases, including flags for true positives, false positives,and false negatives, can be found in Tables S1–S41.

A Common-Disease Phenotypic NetworkAs a first test of the medical validity of the HPO annota-tions for common-disease phenotypes, we visualized thenetwork of phenotypic similarity of a subset of 1,678 dis-eases, such as ‘‘nervous system disease’’ (DOID: 863) or‘‘respiratory system disease’’ (DOID: 1579), belonging to13 DO categories. 1,148 of the 1,678 diseases showed atleast one connection to another disease (phenotypic simi-larity score above a threshold of 2.0), and thus the finalCDN comprised 1,148 diseases. Phenotypic relationships

between these diseases are shown by the linking of allpairs of diseases exceeding the threshold similarity score(Figure 3). Although generated independently of the disor-der classes, the resulting phenotypic network clearly dis-plays clusters corresponding to the disease categories.We then constructed randomized phenotypic networks

as described in the Material and Methods and calculatedthe number of links between diseases from the same dis-ease category. We found that the observed correlationbetween network connections and disease class is highlysignificant (Figure S4). Thus, the phenotypic network ofcommon diseases, as defined by the HPO, is made up ofdense clusters of shared phenotypic features that showcharacteristic patterns of interconnections betweenselected areas of the phenotypic continuum, just as wehad previously observed for Mendelian diseases.2 Thehigh correlation between the computationally creatednetwork clusters and the manually curated disease classifi-cations provides further evidence that the automaticallycreated annotations are clinically meaningful and providea largely correct description of the disease in question.

Phenotypic and Genetic Overlap across ComplexDiseasesGWASs have been performed for a wide range of commondiseases and traits, and over 6,000 strong SNP associationsðp < 10"8Þ have been identified.35 Variation at multiplegenetic loci collectively influences the likelihood of

Human PhenotypeOntology

Title: ...Abstract

...MeSH terms:D012261D019851

SNPGene

HP:0003463HP:0007265

PMID HPO Annotations MeSHDisorder /

Trait

Commondisorder

Raredisorder

Commondisorder

Commondisorder

Gene|

Rare disorder|

Phenotype

associations

Bio-LarK CR

1

23

4

5

Figure 2. Overview of CR and Bioinformatic AnalysisThe analysis was performed in several major steps. (1) Bio-LarK was used to analyze the PubMed-MEDLINE 2014 corpus, which resultedin 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 wereused for producing disease models for each of the diseases. (4) Medical validation of the annotations was performed on the basis ofdisease, 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.

116 The American Journal of Human Genetics 97, 111–124, July 2, 2015

ARTICLE

The Human Phenotype Ontology:Semantic Unification of Common and Rare Disease

Tudor Groza,1,2,25 Sebastian Kohler,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 pheno-

typic 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 astructured, comprehensive, and well-defined set of over11,000 classes (terms) that describe phenotypic abnormal-ities seen in human disease.1,2 The HPO has been used fordeveloping algorithms and computational tools for clinicaldifferential diagnostics,3–5 for the prioritization of candi-date disease-associated genes,6–11 in exome sequencingstudies,6–10 and for diagnostics in clinical exomesequencing.11 In addition, the HPO has been used fortranslational research, including inferring novel drugindications,12 characterizing the proteome of the humanpostsynaptic density,13 analyzing Neandertal exomes,14

and other topics.15–22

The HPO project provides not only a standard pheno-type terminology but also a collection of disease-pheno-type annotations, i.e., computational assertions that adisease is associated with a given phenotypic abnormality.

The HPO currently provides over 116,000 annotations toover 7,000 rare diseases; for instance, the disease Marfansyndrome (MIM: 154700) is annotated with the HPOterms ‘‘arachnodactyly’’ (HP: 0001166), ‘‘ectopia lentis’’(HP: 0001083), and 46 others. The patterns and specificityof the annotations allow the information content (IC) ofeach term to be calculated; the IC reflects the clinical spec-ificity of the term and represents a key component of mostof the aforementioned algorithms.23 Additionally, compu-tational logical definitions are provided for HPO terms. Forinstance, the HPO term ‘‘hypoglycemia’’ is defined onthe basis of ‘‘decreased concentration’’ (PATO: 0001163)in ‘‘blood’’ (UBERON: 0000178) with respect to ‘‘glucose’’(CHEBI: 17234); this definition uses terms from theontologies PATO24 for describing qualities, UBERON fordescribing anatomy,25,26 and ChEBI for describing smallbiological molecules.27 These definitions are useful for anumber of applications, including cross-species phenotypecomparisons6,28,29 and computational quality control.30

1School of Information Technology and Electrical Engineering, University of Queensland, St. Lucia, QLD 4072, Australia; 2Garvan Institute of MedicalResearch, Darlinghurst, Sydney, NSW 2010, Australia; 3Institute for Medical and Human Genetics, Charite-Universitatsmedizin Berlin, AugustenburgerPlatz 1, 13353 Berlin, Germany; 4University of Applied Sciences, Wiesenstrasse 14, 35390 Giessen, Germany; 5Library, Oregon Health & Science University,Portland, OR 97239, USA; 6School of Paediatrics and Child Health, University of Western Australia, Perth, WA 6840, Australia; 7Institute for Immunologyand Infectious Diseases, Murdoch University, Perth, WA 6150, Australia; 8Office of Population Health Genomics, Public Health and Clinical Services Divi-sion, Department of Health, Perth, WA 6004, Australia; 9Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA 6008, Australia;10Telethon Kids Institute, Perth, WA 6008, Australia; 11Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704 Pozna!n, Poland; 12Depart-ment of Epidemiology and Public Health, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; 13Institute for Genome Sciences, Schoolof Medicine, University of Maryland, Baltimore, MD 21201, USA; 14Center for Biomedical Informatics and Information Technology, National Cancer Insti-tute, 9609 Medical Center Drive, Rockville, MD 20850, USA; 15Department of Physiology, Development and Neuroscience, University of Cambridge,Downing Street, Cambridge CB2 3EG, UK; 16The Jackson Laboratory, Bar Harbor, ME 04609, USA; 17Department of Genetics, University of Leicester,Leicester LE1 7RH, UK; 18European Bioinformatics Institute, European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cam-bridge CB10 1SD UK; 19Academic Department of Medical Genetics, The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia; 20Discipline ofGenetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW 2145, Australia; 21Genomics Division, Lawrence Berkeley NationalLaboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA; 22Max Planck Institute for Molecular Genetics, Ihnestrasse 63–73, 14195 Berlin, Germany; 23BerlinBrandenburg Center for Regenerative Therapies, Charite-Universitatsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; 24Institute of Bioin-formatics, Department of Mathematics and Computer Science, Freie Universitat Berlin, Takustrasse 9, 14195 Berlin, Germany25These authors contributed equally to this work*Correspondence: [email protected]://dx.doi.org/10.1016/j.ajhg.2015.05.020. !2015 The AuthorsThis is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

The American Journal of Human Genetics 97, 111–124, July 2, 2015 111

Peter N Robinson

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5 la genetica clínica en pediatria

Health & Medicine

Transcript of 5 la genetica clínica en pediatria