La Genética Clínica en Pediatría. Enfoque práctico para el diagnóstico

1. 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

2. El Diagnóstico en el Área
de la Genética Clínica y
Dismorfología
Enfoque práctico

3. Soc
Fa
F
Sociedad Española de
Asesoramiento Genético
Asociación Española en
Diagnóstico Prenatal
AEDP
Sección de Genética Clínica
y Dismorfología A.E.P

4. La Medicina Clínica es un proceso
básicamente intelectual:
todos los datos se integran
formando un perfil con significado
Jean Aicardi

5. ¿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

6. ¿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.

7. Primer enfoque:
• La premonición, el olfato,…

8. 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.

9. 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

10. Pediatra de
Atención Primaria
Neonatólgo
Neuropediatra
Endocrinólogo
Infantil
Gastro, Nutrición y
Metabolismo
“No relegar la dismorfología en una torre de marfil”

11. Piensa en verde…
Piensa en dismorfología.

12. 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

13. 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.

14. CytoScan®
Dx Assay
To aid in the diagnosis of developmental delay and intellectual disability
Unrivaled performance. Results that matter.
For In Vitro Diagnostic Use

15. 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

16. 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

17. Buen enfoque:
Árbol Genealógico
Exploración
Clínica “con
ojos de
dismorfólogo”
y resto de
hallazgos
Piedra angular

18. 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 re-
vealed 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 ab-
normalities, 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 dis-
abilities, 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 muta-
tions. 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

19. 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

20. 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

21. 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

22. 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 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 healthy
recipients at the two-cell stage, impli-
cating disruption of very early devel-
opmental 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 blasto-
cysts and fetal growth that mimic
many aspects of in vivo dietary and
inflammatory insults (12), suggest-
ing that endogenous cell stress may
be a common pathway driving ad-
verse impacts on offspring. Although
the protocols implemented in ani-
mals are more aggressive than clin-
ical IVF, emerging data suggest that
in IVF-conceived children, blood pres-
sure 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 modi-
fication of the embryo’s epigenome.
A dynamic phase of epigenetic re-
modeling 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 epige-
netic 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 his-
tone 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 con-
ception (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 im-
printed 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 quick-
ly to the blastocyst stage (22). Sex-
dependent transcriptional differences
in molecular pathways controlling
glucose metabolism, protein metab-
olism, DNA methylation, and epige-
netic 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 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, a
protein-deficient diet for 3.5 days be-
fore 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 epi-
genetic marks are not cleared, allowing the pos-
sibility 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 inher-
itance 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 ma-
ternal 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 precon-
ception 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 em-
bryos (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 disor-
ders 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 meta-
bolic 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, at-
tributable 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 smok-
ing 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 exam-
ple, male mice fed a low-protein diet fathered
offspring with decreased hepatic cholesterol esters
and altered hepatic expression of lipid and cho-
lesterol biosynthesis genes, associated with al-
tered epigenetic marks (46). Male mice born to
undernourished mothers sired offspring with
reduced birthweight and impaired glucose toler-
ance (47). Other rat studies showed that nutri-
tional cues from the father result in female
offspring with impaired metabolic health (48),
associated with altered gene methylation and
transcriptome changes within pancreas and adi-
pose tissues (48, 49). Rats exposed to the environ-
mental 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 envi-
ronmental 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 em-
bryo 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 pa-
ternal DNA replication following fertilization
as well as activation of paternal genome tran-
scription in the early embryo. Whereas the
paternal protamines are replaced by maternal
histones in the first 4 to 6 hours after fertil-
ization, 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 devel-
opmental 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.

23. 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

24. 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

25. El niño de la enfermedad sin nombre

28. 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

29. 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

30. (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 cli-
nicians, 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 pres-
ent,” 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 gener-
al 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

32. [Dr. Smith] didn’t want to
relegate dysmorphology
to some ivory tower.
Roger E. Stevenson, MD
“Every Pediatrician should be
a dysmorphologist”

33. Herramientas Para Pediatras
en el área de la Genética Clínica y Dismorfología

35. ¿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

36. 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 muta-
tion in ARFGEF2 (OMIM number, 608097; chro-
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)
Respiratory
failure
Polyvalvular
dysplasia and
aortic dilatation
Hypermobility
Periventricular
heterotopia (dark gray)
or seizures only (light gray)
I
II
III

37. Identify Rare Diseases with a Selfie
How Machine Learning Is
Revolutionizing the Diagnosis of Rare
Diseases
Dekel Gelbman
Moti Shniberg

40. 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 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 a
structured, comprehensive, and well-defined set of over
11,000 classes (terms) that describe phenotypic abnormal-
ities 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 spec-
ificity of the term and represents a key component of most
of the aforementioned algorithms.23
Additionally, compu-
tational 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

41. Hipertelorismo

42. Orejas de implantación baja

43. 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

44. https://
app.face2gene.com
www.fdna.com

45. 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

46. 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

47. 4 www.FDNA.com
We Take Pa2ent Privacy Seriously

48. 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

49. 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

50. 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

51. 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

52. 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

53. 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