medical genitics

1. Medical Genetics

2. What is medical genetics?
⚫Anyapplication of genetics to medical practice
⚫Studyof inheritance of diseases in families
⚫Mappingof disease genes to specific locations on
chromosomes
⚫Analysis of molecular mechanisms through which genes cause
disease
⚫Diagnosis and treatment of disease
⚫Genetic counseling

3. Why is medical genetics important to
you?
⚫ Genetic diseases make up a
large percentage of the total
disease burden in pediatric
populations
⚫ Increasing number of
pediatricdeaths are due to
genetic disease in developing
countries
⚫ Better understanding of
disease process
⚫ Prevention
⚫ Treatment
Genetic
condition
Approximate
prevalence
Down syndrome 1/700 to 1/1000
Cystic Fibrosis 1/2000 to 1/4000
(Caucasian)
Fragile X
syndrome
1/4000 males;
1/8000 females
Neurofibromato
sis type 1
1/3000 to 1/5000

4. Why is making an accurate diagnosis
important?
⚫Allowsfor discussion of natural history, prognosis,
management, treatment, earlier/more frequent disease
screening, recurrence risk and prenatal diagnostic options,
and referral to advocacygroups or clinical trials
⚫Involvesrecognition of phenotypic signs,dysmorphology
exam, family historyand testing

5. Principles of Dysmorphology
⚫ Dysmorphology is the study of congenital
structural malformations or anomalies,
commonly called birth defects,(Dy) is quite a
young discipline in clinical genetics. Dysmorphic
syndrome (DS) includes a particular set of
developmental anomalies that create a recognizable
and consistent pattern of abnormalities. DS has a
known or assumed single aetiology.
⚫Malformation/Anomaly (primary defect)
⚫Basicalteration in structure of abody part usually occurring
by8 – 10 fetal weeks
⚫Example: Cleft lip, polydactyly

6. Major Anomaly
⚫Basic alteration in embryological development severe enough
to require intervention and which potentially has a long-term
impact medicallyand/or psychologically
⚫Ex:spina bifida,omphalocele,cleft lip/palate

8. Spina bifida is an NTD characterized by herniation
of meninges and spinal cord (Fig. 6, panel a:
myelomeningocele) or meninges only (Fig. 6, panel
b: meningocele). Lesion can be open or closed.
Hydrocephalus is a common complication,
especially among children with open
myelomeningocele.
Spina bifida

14. Key findings in spina bifida:
Location – level of the lesion; that is, lumbar spine (the most common location), followed by
sacral, thoracic and cervical.
Covering – open, non-skin covered (myelomeningocele) represents 90% of spina bifida; 10%
have a closed lesion (meningocele – containing only meninges and cerebral spinal fluid).
Size – can vary from single vertebral to multiple levels (thoracic-lumbar).

15. Diagnosis
Prenatal. Spina bifida might be diagnosed prenatally using
ultrasound, but distinguishing if the lesion is open or closed
can be challenging. Maternal serum screening might help
to determine an open versus a closed lesion. Use
programme rules (SOPs) to decide whether to accept
prenatal diagnoses without postnatal confirmation (e.g. in
cases of termination of pregnancy or unexamined fetal
death).

16. Postnatal. The newborn examination usually confirms the
diagnosis. Imaging (when available) can provide additional
information to characterize the location, extent and content
of the lesion, as well as the presence or absence of
frequently co-occurring brain findings (e.g. hydrocephalus,
Chiari II malformation).

17. Clinical and epidemiologic notes
Spina bifida is often an isolated, non-syndromic (~80%)
anomaly. Related findings include:
Chiari II malformation and hydrocephalus.
Hip dislocation, talipes, lower limb paralysis.
Loss of sphincter control, including neurogenic bladder.

18. Additional clinical tips:
Always look for additional anomalies and syndromes
(trisomy 18).
Occurs in OEIS complex (omphalocele–exstrophy of the
bladder–imperforate anus–spinal defects).
Review examinations, procedures and imaging – rare
conditions misdiagnosed as spina bifida include spina bifida
occulta, sacrococcygeal teratoma, isolated
scoliosis/kyphosis, and amniotic band syndrome.
Lipomeningo(myelo)cele is a rare type of spina bifida with
an overlying lipoma; many programmes do not include
lipomeningo(myelo)celes as an NTD.

19. Minor Anomaly
⚫Basicalteration in embrylogical and/or fetal development
which requires no treatment or can be,more or less,
corrected
⚫Ex:postaxial polydactyly,low-set ears, preauricular tag

21. Common multiple congenital anomaly
syndromes
⚫ Down syndrome
⚫Minor anomalies:sandal gap,small ears, singlepalmar crease
⚫Majoranomalies:Congenital heart defects, duodenal atresia, pyloric
stenosis
⚫ Trisomy18 Edward Syndrom
⚫Minor anomalies:small ears with unraveled helics,small mouth, short
sternum, short halluces (first toes)
⚫Majoranomalies:congenitalheart defects, omphalocele,missing
radius bone, diaphragmatic hernia,spina bifida
⚫ V
an derW
oude syndrome(AD) isaconditionthataffectsthe
developmentof theface.
⚫Major anomalies:cleft lip with or without cleft palate
⚫Minor anomalies:pits or fistulasof the lower lip

22. V
an derW
oude syndrome

25. Minor/Normal variant feature
⚫Low frequency(1% - 5%) congenital feature found in the
normal population or asanintegral part ofamultiple
congenital anomalysyndrome
Ex: simian line, 5th finger clinodactyly
, 2-3 toe syndactyly
,
epicanthal fold,accessory nipple

28. Comment on Anomalies
⚫Mostmalformation syndromeshavemore minor / normal
variant type of anomalies than major anomalies
Ex. Down syndrome

29. Comment on Anomalies
⚫ An anomalyis an anomalywhether it is major or minor;
which means theyeach carryequal diagnostic importance. In
fact, becauseminor anomalies are more numerous and often
overlooked, they
, as agroup, maybe potentiallypowerful
diagnostically
.

30. Syndrome
⚫Recurring pattern of structural defects and/or secondary
effects/defects that allow for secure recognition
⚫Combination of features most likely represents aspecific
etiology
⚫Example:Robertssyndrome

31. Robertssyndrome

32. Sequence
⚫Asituation where asingle event (usually undefined) leads to a
single anomaly(or situation) which hasacascading effect of
local and/or distant deformations and/or disruptions
⚫Ex: Potter, Pierre Robin,amniotic bands
⚫Sequences usuallyinfrequentlygenetic, but can be
incorporated aspart of the features of asyndrome

33. Sequence Scenario
Amn. Bands
Potter/Oligo Pierre Robin
seq
Oligohydramnios Micrognathia Bands
Pulmonary hypoplasia Glossoptosis Constrictions
Jt contractures Cleft palate Fusions
Abn. ear cartilage Low-set ears Amputations
Lower inner eye
folds
Cleft lip/palate
Prom. Nasal tip Omphaloceles

34. Oligohydramnios is when you have low amniotic fluid during
pregnancy
Hypoplasia is the incomplete development or
underdevelopment of an organ or tissue.
Glossoptosis refers to an incorrect placement or displacement of
the tongue. At birth, your infant's tongue is farther back in their
mouth than it should be. This positioning can block your child's
airway, affecting their ability to breathe, eat and swallow
Contracture is a permanent shortening of a muscle or joint

35. Pierre Robin
Pierre Robin (Pee-air Roe-bahn) sequence, also
called Pierre Robin syndrome, or PRS, is a
condition where babies are born with a small
lower jaw, have difficulties breathing (airway
obstruction) and often (but not always) have a
cleft of the palate (an opening in the roof of the
mouth).

37. Amniotic bands

40. Non-Mendelian inheritance
⚫Imprinting
⚫Phenotype depends upon
which parent passedon the
gene.
⚫3-4 Mb deletion on
chromosome 15 inherited
from the mother results in
Angelmansyndrome; if
inherited from the father it
results in Prader-Willi
syndrome.

41. Angleman Syndrome

42. Prader-Willi syndrome.

43. Genetic diseases
traditionally - 3 types of diseases
1. genetically determined
2. environmentally determined
3. 1. + 2.
today - distinctions are blurred
up to 20% of pediatric in-patients have genetic abnormality
about 50% of spontaneous abortuses have chromosomal
aberration
only mutations that are not lethal are reservoir of genetic
diseases

44. Factors that affect expression of
disease-causing genes
⚫Reduced penetrance
⚫Individual with adisease-causing mutation maynot have the
disease phenotype.
⚫Offspring are at risk.
⚫Example
⚫ Retinoblastoma(AD)Retinoblastomaisa diseasein which
malignant(cancer)cells formin thetissuesoftheretina. Children
with a family historyof retinoblastomashouldhaveeye exams to
check forretinoblastoma.

46. Factors that affect expression of
disease-causing genes
⚫ Age-dependent penetrance
⚫ Delay of onset of symptoms of agenetic disease.
⚫ Individuals mayhavechildren before they know that they are affected.
⚫ Carriers of the disease-causing gene maypass awaybefore the onset of
symptoms.
⚫ Examples
⚫ Huntington disease
⚫ Hereditarybreast and ovarian cancer

47. Factors that affect expression of
disease-causing genes
⚫V
ariable expression / expressivity
⚫Different than penetrance
⚫Severity of the phenotype varies widely
, even within afamily
.
⚫An individual’s presentation may be so mild that they are not
aware that they are affected and can pass on the condition to
their children.

48. Factors that affect expression of
disease-causing genes
⚫V
ariable expression / expressivity
⚫Factors that mayinfluence variable expression within afamily:
⚫ Environmentalexposures
⚫ Modifier genes
⚫Example
⚫ Neurofibromatosis type I

50. Factors that affect expression of
disease-causing genes
⚫Anticipation
⚫More severe expression and/or earlier ageof onset in more
recent generations.
⚫Sometimes caused byexpansion of DNArepeats

51. Factors that affect expression of
disease-causing genes
⚫Anticipation
⚫Expansion maybe more likelyto occur when inherited through
mother or father, depending on the condition
⚫Examples
⚫ Huntington disease
⚫ Myotonic dystrophy

52. Factors that affect expression of
disease-causing genes
⚫New mutation
⚫Affected proband with no history of the disease in the family
⚫ Especially in anautosomal dominant condition
⚫ Example NF1
⚫ Recurrence risks:
⚫ Low (possible germline mosaicism)
⚫ The risk to offspringdepends on the inheritance pattern of the
condition

53. Factors that affect expression of
disease-causing genes
⚫Germline mosaicism
⚫Relativelyrare phenomenon
⚫T
wo or more offspring affected with no familyhistory
⚫ Especially dominant conditions
⚫More than one geneticallydistinct germ cell line
⚫Increased risk to siblings of an affected proband

54. Factors that affect expression of
disease-causing genes
⚫Germline mosaicism
⚫Examples:
⚫ Duchenne muscular dystrophy
⚫ HemophiliaA
⚫ Achondroplasia
⚫ Neurofibromatosis type I
⚫ Osteogenesis imperfecta type II

55. Factors that affect expression of
disease-causing genes
⚫Skewed X-inactivation (in X-linked conditions)
⚫The majority of the active X-chromosomes carry the mutation
⚫Manifestingheterozyogotes – females with the disease
phenotype, usuallymildlyaffected
⚫Example
⚫ Duchenne muscular dystrophy

56. Other factors
⚫Consanguinity
⚫Relatives share genes,including disease-causing genes,inherited
from acommon ancestor
⚫With consanguinity,offspring are more likely to be affected
with arecessive disorder
⚫More rare recessive disorder, more likelyconsanguinity

57. Other factors
⚫Small families
⚫Pattern of inheritance maynot be evident in small families.

58. Panels
⚫Sequencing for 2 or more genes related to genetic disease
⚫ Panel related to phenotype
⚫ Example: Epilepsypanel
⚫ Whole exome sequencing (WES)
⚫ Sequencingof all exons (coding regions) of thousands of genes (20,000+) simultaneously
⚫ When shouldpanelsbe considered?
⚫ When phenotype doesn’t correspond to asingledisorder
⚫ When disorder in question hashigh degree of genetic heterogeneity
⚫ Other specific tests for the phenotype havenot been diagnostic

59. Interpreting results of genetic tests
⚫ Pathogenic variant: variantisarecognizedcauseofsomeor all
of the patient’sphenotype
⚫ Likely pathogenic variant: previously unreported variant,but
based on its gene location and the predicted effect on protein
function, it is likelyto be the cause of some or all of the patients
phenotype
⚫ Benign variant: not responsible for the patient’sphenotype
⚫ Likely benign variant: previouslyunreported variant, but
based on its gene location and predicted lack of effect on protein
function, it is likelyto be benign and not responsible for the
patient’sphenotype
⚫ V
ariant of unknown or uncertain significance (VUS)